Updated on 2021/11/07

写真a

 
YAMASHITA Toru
 
Organization
Medicine, Dentistry and Pharmaceutical Sciences Associate Professor
Position
Associate Professor
Profile

【学歴】

2001年3月   岡山大学医学部医学科卒業

2007年3月   岡山大学大学院医歯薬学総合研究科博士課程卒業

 

【職歴】

2001年4月 岡山大学医学部附属病院神経内科

2002年5月 国立岡山医療センター内科

2003年4月   慶應義塾大学医学部生理学教室共同研究員

2006年4月   岡山大学医学部附属病院神経内科医員

2009年7月 米国コロンビア大学病理細胞生物学部門博士研究員

2012年9月 岡山大学病院神経内科助教

2013年9月 岡山大学病院神経内科講師

2015年4月 岡山大学大学院医歯薬学総合研究科 脳神経内科学 講師

2020年11月 岡山大学大学院医歯薬学総合研究科 脳神経内科学 准教授~現在に至る

 

【受賞歴】

2010年2月   岡山医学会賞

2010年4月   第34回日本心臓財団草野賞

2016年9月   第6回日本認知症予防学会浦上賞

 

【所属学会】

世界脳循環代謝学会(理事2019-)、日本神経学会(代議員),日本脳循環代謝学会(幹事),日本脳卒中学会(国際委員会副委員)、日本認知症予防学会(評議員)、日本老年医学会(代議員)、日本難病医療ネットワーク学会(評議員)、日本抗加齢医学会(2021年9月~エビデンス評価委員会委員)、日本内科学会等

 

External link

Degree

  • 医学博士 ( 2007.3   岡山大学大学院医歯薬学総合研究科博士課程 )

Research Interests

  • iN cells

  • direct reprogramming

  • 脳虚血

Research Areas

  • Life Science / Neurology

Education

  • Okayama University   大学院医歯薬総合研究科博士課程  

    2001.1 - 2007.3

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    Country: Japan

  • Okayama University   医学部   医学科

    1995.4 - 2001.3

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    Country: Japan

Research History

  • Okayama University   医学部付属病院   Medical Staff   医員(研修医)

    2001.4 - 2002.4

  • 国立岡山医療センター   職員(医療系)

    2002.5 - 2003.3

  • Keio University   医学部生理学教室   Researcher   共同研究員

    2003.4 - 2006.3

  • 米国コロンビア大学   研究員

    2006.4 - 2009.6

  • Okayama University   岡山大学病院   Assistant Professor

    2012.9 - 2013.8

  • Okayama University   岡山大学病院   Lecturer

    2013.9 - 2015.3

  • Okayama University   大学院医歯薬学総合研究科   Lecturer

    2015.4 - 2020.10

  • Okayama University   大学院医歯薬学総合研究科   Associate Professor

    2020.11

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Professional Memberships

  • The International Society for Cerebral Blood Flow and Metabolism (ISCBFM)

    2013.1

  • 日本脳循環代謝学会

    2015.11

  • 日本神経学会

    2015.5

  • 日本認知症予防学会

    2015.4

  • 日本内科学会

    2001.6

Committee Memberships

  • The International Society for Cerebral Blood Flow and Metabolism   Director  

    2019.1 - 2023.12   

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  • 日本脳循環代謝学会   幹事  

    2015.11   

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  • 日本神経学会   代議員  

    2015.5   

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Papers

  • Accelerated accumulation of fibrinogen peptide chains with Aβ deposition in Alzheimer's disease (AD) mice and human AD brains. International journal

    Zhihong Bian, Toru Yamashita, Xiaowen Shi, Tian Feng, Haibo Yu, Xiao Hu, Xinran Hu, Yuting Bian, Hongming Sun, Koh Tadokoro, Mami Takemoto, Yoshio Omote, Ryuta Morihara, Koji Abe

    Brain research   1767   147569 - 147569   2021.9

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    Alzheimer's disease (AD) is a common neurodegenerative disease that is characterized by the abnormal accumulation of intracellular and extracellular amyloid-β (Aβ) as well as disruption of the blood brain barrier (BBB). Fibrinogen plays an essential role in regulating thrombosis, wound healing, and other biological functions. In the present study, we investigated the relationship between three polypeptide chains α, β, and γ (FGA, FGB, and FGG) and Aβ deposition in the APP23 plus chronic cerebral hypoperfusion (CCH) mice model as well as the human AD brain. FGA, FGB, and FGG accumulated when Aβ was deposited in neural cells and cerebral vessels. This deposition was significantly higher in AD plus CCH mice models relative to wild-type brains, and in human AD brains compared to control brains. The present study demonstrates that FGA, FGB, and FGG are associated with AD progress, and can thus be potential targets for the diagnosis and therapy of AD.

    DOI: 10.1016/j.brainres.2021.147569

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  • Neuroprotective effects of Scallop-derived plasmalogen in a mouse model of ischemic stroke. International journal

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

    Brain research   1766   147516 - 147516   2021.9

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    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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  • Successful treatment of anti-GAD antibody-associated autoimmune cerebellar ataxia with combined immunotherapies

    Yoshio Omote, Chika Matsuoka, Ryo Sasaki, Nozomi Hishikawa, Yuko Kawahara, Emi Nomura, Namiko Matsumoto, Yuki Taira, Mami Takemoto, Ryuta Morihara, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   2021.9

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    Anti-glutamic acid decarboxylase (GAD) antibody (Ab)-associated autoimmune cerebellar ataxia (CA) is a rare neurological disorder, and a standardized therapy has not been established. Here, we report on a 58 year-old man with type 1 diabetes mellitus, who developed progressive CA with high levels of serum and cerebrospinal fluid (CSF) anti-GAD-Ab. He was initially treated with intravenous high-dose methylprednisolone and intravenous immunoglobulin (IVIg), but his CA was gradually worsened. Additional combined immunotherapies with plasma exchange, intravenous cyclophosphamide, and rituximab finally stabilized the progressive CA and suppressed the CSF anti-GAD-Ab index. Our case suggests the effectiveness of combined immunotherapies against progressive CA and the usefulness of the CSF anti-GAD-Ab index as a therapeutic indicator.

    DOI: 10.1111/ncn3.12541

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

    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   2021.8

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    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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  • A case of rheumatoid meningoencephalitis induced by pembrolizumab

    Chika Matsuoka, Yoshio Omote, Yuko Kawahara, Ryo Sasaki, Namiko Matsumoto, Ko Tadokoro, Yuki Taira, Mami Takemoto, Ryuta Morihara, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   2021.8

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    Immune checkpoint inhibitors occasionally cause various side effects, but the occurrence of a severe immune-related adverse event (irAE) is rare in neurology. We report on a 56-year-old woman who suffered from rheumatoid arthritis and recurrent uterine cancer. After treatment with pembrolizumab, she showed visual disturbance followed by acute fever and consciousness disturbance with high-intensity lesions around the midbrain aqueduct and bilateral caudate heads on FLAIR images of a brain MRI. Her symptoms improved after steroid therapy. However, symptoms relapsed leading to an elevation of the anti-CCP antibody index. Pembrolizumab-induced rheumatoid meningoencephalitis was suspected, so additional steroid therapy was provided. This improved her symptoms, turning the anti-CCP antibody index negative. The present case is the first case of rheumatoid meningoencephalitis induced by pembrolizumab. The combination of MRI findings and elevated anti-CCP index seems useful for diagnosing rheumatoid meningoencephalitis.

    DOI: 10.1111/ncn3.12540

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  • A Unique Case of Encephalopathy with an Elevated IgG-4 and Extremely High Interleukin-6 Level and Delayed Myelodysplastic Syndrome.

    Namiko Matsumoto, Nozomi Hishikawa, Ken Ikegami, Kota Sato, Yoshio Omote, Mami Takemoto, Toru Yamashita, Kohei Taniguchi, Koji Abe

    Internal medicine (Tokyo, Japan)   60 ( 13 )   2125 - 2128   2021.7

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    We herein report a 75-year-old man who developed disturbed consciousness with polynuclear cell dominant pleocytosis and low glucose and extremely high interleukin (IL)-6 levels in his cerebrospinal fluid. The biopsy specimen from his right supraclavicular lymph node showed the infiltration of inflammatory cells positive for IgG, IgG4 and IL-6. Prednisolone and azathioprine administered under suspicion of IgG4-related disease (IgG4-RD) or multicentric Castleman's disease (MCD) successfully remitted the symptoms. However, he developed myelodysplastic syndrome (MDS) and died 18 months later. The extremely high IL-6 may have been related to the rare neurological manifestations and development of MDS in the present case.

    DOI: 10.2169/internalmedicine.6098-20

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  • Switching the Proteolytic System from the Ubiquitin-Proteasome System to Autophagy in the Spinal Cord of an Amyotrophic Lateral Sclerosis Mouse Model. International journal

    Koh Tadokoro, Toru Yamashita, Jingwei Shang, Yasuyuki Ohta, Emi Nomura, Ryuta Morihara, Yoshio Omote, Mami Takemoto, Koji Abe

    Neuroscience   466   47 - 57   2021.7

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    The degradation of damaged proteins takes place via two major proteolytic pathways: the ubiquitin-proteasome system (UPS) and autophagy. However, since it is unclear how these two proteolytic pathways contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS), we investigated the switching mechanism from UPS to autophagy by pharmacologically modifying these pathways by treating the spinal cords of female ALS mouse model bearing G93A human SOD1 (G93A mice) with MG132 or 3-methyladenine (3MA). G93A mice exhibited a progressive increase in the amount of ubiquitin and p62 aggregates, BAG3 expression, and LC3-II/LC3-I ratio in both astroglia and motor neurons. Treatment with MG132 or 3MA significantly increased the clinical hanging wire score and exacerbated α-motor neuron loss at 18 weeks in G93A mice, and increased the amount of ubiquitin, p62 aggregates, and BAG3 expression. This study's results demonstrate that the molecular switch from UPS to autophagy occurred not only in motor neurons but also in astroglia at the end stage (18 weeks) when the autophagic flux was impaired in G93A mice. This finding suggests that the defense system was disrupted against aggregate-prone protein production in ALS.

    DOI: 10.1016/j.neuroscience.2021.04.034

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  • The first case of chronic inflammatory demyelinating polyneuropathy after transsexualism and continuous testosterone administration

    Yuki Taira, Yoshio Omote, Yuko Kawahara, Emi Nomura, Ryo Sasaki, Namiko Matsumoto, Chika Matsuoka, Mami Takemoto, Ryuta Morihara, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   9 ( 4 )   346 - 348   2021.7

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    We report on a 35-year-old man who had gender dysphoria following unilateral ovariectomy and then received continuous testosterone injection for nine years, inducing chronic inflammatory demyelinating polyneuropathy (CIDP). He developed recurrent muscle weakness and numbness in the extremities and displayed demyelinating neuropathy, detected by nerve conduction studies and a sural nerve biopsy. Repeated intravenous immunoglobulin (IVIg) therapy and the administration of oral prednisolone improved symptoms and inhibited their recurrence. A relatively high level of serum testosterone as a genetic female might have caused the neurotoxicity of the peripheral nerve, leading to CIDP.

    DOI: 10.1111/ncn3.12514

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  • Author Correction: Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis. International journal

    Toru Yamashita, Yoshihiro Kushida, Shohei Wakao, Koh Tadokoro, Emi Nomura, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Mari Dezawa, Koji Abe

    Scientific reports   11 ( 1 )   12828 - 12828   2021.6

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  • Hypoxic stress visualized in the cervical spinal cord of ALS patients. International journal

    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   2021.6

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    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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  • Protective effects of edaravone on white matter pathology in a novel mouse model of Alzheimer's disease with chronic cerebral hypoperfusion. International journal

    Tian Feng, Toru Yamashita, Ryo Sasaki, Koh Tadokoro, Namiko Matsumoto, Nozomi Hishikawa, Koji Abe

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism   41 ( 6 )   1437 - 1448   2021.6

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    White matter lesions (WMLs) caused by cerebral chronic hypoperfusion (CCH) may contribute to the pathophysiology of Alzheimer's disease (AD). However, the underlying mechanisms and therapeutic approaches have yet to be totally identified. In the present study, we investigated a potential therapeutic effect of the free radical scavenger edaravone (EDA) on WMLs in our previously reported novel mouse model of AD (APP23) plus CCH with motor and cognitive deficits. Relative to AD with CCH mice at 12 months (M) of age, EDA strongly improved CCH-induced WMLs in the corpus callosum of APP23 mice at 12 M by improving the disruption of white matter integrity, enhancing the proliferation of oligodendrocyte progenitor cells, attenuating endothelium/astrocyte unit dysfunction, and reducing neuroinflammation and oxidative stress. The present study demonstrates that the long-term administration of EDA may provide a promising therapeutic approach for WMLs in AD plus CCH disease with cognitive deficits.

    DOI: 10.1177/0271678X20968927

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  • Neuroprotective effect of CuATSM in mice stroke model by ameliorating oxidative stress. Reviewed International journal

    Xiaowen Shi, Yasuyuki Ohta, Yumiko Nakano, Xia Liu, Koh Tadokoro, Tian Feng, Emi Nomura, Keiichiro Tsunoda, Ryo Sasaki, Namiko Matsumoto, Yosuke Osakada, Yuting Bian, Zhihong Bian, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    Neuroscience research   166   55 - 61   2021.5

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    Cu-diacetyl-bis (N4-methylthiosemicarbazone) (CuATSM) has both anti-oxidative and anti-inflammatory activities, but its therapeutic efficacy for oxidative stress has not been thoroughly investigated in acute ischemic stroke. Here, the present study was designed to assess the efficacies of CuATSM in acute ischemic stroke by comparing with the standard neuroprotective reagent edaravone. Mice were subjected to transient middle cerebral occlusion (tMCAO) for 60 min, and then intravenously administrated with CuATSM (1.5 mg/kg) or edaravone (3 mg/kg) just after the reperfusion, and examined at 1 and 3 d. Compared with the vehicle group, CuATSM treatment decreased infarct volumes and oxidative stress at 3d after tMCAO, which was further enhanced by combined CuATSM + edaravone treatment as compared with single CuATSM group, but not improve neurobehaviors. The present study demonstrated that CuATSM showed strong antioxidative and neuroprotective effects in acute ischemic stroke, which was enhanced by the combination with edaravone.

    DOI: 10.1016/j.neures.2020.05.009

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  • Positive baseline behavioral and psychological symptoms of dementia predict a subsequent cognitive impairment in cognitively normal population

    Keiichiro Tsunoda, Toru Yamashita, Yosuke Osakada, Ryo Sasaki, Koh Tadokoro, Namiko Matsumoto, Emi Nomura, Noriko Hatanaka, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   9 ( 3 )   218 - 222   2021.5

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    Background: Because behavioral and psychological symptoms of dementia (BPSD) are sometimes prodromal symptoms of dementia, it is important to investigate the relationship between BPSD and subsequent cognitive decline.Methods: We examined the cognitive and affective functions of 76 cognitively normal subjects at initial assessment (baseline) and 1-year follow-up. Cognitive function was assessed using clinical dementia rating (CDR) and Mini-Mental State Examination (MMSE), and affective function was assessed using Abe's BPSD score (ABS) and mild behavioral impairment (MBI).Results: Although there was no change in MMSE, ABS, or MBI after 1 year, the mean CDR score of 0 at baseline increased to 0.1 +/- 0.2 at 1-year follow-up (**P < 0.01 vs baseline). No significant change in MMSE was found in both baseline ABS and MBI positive- or negative-groups. In contrast, baseline MBI-dependent CDR change showed a 13.2% of worsening in MBI-negative subjects and a 62.5% of MBI-positive subjects (dagger dagger P < 0.01), but ABS not.Conclusion: The present data indicate that positive baseline BPSD with MBI was closely related to a subsequent CDR exacerbation. Examining BPSD may be useful for screening cognitively normal population for subsequent dementia development in local communities.

    DOI: 10.1111/ncn3.12492

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  • Non-Tumorigenic Pluripotent Reparative Muse Cells Provide a New Therapeutic Approach for Neurologic Diseases. International journal

    Toru Yamashita, Yoshihiro Kushida, Koji Abe, Mari Dezawa

    Cells   10 ( 4 )   2021.4

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    Muse cells are non-tumorigenic endogenous reparative pluripotent cells with high therapeutic potential. They are identified as cells positive for the pluripotent surface marker SSEA-3 in the bone marrow, peripheral blood, and connective tissue. Muse cells also express other pluripotent stem cell markers, are able to differentiate into cells representative of all three germ layers, self-renew from a single cell, and are stress tolerant. They express receptors for sphingosine-1-phosphate (S1P), which is actively produced by damaged cells, allowing circulating cells to selectively home to damaged tissue. Muse cells spontaneously differentiate on-site into multiple tissue-constituent cells with few errors and replace damaged/apoptotic cells with functional cells, thereby contributing to tissue repair. Intravenous injection of exogenous Muse cells to increase the number of circulating Muse cells enhances their reparative activity. Muse cells also have a specific immunomodulatory system, represented by HLA-G expression, allowing them to be directly administered without HLA-matching or immunosuppressant treatment. Owing to these unique characteristics, clinical trials using intravenously administered donor-Muse cells have been conducted for myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, perinatal hypoxic ischemic encephalopathy, and amyotrophic lateral sclerosis. Muse cells have the potential to break through the limitations of current cell therapies for neurologic diseases, including amyotrophic lateral sclerosis. Muse cells provide a new therapeutic strategy that requires no HLA-matching or immunosuppressant treatment for administering donor-derived cells, no gene introduction or differentiation induction for cell preparation, and no surgery for delivering the cells to patients.

    DOI: 10.3390/cells10040961

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  • 4-Hydroxyl-2-Nonenal Localized Expression Pattern in Retrieved Clots is Associated with Large Artery Atherosclerosis in Stroke Patients. International journal

    Yosuke Osakada, Toru Yamashita, Ryuta Morihara, Namiko Matsumoto, Ryo Sasaki, Koh Tadokoro, Emi Nomura, Yuko Kawahara, Yoshio Omote, Nozomi Hishikawa, Mami Takemoto, Yasuyuki Ohta, Yasuki Suruga, Takayuki Nagase, Yuji Takasugi, Satoshi Inoue, Kyoichi Watanabe, Kentaro Deguchi, Koji Tokunaga, Susumu Sasada, Kazuki Kobayashi, Ryosuke Maeoka, Kenji Fukutome, Kenkichi Takahashi, Hiroyuki Ohnishi, Yoshihiro Kuga, Hideyuki Ohnishi, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   30 ( 3 )   105583 - 105583   2021.3

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    OBJECTIVES: The relationship between stroke etiology and clot pathology remains controversial. MATERIALS AND METHODS: We performed histological analysis of clots retrieved from 52 acute ischemic stroke patients using hematoxylin and eosin staining and immunohistochemistry (CD42b and oxidative/hypoxic stress markers). The correlations between clot composition and the stroke etiological group (i.e., cardioembolic, cryptogenic, or large artery atherosclerosis) were assessed. RESULTS: Of the 52 clots analyzed, there were no significant differences in histopathologic composition (e.g., white blood cells, red blood cells, fibrin, and platelets) between the 3 etiological groups (P = .92). By contrast, all large artery atherosclerosis clots showed a localized pattern with the oxidative stress marker 4-hydroxyl-2-nonenal (P < .01). From all 52 clots, 4-hydroxyl-2-nonenal expression patterns were localized in 28.8% of clots, diffuse in 57.7% of clots, and no signal in 13.5% of clots. CONCLUSIONS: A localized pattern of 4-hydroxyl-2-nonenal staining may be a novel and effective marker for large artery atherosclerosis (sensitivity 100%, specificity 82%).

    DOI: 10.1016/j.jstrokecerebrovasdis.2020.105583

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  • A new telestroke network system in northern area of Okayama prefecture

    Ryo Sasaki, Toru Yamashita, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Taijun Yunoki, Kazuki Kobayashi, Takashi Sawata, Yuki Sato, Junichi Kubota, Masayuki Mizobuchi, Takashi Hayashi, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   9 ( 2 )   166 - 170   2021.3

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    Background: Telestroke network can provide rapid access to specialized treatment and improves on-site management of acute stroke patients through the "hub-and-spoke" model. In the northern part of Okayama Prefecture, there has been a regional gap of stroke care due to the shortage of stroke specialists and facilities. In addition, due to the novel coronavirus disease 2019 (COVID-19), it is required to reduce the unnecessary contact with stroke patients from other hospitals.Aim: We organized a novel cost-free telestroke network with an image and video sharing for neurological diseases in the northern part of Okayama Prefecture to improve the stroke management in the area.Method: We prepared the tablet device on which Skype(R) application was installed for each hospital and recruited the patients who visited or hospitalized in the spoke hospitals and were suspected to have some neurological diseases from April 2019 to May 2020. The patient's clinical data were recorded and analyzed.Results: During the study period, 5 patients were recruited including the cases with the initial diagnosis of stroke or brain tumor. Among them, 2 cases were transferred to the hub hospital, 2 cases were transferred to other hospitals, and 1 case was treated on site under specialist's advice.Conclusion: The new telestroke network system may be beneficial for acute stroke management and reducing the unnecessary patient's transfer in the rural area, especially under coexistence with COVID-19.

    DOI: 10.1111/ncn3.12475

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  • Effect of edaravone on pregnant mice and their developing fetuses subjected to placental ischemia. International journal

    Marwa Atallah, Toru Yamashita, Koji Abe

    Reproductive biology and endocrinology : RB&E   19 ( 1 )   19 - 19   2021.2

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    Growing evidence indicates that reduced uterine perfusion pressure (RUPP) triggers the cascade of events leading to preeclampsia. Edaravone is a powerful free radical scavenger used for the treatment of ischemia/reperfusion diseases due to its anti-oxidative stress and anti-inflammatory properties. Here we investigate the effect of edaravone (3 mg/kg) on different maternal and fetal outcomes of RUPP-induced placental ischemia mice model. RUPP surgery was performed on gestation day (GD) 13 followed by edaravone injection from GD14 to GD18, sacrifice day. The results showed that edaravone injection significantly decreased the maternal blood pressure (113.2 ± 2.3 mmHg) compared with RUPP group (131.5 ± 1.9 mmHg). Edaravone increased fetal survival rate (75.4%) compared with RUPP group (54.4%), increased fetal length, weights, and feto-placental ratio (7.2 and 5.7 for RUPP and RUPP-Edaravone groups, respectively) compared with RUPP group. In addition, RUPP resulted in many fetal morphological abnormalities as well as severe delayed ossification, however edaravone decreased the morphological abnormalities and increased the ossification of the fetal endoskeleton. Edaravone improved the histopathological structure of the maternal kidney and heart as well as decreased the elevated blood urea and creatinine levels (31.5 ± 0.15 mg/dl (RUPP), 25.6 ± 0.1 mg/dl (RUPP+edaravone) for urea and 5.4 ± 0.1 mg/dl (RUPP), 3.5 ± 0.1 mg/dl (RUPP+edaravone) for creatinine) and decreased cleaved caspase-3 expression in the maternal kidney. In conclusion, this study demonstrated that our RUPP mice model recapitulated preeclampsia symptoms and edaravone injection ameliorated most of these abnormalities suggesting its effectiveness and potential application in preeclampsia treatment regimes.

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  • The Oldest Japanese Case of Combined Central and Peripheral Demyelination, which Developed Nine Years After the First Instance of Optic Neuritis.

    Emi Nomura, Yuko Kawahara, Yoshio Omote, Koh Tadokoro, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Hidenori Ogata, Koji Abe

    Internal medicine (Tokyo, Japan)   60 ( 2 )   305 - 308   2021.1

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    Combined central and peripheral demyelination (CCPD) causes demyelination in both the central and peripheral nervous systems. Anti-neurofascin 155 antibody plays an important pathogenic role in CCPD, but evidence concerning an association between this antibody and CCPD remains inconclusive. Although there have been no reports of precedent optic neuritis developing into CCPD, we herein report a Japanese man in whom optic neuritis recurred four times over nine years and who developed CCPD without positive anti-neurofascin 155 antibody. This case suggests the possibility of developing CCPD after optic nerve neuritis and the existence of an unknown antibody that induces CCPD.

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  • A case of Kii amyotrophic lateral sclerosis/parkinsonism dementia complex presenting as progressive parkinsonism with corresponding tau imaging

    Yasuyuki Ohta, Hitoshi Shimada, Ken Ikegami, Keiichiro Tsunoda, Nozomi Hishikawa, Toru Yamashita, Mami Takemoto, Yoshio Omote, Kenji Tagai, Kiwamu Matsuoka, Makoto Higuchi, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   9 ( 1 )   124 - 126   2021.1

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    Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC), frequently observed in the Kii peninsula of Japan, is pathologically characterized by widespread tau pathology in the cerebrum and brainstem. Here, we report a case of Kii ALS/PDC predominantly presenting progressive parkinsonism. Tau positron emission tomography (PET) imaging with F-18-PM-PBB3 suggested tau deposition in the substantia nigra of the midbrain and subcortical areas, but not in the cerebral cortex, which was similar to progressive supranuclear palsy (PSP), suggesting that parkinsonism-predominant type of Kii ALS/PDC may have a similar area of tau deposition to PSP.

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  • A case of autoimmune GFAP astrocytopathy with profound weight loss and increased uptake in the spinal cord on F-18-FDG PET

    Yosuke Osakada, Yoshio Omote, Ken Ikegami, Koh Tadokoro, Kota Sato, Nozomi Hishikawa, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Akio Kimura, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   9 ( 1 )   95 - 97   2021.1

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    A 76-year-old man presented with subacute onset of progressive cognitive impairment, anorexia, tremor, ataxic gait, and urinary dysfunction. He had lost 17 kg in 9 months before his admission (due to persistent anorexia). A brain MRI showed a typical radial pattern of periventricular gadolinium enhancement and longitudinally extensive hyperintensity from cervical to lumbar spinal cord. F-18-FDG PET newly revealed an increased uptake of the tracer in the cervical and lower thoracic cords. After an intravenous methylprednisolone (1000 mg/d for 3 days) followed by oral prednisolone 40 mg/d, his clinical symptoms and abnormal MRI lesions improved. Anti-GFAP antibodies were subsequently identified in CSF obtained on admission, confirming the diagnosis of autoimmune GFAP astrocytopathy.

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  • Recurrent severe and long-lasting cerebellar ataxia attacks in adult-onset neuronal intranuclear inclusion disease

    Yosuke Osakada, Kentaro Deguchi, Shoko Deguchi, Fumiyo Higaki, Wakako Oda, Mari Yoshida, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   9 ( 1 )   107 - 110   2021.1

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    Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions. NIID presents highly variable clinical manifestations such as dementia, ataxia, convulsion, neuropathy, and autonomic dysfunction. A 60-year-old woman developed recurrent severe cerebellar ataxia (SARA score: 30/40 points). She was diagnosed with adult-onset NIID by a characteristic brain diffusion-weighed imaging hyperintensity lesion in subcortical white matter and intranuclear inclusion bodies in a skin biopsy. Her ataxia was more severe and lasted longer (additional 19 days) than a previous case, although she showed remarkable improvement.

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  • Immediate Beneficial Effect of Makeup Therapy on Behavioral and Psychological Symptoms of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software. International journal

    Koh Tadokoro, Toru Yamashita, Satoko Kawano, Junko Sato, Yoshio Omote, Mami Takemoto, Ryuta Morihara, Koichiro Nishiura, Natsuki Sagawa, Tomiko Tani, Koji Abe

    Journal of Alzheimer's disease : JAD   83 ( 1 )   57 - 63   2021

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    BACKGROUND: Possible benefits of makeup therapy, in terms of immediate and late effects on cognitive and affective functions, have not been fully proved for dementia patients. OBJECTIVE: To evaluate the immediate effect of makeup therapy on dementia patients. METHODS: Female nursing home residents with dementia received either only skin care treatment (control group, n = 17) or skin care plus makeup therapy treatment (makeup therapy group, n = 19). Cognitive, affective, and activity of daily living (ADL) scores were evaluated before and just after treatments. Apparent age and emotion were also evaluated with artificial intelligence (AI) software. RESULTS: Makeup therapy significantly improved Abe's behavioral and psychological symptoms of dementia (BPSD) score (ABS, *p < 0.05). AI software judged that makeup therapy significantly made the apparent age younger (*p < 0.05). In particular, patients with moderate ADL scores had a significantly higher happiness score in makeup therapy (*p < 0.05), with a modest correlation to the Mini-Mental State Examination (MMSE, r = 0.42, *p < 0.05). The severe baseline MMSE group reported a greater feeling of satisfaction following makeup therapy (*p < 0.05). CONCLUSION: The present makeup therapy is a promising non-pharmacological approach to immediately alleviate BPSD in female dementia patients, and the present AI software quickly and quantitatively evaluated the beneficial effects of makeup therapy on facial appearance.

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  • Cerebral Microbleeds in Patients with Parkinson's Disease and Dementia with Lewy Bodies: Comparison Using Magnetic Resonance Imaging and 99 mTc-ECD SPECT Subtraction Imaging. International journal

    Mami Takemoto, Toru Yamashita, Yasuyuki Ohta, Koh Tadokoro, Yoshio Omote, Ryuta Morihara, Koji Abe

    Journal of Alzheimer's disease : JAD   80 ( 1 )   331 - 335   2021

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    BACKGROUND: Cerebral microbleeds (CMBs) in patients with Parkinson's disease (PD) or dementia with Lewy bodies (DLB) have not been adequately studied. OBJECTIVE: This study aims to find a difference in the total number, prevalence, and common locations of CMBs between PD and DLB and evaluate 99 mTc-ECD SPECT subtraction images of these two diseases. METHODS: We examined 112 patients with PD (53 males and 59 females; age: 77.4±3.6 years) and 28 age-matched patients with DLB (15 males and 13 females; age: 77.1±6.7 years) using brain magnetic resonance imaging (MRI) and 99 mTc-ECD SPECT subtraction imaging. RESULTS: The total number of CMBs was higher in patients with DLB (41.2%) than in those with PD (11.5%), and the prevalence was significantly higher in the former (0.7±1.1) than the latter (0.2±0.5, p < 0.05). The odds ratio was 5.4 (95% confidence interval [CI]: 1.7-17.4). Furthermore, CMBs were commonly located in the basal ganglia of patients with PD (6 out of 87 patients) but in the occipital lobe of patients with DLB (8 out of 17 patients). 99 mTc-ECD SPECT subtraction imaging indicated lower cerebral blood flow in the posterior cingulate gyrus among the patients with CMB-positive DLB than among those with CMB-positive PD; additionally, the cerebral blood flow was lower in the bilateral basal ganglia and midbrain among patients with CMB-positive DLB compared to those with CMB-negative DLB. CONCLUSION: A reduction in occipital glucose metabolism may be related to CMBs in the occipital lobe of patients with DLB.

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  • Retinal Amyloid Imaging for Screening Alzheimer's Disease. International journal

    Koh Tadokoro, Toru Yamashita, Shuhei Kimura, Emi Nomura, Yasuyuki Ohta, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Ryuta Morihara, Yuki Morizane, Koji Abe

    Journal of Alzheimer's disease : JAD   83 ( 2 )   927 - 934   2021

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    BACKGROUND: Cost-effective and noninvasive methods for in vivo imaging of amyloid deposition are needed to screen Alzheimer's disease (AD). Although retinal amyloid is a possible diagnostic marker of AD, there are very few studies on in vivo retinal amyloid imaging. OBJECTIVE: To examine the usefulness of in vivo imaging of retinal amyloid in AD patients. METHODS: To examine amyloid deposition, 30 Japanese subjects (10 normal control (NC), 7 with mild cognitive impairment (MCI), and 13 with AD) underwent a complete ophthalmic examination, including fundus imaging by scanning laser ophthalmoscopy before and after oral curcumin intake. RESULTS: Retinal amyloid deposition was greater in AD than in NC subjects (*p < 0.05) while MCI showed a slight but insignificant increase of retinal amyloid deposition relative to NC subjects. Retinal amyloid deposition was correlated with whole gray matter atrophy (r = 0.51, *p < 0.05) but not with the cognitive score of the Mini-Mental State Examination, nor with medial temporal lobe atrophy. CONCLUSION: The present noninvasive in vivo detection of retinal amyloid deposition is useful for screening AD patients.

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  • Tocilizumab-induced Leukoencephalopathy with a Reversible Clinical Course.

    Ryo Sasaki, Nozomi Hishikawa, Emi Nomura, Yoshio Omote, Mami Takemoto, Toru Yamashita, Noriko Hatanaka, Yasuto Higashi, Koji Abe

    Internal medicine (Tokyo, Japan)   59 ( 22 )   2927 - 2930   2020.11

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    Tocilizumab (TCZ; Actemra/RoActemra) is an anti-interleukin (IL)-6 receptor antibody for the treatment of rheumatoid arthritis (RA) and other autoimmune diseases and cytokine storms. The present case is a 63-year-old female well-controlled RA patient, who presented with a progressive cognitive impairment after 34 months of TCZ administration. Brain magnetic resonance imaging (MRI) showed leukencephalopathy with a lactic acid peak in magnetic resonance spectroscopy (MRS), a decreased blood flow in single photon emission computed tomography (SPECT), and a decreased accumulation in fluorodeoxyglucose positron emission tomography (FDG-PET). The discontinuation of TCZ improved her cognitive function and brain MRI findings at 3 months after drug cessation. The present case suggests that TCZ may sometimes cause leukoencephalopathy after long-term administration, and thus the early discontinuation of TCZ is recommended to achieve a good prognosis.

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  • Repeat sizes of NOP56 gene in a Japanese Asidan (SCA36) family with clinical anticipation. International journal

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

    Journal of the neurological sciences   418   117150 - 117150   2020.11

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  • Therapeutic benefit of Muse cells in a mouse model of amyotrophic lateral sclerosis. International journal

    Toru Yamashita, Yoshihiro Kushida, Shohei Wakao, Koh Tadokoro, Emi Nomura, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Mari Dezawa, Koji Abe

    Scientific reports   10 ( 1 )   17102 - 17102   2020.10

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    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive motor neuron loss. Muse cells are endogenous reparative pluripotent-like stem cells distributed in various tissues. They can selectively home to damaged sites after intravenous injection by sensing sphingosine-1-phosphate produced by damaged cells, then exert pleiotropic effects, including tissue protection and spontaneous differentiation into tissue-constituent cells. In G93A-transgenic ALS mice, intravenous injection of 5.0 × 104 cells revealed successful homing of human-Muse cells to the lumbar spinal cords, mainly at the pia-mater and underneath white matter, and exhibited glia-like morphology and GFAP expression. In contrast, such homing or differentiation were not recognized in human mesenchymal stem cells but were instead distributed mainly in the lung. Relative to the vehicle groups, the Muse group significantly improved scores in the rotarod, hanging-wire and muscle strength of lower limbs, recovered the number of motor neurons, and alleviated denervation and myofiber atrophy in lower limb muscles. These results suggest that Muse cells homed in a lesion site-dependent manner and protected the spinal cord against motor neuron death. Muse cells might also be a promising cell source for the treatment of ALS patients.

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  • Direct arterial damage and neurovascular unit disruption by mechanical thrombectomy in a rat stroke model. Reviewed International journal

    Ryo Sasaki, Toru Yamashita, Koh Tadokoro, Namiko Matsumoto, Emi Nomura, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of neuroscience research   98 ( 10 )   2018 - 2026   2020.10

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    Mechanical thrombectomy (MT) is a standard treatment for acute ischemic stroke that could cause hemorrhagic complications. We aimed to evaluate the pathology of MT-induced arterial damage and neurovascular unit (NVU) disruption in relation to tissue-type plasminogen activator (tPA) injection for acute ischemic stroke. We induced transient middle cerebral artery occlusion in male SHR/Izm rats for 2 hr. This was followed by reperfusion with/without tPA (3 mg/kg) and "rough suture" insertion that mimicked MT once or thrice (MT1 or MT3). Compared with the control group, the tPA + MT3 group presented with an increase in the cerebral infarct and hemorrhage with severer IgG leakage. Moreover, structural damage reaching the tunica media was detected in the MT3 and tPA + MT3 groups. The tPA + MT3 group presented with increased matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) expression with some MMP9-positive cells expressing a neutrophil marker myeloperoxidase. Furthermore, basal lamina detachment from astrocyte foot processes was observed in the tPA + MT1 and tPA + MT3 groups. These findings suggest that MT causes direct arterial damage, as well as VEGF and MMP9 upregulation, which results in NVU disruption and hemorrhagic complications in acute ischemic stroke, especially when combined with tPA.

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  • A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. International journal

    Ryoichi Nakamura, Kazuharu Misawa, Genki Tohnai, Masahiro Nakatochi, Sho Furuhashi, Naoki Atsuta, Naoki Hayashi, Daichi Yokoi, Hazuki Watanabe, Hirohisa Watanabe, Masahisa Katsuno, Yuishin Izumi, Kazuaki Kanai, Nobutaka Hattori, Mitsuya Morita, Akira Taniguchi, Osamu Kano, Masaya Oda, Kazumoto Shibuya, Satoshi Kuwabara, Naoki Suzuki, Masashi Aoki, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Rina Hashimoto, Ikuko Aiba, Koichi Okamoto, Kouichi Mizoguchi, Kazuko Hasegawa, Yohei Okada, Tomohiko Ishihara, Osamu Onodera, Kenji Nakashima, Ryuji Kaji, Yoichiro Kamatani, Shiro Ikegawa, Yukihide Momozawa, Michiaki Kubo, Noriko Ishida, Naoko Minegishi, Masao Nagasaki, Gen Sobue

    Communications biology   3 ( 1 )   526 - 526   2020.9

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    Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

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  • Clinical anticipation of disease onset in a Japanese Asidan (SCA36) family. International journal

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

    Journal of the neurological sciences   416   117043 - 117043   2020.9

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  • Dynamic changes and mislocalizations of neurodegenerative disease-related proteins in mice stroke model. Reviewed International journal

    Xia Liu, Toru Yamashita, Xiaowen Shi, Yuting Bian, Zhihong Bian, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Brain research   1742   146862 - 146862   2020.9

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    The aggregation and cellular mislocalization of several RNA-binding proteins (RBPs) have been identified as the major hallmarks of neurodegenerative diseases such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). However, it remains obscure whether these pathological changes also occur during cerebral ischemia. In this study, we report that RBPs increased significantly compared with the sham group (*p < 0.05 and **p < 0.01 vs sham), with nuclear depletion and cytoplasmic deposition in neurons in the acute phase of cerebral ischemia. On the other hand, such nucleocytoplasmic mislocalization were not observed in astrocytes. We provide evidence of the alteration of these neurodegeneration-related RBPs after cerebral ischemia, suggesting a potential association between cerebral ischemia and neurodegenerative diseases.

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  • A case of triple seronegative myasthenia gravis with Graves' disease ameliorated after the removal of enlarged thymus with elevated uptake in fluorine-18 fluorodeoxyglucose positron emission tomography

    Namiko Matsumoto, Yoshio Omote, Yumiko Nakano, Mami Takemoto, Nozomi Hishikawa, Kota Sato, Yasuyuki Ohta, Toru Yamashita, Tomohiro Toji, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 5 )   313 - 316   2020.9

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    We report on a 35-year-old woman who complained of myasthenia in ocular, bulbar, and limb muscles, but who was negative for antibodies against acetylcholine receptor, muscle-specific kinase, or low-density lipoprotein receptor-related protein 4, accompanied by the suppression of thyroid-stimulating hormone with elevated free T3 and free T4. Administration of edrophonium significantly ameliorated blepharoptosis, and electromyography revealed 13.9% waning after 3 Hz repetitive stimulation in the left accessory nerve. Thus, she was suspected of having triple seronegative myasthenia gravis or thyrotoxic myasthenia. She was remitted after the resection of her enlarged thymus with an elevated uptake in fluorine-18 fluorodeoxyglucose positron emission tomography, suggesting an unknown autoimmune target that escaped detection by current autoantibody screens. Consequently, thymectomy may still be effective in patients with seronegative MG plus hyperthyroidism.

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  • TTN missense variants in two siblings with asymmetric facial and limb weakness. Reviewed International journal

    Ryo Sasaki, Yasuyuki Ohta, Koh Tadokoro, Namiko Matsumoto, Emi Nomura, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Theerawat Kumutpongpanich, Ichizo Nishino, Koji Abe

    Journal of the neurological sciences   415   116885 - 116885   2020.8

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  • Improvement of a decreased anti-oxidative activity by edaravone in amyotrophic lateral sclerosis patients. Reviewed International journal

    Yasuyuki Ohta, Toru Yamashita, Emi Nomura, Nozomi Hishikawa, Ken Ikegami, Yosuke Osakada, Namiko Matsumoto, Yuko Kawahara, Taijun Yunoki, Yoshiaki Takahashi, Motonori Takamiya, Koh Tadokoro, Ryo Sasaki, Yumiko Nakano, Keiichiro Tsunoda, Kota Sato, Yoshio Omote, Mami Takemoto, Koji Abe

    Journal of the neurological sciences   415   116906 - 116906   2020.8

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    BACKGROUND: The free radical scavenger edaravone is a proven neuroprotective drug for patients with amyotrophic lateral sclerosis (ALS). Our objective was to evaluate the therapeutic effects of edaravone for oxidative stress and anti-oxidative activity in ALS patients. METHODS: Twenty-two ALS patients with a disease duration of 2 years, treated by edaravone, and 25 control participants were evaluated according to their clinical scores, including ALS functional rating scale-revised (ALSFRS-R), and serum and cerebrospinal fluid (CSF) markers of oxidative stress dROM and anti-oxidative activity OXY. RESULTS: Serum and CSF markers of anti-oxidative activity OXY were significantly decreased in ALS patients at pre-treatment compared with controls (##p < .01), which was improved in the course of edaravone treatment. Both serum and CSF OXY were significantly correlated with ALS clinical scores including ALSFRS-R (*p < .05, **p < .01, ***p < .001). Furthermore, serum OXY at pre-treatment was significantly correlated with a change in the ALSFRS-R score in the sixth cycle of edaravone treatment (*p < .05). CONCLUSIONS: The present study suggests significant correlations between anti-oxidative activity and ALS clinical severity, and the therapeutic efficacy of edaravone for decreased anti-oxidative activity in ALS.

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  • Antioxidative effects of a novel dietary supplement Neumentix in a mouse stroke model. Reviewed International journal

    Yuki Taira, Toru Yamashita, Yuting Bian, Jingwei Shang, Namiko Matsumoto, Ryo Sasaki, Koh Tadokoro, Emi Nomura, Keiichiro Tsunoda, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   29 ( 8 )   104818 - 104818   2020.8

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    BACKGROUND: During an acute stroke, reactive oxygen species are overproduced and the endogenous antioxidative defense systems are disrupted. Therefore, antioxidative therapy can be a promising scheme to reduce the severity of stroke. Neumentix is a novel antioxidative supplement produced from a patented mint line and contains a high content of rosmarinic acid (RA). Although Neumentix has proven diverse efficacy and safety in clinical trials, its effect on strokes is unclear. METHODS: Mice that were treated with Neumentix or vehicle for 14 days underwent transient middle cerebral artery occlusion (tMCAO) for 60 min. Mice were sacrificed 5 days after tMCAO. RESULTS: Neumentix preserved body weight after tMCAO, showed a high antioxidative effect in serum, and reduced infarction volume compared to the vehicle. The expression of 4-hydroxy-2-nonenal, Nε-(carboxymethyl) lysine, and 8-hydroxy-2'-deoxyguanosine was reduced in Neumentix-treated mice. CONCLUSION: The antioxidative effect of Neumentix was confirmed. This is the first report to demonstrate the antioxidative effect of Neumentix on strokes.

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  • Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36. Reviewed International journal

    Zachary T McEachin, Tania F Gendron, Nisha Raj, María García-Murias, Anwesha Banerjee, Ryan H Purcell, Patricia J Ward, Tiffany W Todd, Megan E Merritt-Garza, Karen Jansen-West, Chadwick M Hales, Tania García-Sobrino, Beatriz Quintáns, Christopher J Holler, Georgia Taylor, Beatriz San Millán, Susana Teijeira, Toru Yamashita, Ryuichi Ohkubo, Nicholas M Boulis, Chongchong Xu, Zhexing Wen, Nathalie Streichenberger, Brent L Fogel, Thomas Kukar, Koji Abe, Dennis W Dickson, Manuel Arias, Jonathan D Glass, Jie Jiang, Malú G Tansey, María-Jesús Sobrido, Leonard Petrucelli, Wilfried Rossoll, Gary J Bassell

    Neuron   107 ( 2 )   292 - 305   2020.7

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    GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.

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  • Up-regulation of sphingosine-1-phosphate receptors and sphingosine kinase 1 in the peri-ischemic area after transient middle cerebral artery occlusion in mice. Reviewed International journal

    Namiko Matsumoto, Toru Yamashita, Jingwei Shang, Tian Feng, Yosuke Osakada, Ryo Sasaki, Koh Tadokoro, Emi Nomura, Keiichiro Tsunoda, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Brain research   1739   146831 - 146831   2020.7

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    There is thought to be a strong relationship between sphingosine-1-phosphate (S1P) signaling and pathophysiolosy of cerebral ischemia. We examined the change of expression and distribution of S1P receptors (S1PRs) and sphingosine kinases (SphKs) after cerebral ischemia in male C57BL6/J mice using immunohistochemical analysis at 1, 5, 14, and 28 days after 30 min of transient middle cerebral artery occlusion (tMCAO). S1PR1, 3, and 5 were transiently induced in the cells, which were morphologically similar to neurons in the peri-infarct lesion with a peak seen at 1 day after tMCAO (p < 0.01 vs. sham control). S1PR2 appeared in the inner layer of vessels in the ischemic core (p < 0.01 vs. sham control) and the peri-infarct lesion (p < 0.01 vs. sham control) at the acute phase after tMCAO. However, SphK1 was strongly induced at 1 and 5 days after tMCAO (p < 0.01 vs. sham control) in the peri-infarct lesion, whereas SphK2 expression did not change. Western blot analysis at 1 and 5 days after 30 min of tMCAO revealed that the expression of S1PRs were transiently enhanced at the acute phase, which was consistent with the immunohistochemical results. Double immunofluorescent analysis revealed S1PR2/NG2- and S1PR2/CD31-, S1PR3/CD31-, and S1PR5/CD31-double positive cells in the peri-infarct lesion 1 day after tMCAO. The present results suggest that S1PRs and SphK1 may be important therapeutic targets for rescuing the peri-infarct lesion.

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  • Familial dropped head syndrome with extremity muscle weakness

    Keiichiro Tsunoda, Nozomi Hishikawa, Yoshio Omote, Ken Ikegami, Yumiko Nakano, Kota Sato, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 4 )   189 - 191   2020.7

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    We report a new case of familial dropped head syndrome (DHS) due to myopathy. The proband is a 63-year-old woman, and her younger sister and son also showed DHS. She was not good at sport since elementary school and showed unique muscle weakness in her paraspine and four limbs. A blood test showed a slight increase in creatine kinase (237 IU/mL) and myoglobin (95 ng/mL). An electromyogram showed myogenic change, and computed tomography revealed a normal muscle volume of the neck but paraspinal muscle atrophy. Muscle biopsy of the right femoral muscle found type 2 fiber atrophy. Based on these unique clinical features, this is the first report of familial DHS which probably due to congenital myopathy.

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  • Adult-onset frequent non-convulsive status epilepticus in a patient with ring chromosome 20 syndrome

    Xia Liu, Yoshio Omote, Ken Ikegami, Koh Tadokoro, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 4 )   202 - 204   2020.7

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    We report a 31-year-old woman with ring chromosome 20 syndrome who presented with epilepsy staring from 16 years old and loss of consciousness from 30 years old. Her neurological examinations and psychological testing were normal, without dysmorphic features. No abnormalities were found in neuroimaging. Electroencephalogram recording showed typical non-convulsive status epilepticus associated with alteration of consciousness. Her diagnosis was based on the cytogenetic analysis indicating that her karyotype was 46, XX, r(20)(p13q13.3)[9]/46, XX[21]. She had refractory epilepsy and improved by a combination of valproate and lacosamide.

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  • The Efficacy of Sertraline, Escitalopram, and Nicergoline in the Treatment of Depression and Apathy in Alzheimer's Disease: The Okayama Depression and Apathy Project (ODAP). Reviewed International journal

    Mami Takemoto, Yasuyuki Ohta, Nozomi Hishikawa, Toru Yamashita, Emi Nomura, Keiichiro Tsunoda, Ryo Sasaki, Koh Tadokoro, Namiko Matsumoto, Yoshio Omote, Koji Abe

    Journal of Alzheimer's disease : JAD   76 ( 2 )   769 - 772   2020.6

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    BACKGROUND: Neuropsychiatric symptoms of dementia such as depression and apathy in patients with Alzheimer's disease (AD) are associated with a lower quality of life. OBJECTIVE: We aimed to determine the efficacy of two antidepressants and one antipathy drug in the treatment of depression and apathy in AD patients. METHODS: In the present study, we evaluated the efficacy of sertraline (n = 11; average dose = 31.8 mg), escitalopram (n = 13; average dose = 7.3 mg), and nicergoline (n = 9; average dose = 14.5 mg) in treating depression and apathy over a period of 3 months (M).The 33 patients with AD demonstrated high Geriatric Depression Scale (GDS) (>5) or a high Apathy Scale (AS) (>16) scores. RESULTS: The patients receiving escitalopram treatment showed a significant improvement in GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, p = 0.04), and the patients receiving sertraline treatment showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, p = 0.05); however, no significant changes were noted in patients receiving nicergoline. CONCLUSION: These results provide novel information on the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD.

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  • Recovery from hypoxemia and Hypercapnia following noninvasive pressure support ventilation in a patient with statin-associated necrotizing myopathy: a case report. Reviewed International journal

    Yuriko Yamamura, Yoshinori Matsumoto, Koh Tadokoro, Yasuyuki Ohta, Kota Sato, Toru Yamashita, Masahiro Yamamura, Ken-Ei Sada, Koji Abe, Jun Wada

    BMC pulmonary medicine   20 ( 1 )   156 - 156   2020.6

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    BACKGROUND: Statin-associated necrotizing myopathy (SANM) is a rare autoimmune disorder caused by administration of statins. SANM is characterized by weakness due to necrosis and regeneration of myofibers. Here we report the first case of SANM with acute respiratory failure treated with noninvasive pressure support ventilation in addition to immunosuppressants. CASE PRESENTATION: A 59-year-old woman who had been treated with 2.5 mg/day of rosuvastatin calcium for 5 years stopped taking the drug 4 months before admission to our hospital due to elevation of creatine kinase (CK). Withdrawal of rosuvastatin for 1 month did not decrease the level of CK, and she was admitted to our hospital due to the development of muscle weakness of her neck and bilateral upper extremities. Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase antibodies were positive. Magnetic resonance imaging showed myositis, and muscle biopsy from the right biceps brachii muscle showed muscle fiber necrosis and regeneration without inflammatory cell infiltration, suggesting SANM. After the diagnosis, she received methylprednisolone pulse therapy (mPSL, 1 g/day × 3 days, twice) and subsequent oral prednisolone therapy (PSL, 30 mg/day for 1 month, 25 mg/day for 1 month and 22.5 mg/day for 1 month), leading to improvement of her muscle weakness. One month after the PSL tapering to 20 mg/day, her muscle weakness deteriorated with oxygen desaturation (SpO2: 93% at room air) due to hypoventilation caused by weakness of respiratory muscles. BIPAP was used for the management of acute respiratory failure in combination with IVIG (20 g/day × 5 days) followed by mPSL pulse therapy (1 g/day × 3 days), oral PSL (30 mg/day × 3 weeks, then tapered to 25 mg/day) and tacrolimus (3 mg/day). Twenty-seven days after the start of BIPAP, she was weaned from BIPAP with improvement of muscle weakness, hypoxemia and hypercapnia. After she achieved remission with improvement of muscle weakness and reduction of serum CK level to a normal level, the dose of oral prednisolone was gradually tapered to 12.5 mg/day without relapse for 3 months. CONCLUSIONS: Our report provides new insights into the role of immunosuppressants and biphasic positive airway pressure for induction of remission in patients with SANM.

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  • A Polyphenolic Complex Attenuates Inflammatory Response and Blood- Brain Barrier Disruption. Reviewed International journal

    Yuting Bian, Toru Yamashita, Yuki Taira, Jingwei Shang, Keiichiro Tsunoda, Tian Feng, Ryo Sasaki, Xia Liu, Xiaowen Shi, Koh Tadokoro, Emi Nomura, Namiko Matsumoto, Yusuke Osakada, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Current neurovascular research   17 ( 3 )   286 - 293   2020.5

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    BACKGROUND: Cerebral ischemia causes strong inflammatory response. Neumentix is a dietary supplement containing 14.9% rosmarinic acid and 29.9% total phenolic content, which was proved to be beneficial against inflammatory response. Therefore, we investigated Neumentix's effect on anti-inflammatory and blood brain barrier (BBB) disruption in transient middle cerebral artery occlusion (tMCAO) model mice. METHODS: After the pretreatment of vehicle or Neumentix 134 mg/kg/d, intraperitoneal injection (i.p.) (containing rosmarinic acid 20mg/kg/d) for 14 days, mice were subjected to tMCAO for 60 min and kept receiving vehicle or Neumentix daily 5 days afterwards. RESULTS: Neumentix treatment ameliorated neurobehavioral impairment in the corner test (5d after tMCAO, **p<0.01), reduced infarct volume (#p<0.05), suppressed expression of ionized calcium-binding adapter molecule-1 (Iba-1), tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) (### p <0.001), and improved the integrity of BBB (§p<0.05) at the 5 days after tMCAO. Conclusios: Our present study provided an evidence of Neumentix's anti-inflammatory and neuroprotection effect against BBB disruption on experimental tMCAO model mice, suggesting that Neumentix could be potential therapeutic agent for stroke.

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  • Bone Marrow Stromal Cell Transplantation Drives Molecular Switch from Autophagy to the Ubiquitin-Proteasome System in Ischemic Stroke Mice. Reviewed International journal

    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   2020.5

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    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.

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  • Diabetic painful truncal neuropathy with hypohidrosis and facial palsy

    Keiichiro Tsunoda, Yoshio Omote, Nozomi Hishikawa, Ken Ikegami, Yumiko Nakano, Kota Sato, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 3 )   155 - 157   2020.5

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    Truncal neuropathy is a rare phenotype of diabetic neuropathy. Here, we report the first case of diabetic painful truncal neuropathy complaining of back pain with hypohidrosis confirmed by a sweat test accompanied by cranial nerve palsy. The patient had poorly controlled type 2 diabetes mellitus and suffered from back pain followed by facial palsy. After pulse therapy with methylprednisolone facial palsy improved, but back pain was intractable with a loss of body weight. The sweat test showed hypohidrosis on the back and soles on his feet. Sural nerve biopsy revealed decreased small fibers and mild axonopathy. After palliative therapy, his symptoms gradually improved.

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  • A spontaneous recovery of anti-galactocerebroside antibody-associated encephalitis without evidence of Mycoplasma infection

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

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 3 )   164 - 166   2020.5

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    Anti-galactocerebroside (Gal-C) antibody is characteristic of encephalomyelitis and Guillain-Barre syndrome subsequent to mycoplasma infection. Here, we report a 75-year-old Japanese man who presented somnolence, signs of meningeal irritation, and parkinsonian features with positive serum inflammatory markers and cerebrospinal fluid (CSF) pleocytosis. Although anti-Mycoplasma pneumoniae antibody was negative, anti-Gal-C antibody was later detected in his serum. The present case recovered spontaneously without any other specific therapies.

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  • Discrepancy of subjective and objective sleep problems in Alzheimer's disease and mild cognitive impairment detected by a home-based sleep analysis Reviewed International journal

    Koh Tadokoro, Yasuyuki Ohta, Nozomi Hishikawa, Emi Nomura, Yosuke Wakutani, Yoshiki Takao, Yoshio Omote, Mami Takemoto, Toru Yamashita, Koji Abe

    JOURNAL OF CLINICAL NEUROSCIENCE   74   76 - 80   2020.4

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    There is a strong relationship between Alzheimer's disease (AD) and sleep problems, and a sleep condition is informative for evaluating the AD status. In the present study, we evaluated subjective sleep problems in AD and mild cognitive impairment (MCI) with self-check questionnaires and objective sleep problems with a convenient home-based portable device, WatchPAT. A total of 63 subjects with normal cognition (NC) (n = 22), MCI (n = 20), and AD (n = 21) were cross-sectionally investigated. AD patients showed a better self-check Pittsburgh sleep quality index (PSQI) score (*p < 0.05) than NC and MCI patients. On the other hand, WatchPAT analysis showed a significantly reduced rapid eye movement (REM) sleep (*p < 0.05) and increased light sleep in AD patients (*p < 0.05) compared with NC subjects, and mildly reduced REM and increased light sleep in MCI subjects. The present study revealed a gap between the subjective self-check sleep questions and the objective WatchPAT analysis in AD patients. Thus, a home-based sleep study with WatchPAT is a useful tool to detect an objective sleep problem in AD and the risk of MCI conversion into AD.

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  • LGI1 antibody-associated limbic encephalitis started from unilateral basal ganglia to medial temporal lobe and insula

    Xia Liu, Yoshio Omote, Yosuke Osakada, Koh Tadokoro, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 2 )   68 - 71   2020.3

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    Leucine-rich glioma-inactivated 1 (LGI1) antibody-associated limbic encephalitis is a rare autoimmune encephalitis. Here, we report a 39-year-old woman presented with generalized tonic-clonic seizures, night delirium, bilateral upper limb tremor, and hyponatremia. Her symptoms did not improve with initial steroid therapy, and brain magnetic resonance imaging (MRI) showed a progression of abnormalities from right basal ganglia to medial temporal lobe and insula. The presence of LGI1 antibodies in the patient's serum confirmed the clinical diagnosis. After the combined treatments of methylprednisolone, plasma exchange, and intravenous immunoglobulin, her clinical symptoms resolved completely.

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  • A juvenile case of idiopathic hypertrophic pachymeningitis involved cavernous sinus and proximal trigeminal nerve

    Zhihong Bian, Yoshio Omote, Koh Tadokoro, Ken Ikegami, Yosuke Osakada, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 2 )   82 - 85   2020.3

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    Idiopathic hypertrophic pachymeningitis (HP) is a rare inflammatory disorder characterized by local or diffuse thickening of the cranial or spinal dura mater, which is primarily reported in adults. Here, we report a juvenile idiopathic HP case presenting diplopia and multiple cranial nerve palsies. Although cranial magnetic resonance imaging (MRI) shows evident lesions in cavernous sinus and preganglionic segment of trigeminal nerve, only cerebrospinal fluid (CSF) showed elevated protein (55 mg/dL) and myelin basic protein (MBP, 355 pg/mL) but negative systemic inflammatory markers. Steroid therapy greatly improved the symptom and the CSF data in 1 month.

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  • A unique case with positive anti-myelin oligodendrocyte glycoprotein antibody presenting multiple brain lesions

    Namiko Matsumoto, Kota Sato, Nozomi Hishikawa, Yuko Kawahara, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Kentaro Fujii, Kazuhiko Kurozumi, Isao Date, Toshiyuki Takahashi, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 2 )   92 - 95   2020.3

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    The accurate diagnosis of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases is sometimes challenging due to its various central nervous system (CNS) lesions. Here, we report a 22-year-old man with positive anti-MOG antibody presenting multiple brain lesions including a brainstem tumefactive demyelinating lesion (TDL), cortical edematous lesions, and a periventricular white matter lesion. These variety of lesions made the diagnosis challenging, especially because TDL is quite rare among MOG antibody-associated disease patients. The present case suggests the importance to check anti-MOG antibody for patients presenting atypical multiple CNS lesions.

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  • Different clinical and neuroimaging features of Japanese dementia siblings with a new N-terminal mutation (Val225Ala) of APP gene. Reviewed International journal

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

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia   72   482 - 484   2020.2

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

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  • A novel homoplasmic mitochondrial DNA mutation (m.13376T>C, p.I347T) of MELAS presenting characteristic medial temporal lobe atrophy. Reviewed International journal

    Ryo Sasaki, Yasuyuki Ohta, Noriko Hatanaka, Koh Tadokoro, Emi Nomura, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Yoshio Omote, Eisaku Morimoto, Sanae Teshigawara, Jun Wada, Yu-Ichi Goto, Koji Abe

    Journal of the neurological sciences   408   116460 - 116460   2020.1

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  • Molecular switching from ubiquitin-proteasome to autophagy pathways in mice stroke model. Reviewed International journal

    Xia Liu, Toru Yamashita, Jingwei Shang, Xiaowen Shi, Ryuta Morihara, Yong Huang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism   40 ( 1 )   214 - 224   2020.1

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    The ubiquitin-proteasome system (UPS) and autophagy are two major pathways to degrade misfolded proteins that accumulate under pathological conditions. When UPS is overloaded, the degeneration pathway may switch to autophagy to remove excessive misfolded proteins. However, it is still unclear whether and how this switch occurs during cerebral ischemia. In the present study, transient middle cerebral artery occlusion (tMCAO) resulted in accelerated ubiquitin-positive protein aggregation from 0.5 h of reperfusion in mice brain after 10, 30 or 60 min of tMCAO. In contrast, significant reduction of p62 and induction of LC3-II were observed, peaking at 24 h of reperfusion after 30 and 60 min tMCAO. Western blot analyses showed an increase of BAG3 and HDAC6 at 1 or 24 h of reperfusion that was dependent on the ischemic period. In contract, BAG1 decreased at 24 h of reperfusion after 10, 30 or 60 min of tMCAO after double immunofluorescent colocalization of ubiquitin, HSP70, p62 and BAG3. These data suggest that a switch from UPS to autophagy occurred between 10 and 30 min of cerebral ischemia depending on the BAG1/BAG3 ratio and level of HDAC6.

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  • A dramatic increase in serum CK levels after switching from oral to intravenous administration of LEV

    Mami Takemoto, Taijun Yunoki, Kota Sato, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Jingwei Shang, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   8 ( 1 )   39 - 41   2020.1

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    The authors report on a 22-year-old Japanese woman who started oral administration of 1000 mg levetiracetam (LEV) for her epilepsy after the second convulsive seizure. She was free from seizures for the subsequent 111 days, but a third tonic-clonic seizure happened and she was transferred to our hospital (Day 1). Her consciousness state was drowsy and 1000 mg LEV continued for two days, but intravenously. Although her state became clear, her serum creatine kinase (CK), myoglobin (Mb), and creatine (Cre) levels were significantly elevated (18 179 IU/L, 2783 ng/mL, and 0.8 mg/mL) with a peak at Day 5 of CK 26, 189 IU/L. After stopping intravenous injection of LEV, serum CK returned to its normal level promptly. The present case suggests that we should take more care in monitoring for rhabdomyolysis on switching from oral to intravenous administration of LEV.

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  • A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology. Reviewed International journal

    Koji Abe, Jingwei Shang, Xiaowen Shi, Toru Yamashita, Nozomi Hishikawa, Mami Takemoto, Ryuta Morihara, Yumiko Nakano, Yasuyuki Ohta, Kentaro Deguchi, Masaki Ikeda, Yoshio Ikeda, Koichi Okamoto, Mikio Shoji, Masamitsu Takatama, Motohisa Kojo, Takeshi Kuroda, Kenjiro Ono, Noriyuki Kimura, Etsuro Matsubara, Yosuke Osakada, Yosuke Wakutani, Yoshiki Takao, Yasuto Higashi, Kyoichi Asada, Takehito Senga, Lyang-Ja Lee, Kenji Tanaka

    Journal of Alzheimer's disease : JAD   73 ( 1 )   217 - 227   2020

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    BACKGROUND: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer's disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established. OBJECTIVE: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology. METHODS: With only 1.5μl of serum, we examined a new target plate "BLOTCHIP®" plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n = 100), MCI (n = 60), and AD (n = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains. RESULTS: Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains. CONCLUSION: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.

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  • Early Emergence of Neuropsychiatric Symptoms in Cognitively Normal Subjects and Mild Cognitive Impairment. Reviewed International journal

    Keiichiro Tsunoda, Toru Yamashita, Yosuke Osakada, Ryo Sasaki, Koh Tadokoro, Namiko Matsumoto, Emi Nomura, Ryuta Morihara, Yumiko Nakano, Yoshiaki Takahashi, Noriko Hatanaka, Jingwei Shang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of Alzheimer's disease : JAD   73 ( 1 )   209 - 215   2020

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    The world is rapidly aging and facing an increase in the number of dementia patients, so it is important to detect the preclinical stage of dementia in such countries. We examined both cognitive and affective functions among cognitively normal control (n = 218), mild cognitive impairment (MCI, n = 146), and Alzheimer's disease (AD, n = 305) subjects using two evaluation tools for behavioral and psychological symptoms of dementia (BPSD) [Abe's BPSD score (ABS) and mild behavioral impairment (MBI)]. BPSD were present in 12.4% (ABS) and 9.6% (MBI) of cognitively normal people, 34.9% and 32.2% in MCI subjects, and 66.2% and 51.1% in AD patients. Both ABS (§p<0.05) and MBI (§§p < 0.01) score showed worse score with cognitive decline of the Mini-Mental State Examination in the AD group in BPSD-positive participants. Similar correlations were found in all participants in AD group (||||p < 0.01 versus ABS and MBI). Among the subscales in BPSD-positive participants, an apathy/indifference score of ABS and a decreased motivation of MBI showed significant differences in AD patients compared to the control and MCI subjects (**p<0.01). In addition, subscale analyses further showed a downward trend from the control to MCI and AD subjects in four ABS subscales and three MBI subscales. The present study showed the preclinical presence of BPSD in cognitively normal people, more so in MCI subjects, and ABS detected BPSD more sensitively than MBI in all three groups.

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  • Female dominant association of sarcopenia and physical frailty in mild cognitive impairment and Alzheimer's disease. Reviewed International journal

    Yasuyuki Ohta, Emi Nomura, Noriko Hatanaka, Yosuke Osakada, Namiko Matsumoto, Ryo Sasaki, Keiichiro Tsunoda, Mami Takemoto, Koh Tadokoro, Nozomi Hishikawa, Yosuke Wakutani, Toru Yamashita, Kota Sato, Yoshio Omote, Koji Abe

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia   70   96 - 101   2019.12

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    Associations of sarcopenia and physical frailty in cognitive and affective (depression, apathy, and behavioral and psychological symptoms of dementia) functions of mild cognitive impairment (MCI) and Alzheimer's disease (AD) were not fully evaluated previously, especially not for gender differences. 165 AD, 84 MCI, and 48 control participants (175 female, 122 male) were evaluated for cognitive, affective, activities of daily living (ADL), and physical functions associated with sarcopenia and physical frailty. In both sexes, cognitive and affective functions, ADL, and physical functions worsened in MCI and AD compared to control subjects. Physical dysfunctions, especially slow gait speed (3 m up and go test), were significantly associated with cognitive, affective, and ADL declines in participants (control subjects, MCI, and AD) of each gender, which were especially noticeable in females. The present study may be the first to suggest significant associations of sarcopenia and physical frailty with cognitive and affective functions of MCI and AD, especially in females.

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  • Intracranial invasive fungal aneurysm due to Aspergillus sinusitis successfully treated by voriconazole plus internal carotid artery ligation therapy in an aged woman

    Mami Takemoto, Yasuyuki Ohta, Koh Tadokoro, Ryo Sasaki, Yoshiaki Takahashi, Kota Sato, Toru Yamashita, Nozomi Hishikawa, Jingwei Shang, Masafumi Hiramatsu, Kenji Sugiu, Tomohito Hishikawa, Isao Date, Koji Abe

    NEUROLOGY ASIA   24 ( 4 )   363 - 367   2019.12

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    A fungal carotid aneurysm is an infrequently occurring infectious aneurysm that is usually treated by antifungal therapy plus surgical debridement of the infected vessel. We herein report an extremely rare case involving a patient with a medical history of bladder cancer treated by Bacillus Calmette-Guerin (BCG) who developed a fungal aneurysm of the internal carotid artery and thrombosis of the superior ophthalmic vein caused by maxillary Aspergillus sinusitis. The patient was successfully treated by antifungal, anticoagulant, and antiplatelet drugs combined with internal carotid artery ligation therapy. Internal carotid artery fungal aneurysm is associated with a high mortality rate, but the present case suggests that it can be successfully treated by antifungal therapy combined with a less invasive endovascular therapy.

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  • Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer's disease model mouse. Reviewed International journal

    Jingwei Shang, Toru Yamashita, Feng Tian, Xianghong Li, Xia Liu, Xiaowen Shi, Yumiko Nakano, Keiichiro Tsunoda, Emi Nomura, Ryo Sasaki, Koh Tadokoro, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Brain research   1723   146379 - 146379   2019.11

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    Abnormal accumulation of amyloid-β (Aβ) peptide defines progression of Alzheimer's disease (AD) pathology in brain. Here, we investigated expressive changes of two main Aβ transport receptors low-density lipoprotein receptor related protein-1 (LRP1) and receptor for advanced glycation end products (RAGE) in a novel AD mice (APP23) with chronic cerebral hypoperfusion (CCH) model, moreover, examined a protective effect of a free radical scavenger edaravone (Eda). In contrast to wild type (WT) and APP23 mice, CCH strongly accelerated abnormal Aβ40 depositions and cerebral amyloid angiopathy (CAA) pathology, increased both LRP1 and RAGE expressions in brain parenchyma, while a decrease of LRP1 and an increase of RAGE were observed in vascular endothelial cells at age 12 months (M) of AD mice. Furthermore, CCH strongly increased expressions of two hypoxia-related proteins hypoxia inducible factor-1α (HIF-1α) and heme oxygenase-1 (HO-1), two oxidative-related proteins 4-hydroxy-2-nonenal (4-HNE) and 8-hydroxy-2'-deoxyguanosine (8-OHdG), and decreased both two vital nutrient transporter proteins major facilitator super family domain containing 2a (Mfsd2a) and glucose transporter 1 (Glut1) expressions. Such the above abnormal pathological changes were significantly ameliorated by edaravone treatment. The present study demonstrated that CCH strongly enhanced primary AD pathology causing double imbalances of Aβ efflux and influx transport related proteins in the cortical blood vessels in AD mice, and that such a neuropathologic abnormality was greatly ameliorated by Eda.

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  • Spastic Paraplegia Accompanied by Extrapyramidal Sign and Frontal Cognitive Dysfunction. Reviewed

    Ryo Sasaki, Yasuyuki Ohta, Kota Sato, Koh Tadokoro, Yoshiaki Takahashi, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Hiroyuki Ishiura, Shoji Tsuji, Koji Abe

    Internal medicine (Tokyo, Japan)   58 ( 21 )   3163 - 3165   2019.11

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    A complicated form of spastic paraplegia is a neurodegenerative disorder presenting as progressive spasticity in the bilateral lower limbs accompanied by some clinical features. The present case showed spastic paralysis and hyperreflexia in all extremities as well as lead pipe rigidity in the neck and bilateral upper extremities (R < L), decreased scores on frontal cognitive tests, a decreased accumulation of the right dorsal putamen on a DAT scan, and hypoperfusion of the bilateral frontal lobes on 99mTc-ECD single photon emission computed tomography (SPECT). The present case provides a new spectrum of spastic paraplegia based on the evidence of clinical scores and the findings of brain functional imaging.

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  • Yoga-plus exercise mix promotes cognitive, affective, and physical functions in elderly people. Reviewed International journal

    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   2019.11

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    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.

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  • [Edaravone: A New Treatment for ALS]. Reviewed

    Toru Yamashita, Koji Abe

    Brain and nerve = Shinkei kenkyu no shinpo   71 ( 11 )   1245 - 1251   2019.11

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    In 1993, a mutation in the superoxyde dismutase gene, SOD1, was found causative for familial ALS, suggesting that free radical-related injury may be involved in ALS pathogenesis. Therefore, clinical trials were conducted with ALS patients using a free radical scavenger, edaravone, which was already approved for acute phase treatment of cerebral infarction in Japan. Because edaravone showed a therapeutic effect in suppressing the progression of ALS symptoms, it was approved as a new therapeutic agent in Japan, in June, 2015. In this article, we discuss the recent progress of basic and clinical research for the development of new ALS treatments.

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  • A Japanese patient with a VCP mutation c.290G > A (p.G97E) presenting a rapid progressive respiratory failure

    Emi Nomura, Yasuyuki Ohta, Kota Sato, Yuko Kawahara, Mami Takemoto, Yoshiaki Takahashi, Namiko Matsumoto, Taijun Yunoki, Toru Yamashita, Nozomi Hishikawa, Ichizo Nishino, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   7 ( 6 )   361 - 364   2019.11

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    Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder caused by mutations in the valosin-containing protein (VCP) gene. IBMPFD usually presents progressive limb muscle weakness resulting in wheelchaired after mean course of 9 years with myopathy, and Paget's osteolytic lesions and frontotemporal dementia (FTD) rarely present respiratory failure. Different from previous reports, we reported a Japanese IBMPFD patient with a VCP mutation c.290G > A (p.G97E), presenting a progressive respiratory failure accompanied by wheelchaired in only 6 years after myopathy onset, suggesting unique relationship between clinical severity and c.290G > A (p.G97E) mutation of VCP gene in Japanese.

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  • A unique stroke case with contralateral sulcal hyperintensity on fluid-attenuated inversion recovery image changed to linear serpiginous structures

    Yosuke Osakada, Yoshiaki Takahashi, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   7 ( 6 )   351 - 353   2019.11

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    An 83-year-old man developed acute ischemic stroke. Brain magnetic resonance imaging (MRI) showed ischemic stroke in the left parietal lobe gyri, but fluid-attenuated inversion recovery (FLAIR) showed hyperintensity in the contralateral right temporal-occipital lobe sulci. Follow-up FLAIR image showed the gradual disappearance of the sulcal hyperintensity in the sulci and changed to linear serpiginous structures. This is a unique stroke case showing transitioned FLAIR findings suggesting that the sulcal hyperintensity findings are more severe and an earlier ischemic condition than the linear serpiginous structures.

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  • Twendee X Ameliorates Phosphorylated Tau, α-Synuclein and Neurovascular Dysfunction in Alzheimer's Disease Transgenic Mice With Chronic Cerebral Hypoperfusion. Reviewed International journal

    Xia Liu, Toru Yamashita, Jingwei Shang, Xiaowen Shi, Ryuta Morihara, Yong Huang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   28 ( 10 )   104310 - 104310   2019.10

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    BACKGROUND: The pathological impact of chronic cerebral hypoperfusion (CCH) on Alzheimer's disease (AD) is still poorly understood. In the present study, we investigated the role of CCH on an AD mouse model in phosphorylated tau and α-synuclein pathology, neurovascular unit, cerebrovascular remodeling, and neurovascular trophic coupling. Moreover, examined protective effect of a new antioxidant Twendee X (TwX). METHODS: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors to gradually decrease the cerebral blood flow. The effects of the administration of TwX were evaluated by immunohistochemical analysis and Immunofluorescent histochemistry. RESULTS: The present study revealed that the expressions of phospho-tau and phospho-α-synuclein were significantly increased in the APP23 + CCH mice group as compared with wild type and APP23 mice groups (*P < .05 and ⁎⁎P < .01 versus WT; #P < .05 and ##P < .01 versus APP23). In addition, CCH significantly exacerbated MMP-9 activation relating to blood-brain barrier destruction (⁎⁎P < .01 versus WT; #P < .05, and ##P < .01 versus APP23), enhanced neurovascular remodeling, and impaired a neurovascular trophic coupling in the vascular endothelial BDNF expression of the APP23 + CCH group. TwX treatment (20 mg/kg/day, from 4.5 to 12 months) significantly reduced tau and α-synuclein pathologies, ameliorated neurovascular dysfunction compared with APP23 + CCH group. CONCLUSIONS: Our findings indicate that administration of a new antioxidative mixture TwX substantially reduced the above neuropathologic abnormalities, suggesting a potential therapeutic benefit of TwX for AD with CCH.

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  • Sleep problems in subacute myelo-optico neuropathy (SMON). Reviewed International journal

    Nozomi Hishikawa, Mami Takemoto, Kota Sato, Toru Yamashita, Yasuyuki Ohta, Kenichi Sakai, Koji Abe

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia   68   128 - 133   2019.10

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    Subacute myelo-optico neuropathy (SMON) patients typically suffer from sequelae that cause sleep disturbances. We sought to examine the prevalence of sleep problems among SMON patients. We conducted a questionnaire-based survey concerning sleep problems among 106 SMON patients, and 110 age- and gender-matched control participants. The prevalence of subjective insomnia (6 ≤ Athens Insomnia Scale score) was 89.6% among SMON patients, which was significantly higher than among control participants 54.4%. Sleep quality measured with the Pittsburgh Sleep Quality Index (PSQI) revealed that the prevalence of poor sleepers (6 ≤ PSQI score) was higher among SMON patients than control participants (75.6% vs 39.6%, respectively). Subscale analyses of rapid eye movement sleep behavior disorder screening questionnaire revealed that scores on two items ("dreams match nocturnal behavior" and "limb movements") were significantly higher among SMON patients than control participants. In addition, daytime sleepiness scores were significantly higher among SMON patients than control participants (4 ≤ Epworth Sleepiness Scale scores: 54.0% vs 29.0%, respectively). The current study revealed that most SMON patients suffer from insomnia with dissatisfactory sleep quality, likely due to their long-term physical sequelae. Moreover, SMON patients showed higher rates of daytime sleepiness and sleep medication intake, which could be related to reduced activity during the day, as well as insomnia.

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  • Chronic Cerebral Hypoperfusion Activates the Coagulation and Complement Cascades in Alzheimer's Disease Mice. Reviewed International journal

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

    Neuroscience   416   126 - 136   2019.9

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    Alzheimer's disease (AD) in the elderly is frequently accompanied by chronic cerebral hypoperfusion (CCH), which impairs the clearance of amyloid beta (Aβ) due to the dysfunction of the blood-brain barrier (BBB) and accelerates the AD pathology. Since the coagulation and complement cascades are associated with BBB dysfunction and AD pathology, we investigated the expression changes of coagulation (fibrinogen alpha chain-FGA, coagulation factor XIII A chain-Factor XIIIα) and complement (plasma protease C1 inhibitor-C1-INH, Complement component 3-C3) factors in the brain of novel AD model (APP23) mice with CCH at 12 months of age. Immunohistochemical and immunofluorescent analysis showed that the expressions of FGA, Factor XIIIα, C1-INH and C3 were significantly increased in cerebral neocortex, hippocampus, and thalamus of APP23 + CCH group (n = 12) as compared with wild type (WT, n = 10) and APP23 (n = 10) groups (⁎P < .05 and ⁎⁎P < .01 vs WT; #P < .05 and ##P < .01 vs APP23), especially near and inside of neurovascular unit. The present study suggests that CCH activated both the coagulation and complement cascades in a novel AD model mice brain accompanied by the acceleration of AD pathology.

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  • Imaging Hypoxic Stress and the Treatment of Amyotrophic Lateral Sclerosis with Dimethyloxalylglycine in a Mice Model. Reviewed International journal

    Emi Nomura, Yasuyuki Ohta, Koh Tadokoro, Jingwei Shang, Tian Feng, Xia Liu, Xiaowen Shi, Namiko Matsumoto, Ryo Sasaki, Keiichiro Tsunoda, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Takahiro Kuchimaru, Shinae Kizaka-Kondoh, Koji Abe

    Neuroscience   415   31 - 43   2019.9

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    Hypoxia inducible factor-1α (HIF-1α) is a key transcription factor that maintains oxygen homeostasis. Hypoxic stress is related to the pathogenesis of amyotrophic lateral sclerosis (ALS), and impaired HIF-1α induces motor neuron degeneration in ALS. Dimethyloxalylglycine (DMOG) upregulates the stability of HIF-1α expression and shows neuroprotective effects, but has not been used in ALS as an anti-hypoxic stress treatment. In the present study, we investigated hypoxic stress in ALS model mice bearing G93A-human Cu/Zn superoxide dismutase by in vivo HIF-1α imaging, and treated the ALS mice with DMOG. In vivo HIF-1α imaging analysis showed enhanced hypoxic stress in both the spinal cord and muscles of lower limbs of ALS mice, even at the pre-symptomatic stage. HIF-1α expression decreased as the disease progressed until 126 days of age. DMOG treatment significantly ameliorated the decrease in HIF-1α expression, the degeneration of both spinal motor neurons and myofibers in lower limbs, gliosis and apoptosis in the spinal cord. This was accompanied by prolonged survival. The present study suggests that in vivo bioluminescence resonance energy transfer (BRET) HIF-1α imaging is useful for evaluating hypoxic stress in ALS, and that the enhancement of HIF-1α is a therapeutic target for ALS patients.

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  • Late presented congenital myasthenic syndrome with novel compound heterozygous CHRNE mutations mimicking seronegative myasthenia gravis

    Yumiko Nakano, Keiichiro Tsunoda, Toru Yamashita, Jun Mitsui, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Tatsushi Toda, Shoji Tsuji, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   7 ( 5 )   288 - 290   2019.9

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    We found a late presented congenital myasthenic syndrome (CMS) patient with novel CHRNE gene mutations. Although our patient has shown blepharoptosis since youth, fatigable muscle weakness began at age 71. Genetic analysis revealed novel compound heterozygous CHRNE mutations (c.1032+2T>G, c.1306_1307 delGA). His myasthenic symptoms were well managed by oral anti-cholinesterase drug until he died at 82-year-old. The present case showed mild myasthenic symptoms with very late presentation and slow progression. Late presented CMS is often underdiagnosed; therefore, genetic testing is important to distinguish it from other myasthenic disease.

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  • A Unique Recurrent Stroke Case due to Bilateral Vertebral Artery Dissection with Familial Hirschsprung Disease. Reviewed International journal

    Kota Sato, Ryo Sasaki, Yasuyuki Ohta, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   28 ( 8 )   e113-e115   2019.8

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    Vertebral artery (VA) dissection is one major cause of brain infarction in young and middle-aged adults. Risk factors for VA dissection are hypertension, diabetes mellitus, hyperlipidemia, trauma, and genetic factors. A 32-year-old man with familial Hirschsprung disease at the age of 2 presented cerebellar ischemic stroke due to bilateral VA dissections. A stroke recurred within 17 days despite oral dual antiplatelet therapy. Bilateral VA dissections and recurrent dissections are related to genetic mutations associated with connective tissue diseases. A part of familial Hirschsprung disease has genetic factors in common with cerebrovascular disease. There may be a common genetic background between his VA dissection and Hirschsprung disease.

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  • In vivo direct reprogramming of glial linage to mature neurons after cerebral ischemia. Reviewed International journal

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

    Scientific reports   9 ( 1 )   10956 - 10956   2019.7

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    The therapeutic effect of in vivo direct reprogramming on ischemic stroke has not been evaluated. In the present study, a retroviral solution (1.5-2.0 × 107 /ul) of mock pMX-GFP (n = 13) or pMX-Ascl1/Sox2/NeuroD1 (ASN) (n = 14) was directly injected into the ipsilateral striatum and cortex 3 days after 30 min of transient cerebral ischemia. The reprogrammed cells first expressed neuronal progenitor marker Dcx 7 and 21 days after viral injection, then expressed mature neuronal marker NeuN. This was accompanied by morphological changes, including long processes and synapse-like structures, 49 days after viral injection. Meanwhile, therapeutic improvement was not detected both in clinical scores or infarct volume. The present study provides a future novel self-repair strategy for ischemic stroke with beneficial modifications of the inducer-suppressor balance.

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  • Clinical and Pathological Benefit of Twendee X in Alzheimer's Disease Transgenic Mice with Chronic Cerebral Hypoperfusion. Reviewed International journal

    Xia Liu, Toru Yamashita, Jingwei Shang, Xiaowen Shi, Ryuta Morihara, Yong Huang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   28 ( 7 )   1993 - 2002   2019.7

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    BACKGROUND: Multiple pathogeneses are involved in Alzheimer's disease (AD), such as amyloid-β accumulation, neuroinflammation, and oxidative stress. The pathological impact of chronic cerebral hypoperfusion on Alzheimer's disease is still poorly understood. METHODS: APP23 mice were implanted to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive chronic cerebral hypoperfusion (CCH). The effects of the administration of Twendee X (TwX) were evaluated by behavioral analysis, immunohistochemical analysis, and immunofluorescent histochemistry. RESULTS: In the present study, chronic cerebral hypoperfusion, which is commonly found in aged Alzheimer's disease, significantly exacerbated motor dysfunction of APP23 mice from 5 months and cognitive deficit from 8 months of age, as well as neuronal loss, extracellular amyloid-β plaque and intracellular oligomer formations, and amyloid angiopathy at 12 months. Severe upregulations of oxidative markers and inflammatory markers were found in the cerebral cortex, hippocampus, and thalamus at 12 months. Twendee X treatment (20 mg/kg/d, from 4.5 to 12 months) substantially rescued the cognitive deficit and reduced the above amyloid-β pathology and neuronal loss, alleviated neuroinflammation and oxidative stress. CONCLUSIONS: The present findings suggested a potential therapeutic benefit of Twendee X for Alzheimer's disease with chronic cerebral hypoperfusion.

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  • A pneumococcal meningoencephalitis with a small spleen

    Keiichiro Tsunoda, Kota Sato, Yoshiaki Takahashi, Koh Tadokoro, Ryo Sasaki, Emi Nomura, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   7 ( 4 )   215 - 217   2019.7

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    Streptococcus pneumoniae is a major cause of bacterial meningitis usually in children or elder adults. We report a case of a 38-year-old man having pneumococcal meningoencephalitis with a small spleen (35 cm(3)), compared to seven previous patients with pneumococcal meningitis in our department. Among the eight patients, four cases were due to sinusitis, but the origin could not be identified in the other four cases, including the present case who was the youngest patient with the smallest splenic size. Of interest in the present analysis was the negative or positive correlation between splenic size and age, with or without sinusitis. This is the first report on pneumococcal meningoencephalitis that takes into consideration age, splenic size, and the origin of infection.

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  • Acceleration of NLRP3 inflammasome by chronic cerebral hypoperfusion in Alzheimer's disease model mouse. Reviewed International journal

    Jingwei Shang, Toru Yamashita, Yun Zhai, Yumiko Nakano, Ryuta Morihara, Xianghong Li, Feng Tian, Xia Liu, Yong Huang, Xiaowen Shi, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Neuroscience research   143   61 - 70   2019.6

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    Cerebral neuroinflammation defines a novel pathway for progressing Alzheimer's disease (AD) pathology. We investigated immunohistological changes of neuroinflammation with nucleotide-binding domain and leucine-rich repeat (NLR)-protein 3 (NLRP3), activated caspase-1 and interleukin-1 beta (IL-1β) in a novel AD (APP23) mice with chronic cerebral hypoperfusion (CCH) model from 4 months (M) of age, moreover, examined protective effect of galantamine. CCH strongly enhanced NLRP3, activated caspase-1 and IL-1β expressions in hippocampus and thalamus at age 12 M of AD mice. CCH also exaggerated amyloid-beta (Aβ) 40 depositions in cerebral cortex. Furthermore, CCH exacerbated a marked dissociation of neurovascular unit (NVU). These pathological changes were ameliorated by galantamine treatment. The present study demonstrated that CCH strongly enhanced primary AD pathology including neuroinflammation, Aβ accumulations and NVU dissociation in AD mice, which was greatly protected by an allosterically potentiating ligand galantamine.

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  • A unique Japanese CPEO family with a novel homozygous m.14819 T > G (p. S25A) substitution. Reviewed International journal

    Emi Nomura, Yasuyuki Ohta, Koh Tadokoro, Kota Sato, Ryo Sasaki, Yoshiaki Takahashi, Toru Yamashita, Mami Takemoto, Nozomi Hishikawa, Yu-Ichi Goto, Koji Abe

    Journal of the neurological sciences   400   145 - 147   2019.5

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  • Enhanced oxidative stress and the treatment by edaravone in mice model of amyotrophic lateral sclerosis. Reviewed International journal

    Yasuyuki Ohta, Emi Nomura, Jingwei Shang, Tian Feng, Yong Huang, Xia Liu, Xiaowen Shi, Yumiko Nakano, Nozomi Hishikawa, Kota Sato, Mami Takemoto, Toru Yamashita, Koji Abe

    Journal of neuroscience research   97 ( 5 )   607 - 619   2019.5

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    Oxidative stress is associated with the degeneration of both motor neurons and skeletal muscles in amyotrophic lateral sclerosis (ALS). A free radical scavenger edaravone has been proven as a therapeutic drug for ALS patients, but the neuroprotective mechanism for the oxidative stress of ALS has not been fully investigated. In this study, we investigated oxidative stress in ALS model mice bearing both oxidative stress sensor nuclear erythroid 2-related factor 2 (Nrf2) and G93A-human Cu/Zn superoxide dismutase (Nrf2/G93A) treated by edaravone. In vivo Nrf2 imaging analysis showed the accelerated oxidative stress both in spinal motor neurons and lower limb muscles of Nrf2/G93A mice according to disease progression in addition to the enhancement of serum oxidative stress marker dROMS. These were significantly alleviated by edaravone treatment accompanied by clinical improvements (rotarod test). The present study suggests that in vivo optical imaging of Nrf2 is useful for detecting oxidative stress in ALS, and edaravone alleviates the degeneration of both motor neurons and muscles related to oxidative stress in ALS patients.

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  • Multi-modal combination therapy rescued a frequent ischemic stroke patient due to giant cell arteritis

    Yoshiaki Takahashi, Kota Sato, Namiko Matsumoto, Yuko Kawahara, Taijun Yunoki, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   7 ( 3 )   132 - 135   2019.5

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    Ischemic stroke (IS) due to giant cell arteritis (GCA) is rare, but highly mortal. Here, we report a 72-year-old man who showed frequent IS with GCA. Initial therapy with prednisolone increased the frequency of IS, which disappeared after continuous multi-modal combination therapy with corticosteroids, immunosuppressive agents, antiplatelets, and statin. The present case was discharged with independent walk, suggesting that a multi-modal combination therapy rescued the GCA patient from frequent IS.

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  • Very rare solitary primary peripheral nerve onset cytotoxic molecule-positive peripheral T-cell lymphoma (PTCL)

    Namiko Matsumoto, Kota Sato, Yoshiaki Takahashi, Yuko Kawahara, Taijun Yunoki, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Maiko Sakamoto, Eisei Kondou, Rei Shibata, Tadashi Yoshino, Toshifumi Ozaki, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   7 ( 3 )   146 - 149   2019.5

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    Here we present the first report of solitary primary peripheral nerve onset cytotoxic molecule (CM)-positive peripheral T-cell lymphoma (PTCL) diagnosed after nerve biopsy. An 84-year-old female with rheumatoid arthritis (RA) complained of asymmetric severe tenderness in her upper limbs. The biopsy pathology revealed a direct invasion of CM-positive PTCL. When RA patients complain of numbness, tenderness, or weakness, lymphomatic peripheral nerve invasion should be considered.

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  • Improving Anxiety in Subacute Myelo-optico-neuropathy (SMON) after an Automated Telephone Call Service. Reviewed

    Yasuyuki Ohta, Nozomi Hishikawa, Kota Sato, Mami Takemoto, Toru Yamashita, Shinji Doutare, Koji Abe

    Internal medicine (Tokyo, Japan)   58 ( 8 )   1081 - 1085   2019.4

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    Objective We evaluated the clinical effects of a telephone call service for psychological symptoms such as anxiety, depression or apathy in subacute myelo-optico-neuropathy (SMON) patients living alone or with a single caregiver. Methods Up to 16 SMON patients (4 men, 12 women) and 32 control subjects were evaluated by the geriatric depression scale (GDS), apathy scale (AS) and state and trait anxiety inventory (STAI) forms X-I, including the P and A values for depression, apathy and state anxiety including disturbed peace of mind and enhanced anxiety, respectively, before (pre) and three months after (post) the telephone call service. Results The SMON patients, especially women, had significantly worse baseline scores in GDS (depression), AS (apathy) and STAI (state anxiety) than control subjects. The automated telephone call service significantly improved the high baseline STAI scores, including the P and A scores (disturbed peace of mind and enhanced anxiety), of SMON patients but not the GDS or AS scores. Conclusion SMON patients, especially women, living alone or with a single caregiver showed higher baseline depression, apathy and anxiety scores than the control subjects. The present automated telephone call service proved to be a useful care tool for improving the anxiety of SMON patients with high STAI P and A scores.

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  • Characteristic Clinical Features of Werner Syndrome with a Novel Compound Heterozygous WRN Mutation c.1720+1G>A Plus c.3139-1G>C. Reviewed

    Namiko Matsumoto, Yasuyuki Ohta, Kentaro Deguchi, Masayuki Kishida, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Aki Watanabe, Koutaro Yokote, Minoru Takemoto, Junko Oshima, Koji Abe

    Internal medicine (Tokyo, Japan)   58 ( 7 )   1033 - 1036   2019.4

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    Werner syndrome (WS) is an autosomal recessive progeroid disorder caused by mutations in the WRN gene (WRN). Most Japanese WS patients are born from a consanguineous marriage with homozygous WRN mutations. We herein report a rare WS patient born from non-consanguineous parents with compound heterozygous WRN mutations with a novel heterogeneous c.1720+1G>A substitution plus the most frequent heterogeneous c.3139-1G>C substitution among Japanese. Although the present case showed clinical characteristics common to previous Japanese WS patients, he had not developed any malignant tumors as of 43 years of age, suggesting that WS patients with this particular genetic mutation have a different phenotype than others.

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  • A Rare Case of Klinefelter Syndrome Accompanied by Spastic Paraplegia and Peripheral Neuropathy. Reviewed

    Ryo Sasaki, Yasuyuki Ohta, Yoshiaki Takahashi, Keiichiro Tsunoda, Koh Tadokoro, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    Internal medicine (Tokyo, Japan)   58 ( 3 )   437 - 440   2019.2

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    Klinefelter syndrome is a chromosomal disorder with a typical karyotype of 47, XXY, accompanied by various neurological symptoms. We herein report the first case of Klinefelter syndrome with a rare mosaic form of 47, XXY and 48, XXXY, combined with both spastic paraplegia and peripheral motor neuropathy. This case showed spasticity and hyperreflexia with pathological reflexes and ankle clonus as well as muscle weakness in all extremities. A motor nerve conduction study and the magnetic motor evoked potential suggested motor axonal neuropathy and corticospinal tract disorders. The present case suggests that Klinefelter syndrome can present with both upper and lower motor neuron degeneration.

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  • GPIHBP1 autoantibody syndrome during interferon beta 1a treatment

    Jun Eguchi, Kazuya Miyashita, Isamu Fukamachi, Katsuyuki Nakajima, Masami Murakami, Yuko Kawahara, Toru Yamashita, Yasuyuki Ohta, Koji Abe, Atsuko Nakatsuka, Mai Mino, Satoru Takase, Hiroaki Okazaki, Robert A. Hegele, Michael Ploug, Xuchen Hu, Jun Wada, Stephen G. Young, Anne P. Beigneux

    JOURNAL OF CLINICAL LIPIDOLOGY   13 ( 1 )   62 - 69   2019.2

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    BACKGROUND: Autoantibodies against glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) cause chylomicronemia by blocking the ability of GPIHBP1 to bind lipoprotein lipase (LPL) and transport the enzyme to its site of action in the capillary lumen.OBJECTIVE: A patient with multiple sclerosis developed chylomicronemia during interferon (IFN) beta 1a therapy. The chylomicronemia resolved when the IFN beta 1a therapy was discontinued. Here, we sought to determine whether the drug-induced chylomicronemia was caused by GPIHBP1 autoantibodies.METHODS: We tested plasma samples collected during and after IFN beta 1a therapy for GPIHBP1 autoantibodies (by western blotting and with enzyme-linked immunosorbent assays). We also tested whether the patient's plasma blocked the binding of LPL to GPIHBP1 on GPIHBP1-expressing cells.RESULTS: During IFN beta 1a therapy, the plasma contained GPIHBP1 autoantibodies, and those autoantibodies blocked GPIHBP1's ability to bind LPL. Thus, the chylomicronemia was because of the GPIHBP1 autoantibody syndrome. Consistent with that diagnosis, the plasma levels of GPIHBP1 and LPL were very low. After IFN beta 1a therapy was stopped, the plasma triglyceride levels returned to normal, and GPIHBPI autoantibodies were undetectable.CONCLUSION: The appearance of GPIHBP1 autoantibodies during IFN Pla therapy caused chylomicronemia. The GPIHBP1 autoantibodies disappeared when the IFN beta 1a therapy was stopped, and the plasma triglyceride levels fell within the normal range. (C) 2018 National Lipid Association. All rights reserved.

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  • Asymmetrical and Isolated Hypoglossal Nerve Palsy Accompanied by a New Subset of Anti-ganglioside Antibodies in a Patient with Diffuse Large B Cell Lymphoma. Reviewed

    Yasuyuki Ohta, Yuko Kawahara, Koh Tadokoro, Kota Sato, Ryo Sasaki, Yoshiaki Takahashi, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Takeru Asano, Tomoko Inomata, Koji Abe

    Internal medicine (Tokyo, Japan)   58 ( 2 )   283 - 286   2019.1

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    Malignant lymphoma sometimes involves peripheral nerves due to paraneoplastic syndrome associated with anti-ganglioside antibodies. We report a very rare case of malignant lymphoma accompanied by an asymmetrical and isolated hypoglossal nerve palsy associated with a new subset of anti-ganglioside antibodies. Magnetic resonance imaging and 18F-2-deoxy-2-fluoro-D-glucose position emission tomography showed no abnormalities of the hypoglossal nerve nucleus; however, the patient' s serum was positive for anti-sulfated glucuronyl paragloboside IgM antibodies as well as anti-GM1 IgM and anti-GQ1b IgM antibodies. The present case might suggest a paraneoplastic asymmetrical and isolated hypoglossal nerve palsy associated with a new subset of anti-ganglioside antibodies.

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  • Clinical Benefits of Antioxidative Supplement Twendee X for Mild Cognitive Impairment: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Prospective Interventional Study. Reviewed International journal

    Koh Tadokoro, Ryuta Morihara, Yasuyuki Ohta, Nozomi Hishikawa, Satoko Kawano, Ryo Sasaki, Namiko Matsumoto, Emi Nomura, Yumiko Nakano, Yoshiaki Takahashi, Mami Takemoto, Toru Yamashita, Setsuko Ueno, Yosuke Wakutani, Yoshiki Takao, Nobutoshi Morimoto, Yumiko Kutoku, Yoshihide Sunada, Katsushi Taomoto, Yasuhiro Manabe, Kentaro Deguchi, Yasuto Higashi, Haruhiko Inufusa, Fukka You, Toshikazu Yoshikawa, Markus Matuschka von Greiffenclau, Koji Abe

    Journal of Alzheimer's disease : JAD   71 ( 3 )   1063 - 1069   2019

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    Oxidative stress is part of the entire pathological process that underlies the development of Alzheimer's disease (AD), including the mild cognitive impairment (MCI) stage. Twendee X (TwX) is a supplement containing a strong antioxidative mix of eight antioxidants, which has been shown to have a clinical and therapeutic benefit in AD model mice. Here, we conducted a multicenter, randomized, double-blind, and placebo-controlled prospective interventional study to evaluate the efficacy of TwX in mitigating MCI. The primary outcomes were differences in Mini-Mental State Examination (MMSE) and Hasegawa Dementia Scale-revised (HDS-R) scores between baseline and six months for placebo and TwX groups. Seventy-eight subjects with MCI were randomized into placebo (n = 37) and TwX (n = 41) groups. MMSE scores at six months differed significantly between the TwX and placebo groups (p = 0.018), and HDS-R scores for the TwX group exhibited a significant improvement at six months relative to baseline (p = 0.025). The TwX group did not show any change in affective or activities of daily living scores at six months. The present study indicates that strong antioxidative supplement TwX is clinical beneficial for cognitive function in subjects with MCI.

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  • Acute Anti-Inflammatory Markers ITIH4 and AHSG in Mice Brain of a Novel Alzheimer's Disease Model. Reviewed International journal

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

    Journal of Alzheimer's disease : JAD   68 ( 4 )   1667 - 1675   2019

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    Alzheimer's disease (AD) is the most common dementia and a progressive neurodegenerative disorder aggravated by chronic hypoperfusion (HP). Since numerous evidence suggests that inflammation is related with AD pathology, we investigated the expression change of two anti-inflammatory markers, inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and alpha-2-HS-glycoprotein (AHSG), in a novel AD model (APP23) with HP at 12 month of age. As compared with wild type (WT, n = 10), immunohistochemical analysis showed a higher ITIH4 and a lower AHSG expressions in the cerebral cortex, hippocampus, and thalamus of the APP23 + HP group (n = 12) than the simple APP23 (n = 10) group (*p < 0.05 and **p < 0.01 versus WT; #p < 0.05 and # #p < 0.01 versus APP23). The present study provides an upregulation of anti-inflammatory ITIH4 and a downregulation of pro-inflammatory TNFα-dependent AHSG in a novel AD plus HP mice model.

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  • Clinical and Pathological Benefits of Edaravone for Alzheimer's Disease with Chronic Cerebral Hypoperfusion in a Novel Mouse Model. Reviewed International journal

    Tian Feng, Toru Yamashita, Jingwei Shang, Xiaowen Shi, Yumiko Nakano, Ryuta Morihara, Keiichiro Tsunoda, Emi Nomura, Ryo Sasaki, Koh Tadokoro, Namiko Matsumoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of Alzheimer's disease : JAD   71 ( 1 )   327 - 339   2019

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    Alzheimer's disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis.

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  • GPIHBP1 autoantibody syndrome during interferon β1a treatment

    Jun Eguchi, Kazuya Miyashita, Isamu Fukamachi, Katsuyuki Nakajima, Masami Murakami, Yuko Kawahara, Toru Yamashita, Yasuyuki Ohta, Koji Abe, Atsuko Nakatsuka, Mai Mino, Satoru Takase, Hiroaki Okazaki, Robert A. Hegele, Michael Ploug, Xuchen Hu, Jun Wada, Stephen G. Young, Anne P. Beigneux

    Journal of Clinical Lipidology   13 ( 1 )   62 - 69   2019

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    © 2018 National Lipid Association Background: Autoantibodies against glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1 (GPIHBP1) cause chylomicronemia by blocking the ability of GPIHBP1 to bind lipoprotein lipase (LPL) and transport the enzyme to its site of action in the capillary lumen. Objective: A patient with multiple sclerosis developed chylomicronemia during interferon (IFN) β1a therapy. The chylomicronemia resolved when the IFN β1a therapy was discontinued. Here, we sought to determine whether the drug-induced chylomicronemia was caused by GPIHBP1 autoantibodies. Methods: We tested plasma samples collected during and after IFN β1a therapy for GPIHBP1 autoantibodies (by western blotting and with enzyme-linked immunosorbent assays). We also tested whether the patient's plasma blocked the binding of LPL to GPIHBP1 on GPIHBP1-expressing cells. Results: During IFN β1a therapy, the plasma contained GPIHBP1 autoantibodies, and those autoantibodies blocked GPIHBP1's ability to bind LPL. Thus, the chylomicronemia was because of the GPIHBP1 autoantibody syndrome. Consistent with that diagnosis, the plasma levels of GPIHBP1 and LPL were very low. After IFN β1a therapy was stopped, the plasma triglyceride levels returned to normal, and GPIHBP1 autoantibodies were undetectable. Conclusion: The appearance of GPIHBP1 autoantibodies during IFN β1a therapy caused chylomicronemia. The GPIHBP1 autoantibodies disappeared when the IFN β1a therapy was stopped, and the plasma triglyceride levels fell within the normal range.

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  • A unique case of hemi-tongue pseudohypertrophy, necrotizing myopathy, and erythema nodosum. Reviewed International journal

    Kota Sato, Yoshiaki Takahashi, Toru Yamashita, Mami Takemoto, Nozomi Hishikawa, Shang Jinwei, Yasuyuki Ohta, Koji Abe

    Neurology international   10 ( 4 )   7852 - 7852   2018.12

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    A 46-year-old woman developed slowly progressive tongue weakness with a pseudohypertrophic change on the right side of her tongue. She subsequently developed weakness in her proximal lower extremities, skin erythema and a sustained increase of muscle enzymes at 11 M after the onset. A biopsy of the quadriceps muscle showed necrotizing myopathy and a skin biopsy showed erythema nodosum. The present case showed characteristic clinical manifestations that may represent a rare variant of sarcoidosis.

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  • Neurolymphomatosis in the Cauda Equina Diagnosed by an Open Biopsy. Reviewed

    Ryo Sasaki, Yasuyuki Ohta, Yuto Yamada, Koh Tadokoro, Yoshiaki Takahashi, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Takao Yasuhara, Isao Date, Shuntaro Ikegawa, Nobuharu Fujii, Koji Abe

    Internal medicine (Tokyo, Japan)   57 ( 23 )   3463 - 3465   2018.12

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    Neurolymphomatosis is a rare form of extranodal malignant lymphoma defined as the infiltration of malignant lymphocytes into the central or peripheral nerve. We herein report a case of neurolymphomatosis in the cauda equina diagnosed by an open surgical biopsy. He presented with muscle weakness, atrophy, numbness and hypoesthesia in the bilateral lower extremities with the accumulation of 18fluoro-2-deoxyglucose (FDG) in the bilateral cauda equina. Cerebrospinal fluid cytology (three times) and flow cytometry (two times) and biopsies of the left sural nerve, bone marrow, paranasal sinus and left testis were all negative for malignancy, so finally we performed a surgical open biopsy of the cauda equina by laminectomy and diagnosed him with diffuse large B-cell lymphoma in the cauda equina. He was successfully treated with the disappearance of the FDG accumulation for a long time. The present case suggested that an early open biopsy of the cauda equina may be considered for cases of suspected neurolymphomatosis in the cauda equina for a good outcome.

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  • Neuroprotective effects of SMTP-44D in mice stroke model in relation to neurovascular unit and trophic coupling. Reviewed International journal

    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   2018.12

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    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.

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  • Different clinicopathological features between Japanese siblings with facioscapulohumeral muscular dystrophy 2 with a novel nonsense SMCHD1 mutation (Arg552∗). Reviewed International journal

    Yasuyuki Ohta, Koh Tadokoro, Ryo Sasaki, Yoshiaki Takahashi, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Jingwei Shang, Toru Yamashita, Yasushi Takehisa, Ichizo Nishino, Koji Abe

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia   58   215 - 217   2018.12

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    Facioscapulohumeral muscular dystrophy (FSHD) 2 is caused by a combination of heterozygous structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) mutation plus DNA hypomethylation on D4Z4. Here we report two Japanese FSHD2 siblings (brother and sister) with a new SMCHD1 nonsense mutation (a heterogeneous c. 1654C > T substitution, leading to a stop codon Arg552∗). They showed the typical phenotype of FSHD2 such as asymmetric muscle weakness and atrophy in bilateral facial, scapular and humeral muscles, but different clinicopathological features between them. The brother and asymptomatic mother showed normal D4Z4 methylation plus the same SMCHD1 mutation, but the sister showed the SMCHD1 mutation plus D4Z4 hypomethylation, suggesting an interesting correlation of the new SMCHD1 nonsense mutation and D4Z4 hypomethylation.

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  • Reduction of Ischemia Reperfusion-Related Brain Hemorrhage by Stachybotrys Microspora Triprenyl Phenol-7 in Mice With Antioxidant Effects. Reviewed International journal

    Yong Huang, Yasuyuki Ohta, Jingwei Shang, Xianghong Li, 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 ( 12 )   3521 - 3528   2018.12

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    BACKGROUND: Stachybotrys microspora triprenyl phenol-7 (SMTP-7) has both thrombolytic and anti-inflammatory effects, but its neuroprotective effects on cerebral ischemia are still unclear. The present study assessed the antioxidative and neurovascular unit (NVU) protective effects of SMTP-7 using transient middle cerebral artery occlusion (tMCAO) mice. METHODS: After 60 minutes 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 24 hours after reperfusion. We histologically assessed the hemorrhage and expressive changes of antioxidative markers in brains. RESULTS: SMTP-7 treatment showed a similar antithrombotic effect to tPA, but significantly decreased the hemorrhage volumes and the number of 4-HNE, 3-NT and 8-OHdG positive cells, meanwhile, ameliorated the decrease of collagen IV in the ischemic brains. However, tPA + SMTP-7 treatment did not decrease hemorrhage volumes nor showed NVU protective effect. CONCLUSIONS: The present study suggested that SMTP-7 provided therapeutic benefits for ischemic stroke through antioxidative and NVU protective effects unlike tPA alone or tPA + SMTP-7.

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  • Cervical compressive myelopathy caused by malfunction of a programmable cerebrospinal fluid shunt valve

    Kota Sato, Toru Yamashita, Keichiro Tsunoda, Mami Takemoto, Nozomi Hishikawa, Jinwei Shang, Yasuyuki Ohta, Ken Kuwahara, Takao Yasuhara, Isao Date, Koji Abe

    INTERDISCIPLINARY NEUROSURGERY-ADVANCED TECHNIQUES AND CASE MANAGEMENT   14   183 - 185   2018.12

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    The primary treatment for hydrocephalus is ventricular shunt placement, and a programmable valve is widely used for ventriculoperitoneal (VP) shunt surgery to reduce over/under drainage of cerebrospinal fluid (CSF). Here, we report a rare case of a patient who developed successive VP shunt malfunction causing spastic muscle weakness in extremities associated cervical epidural venous distension and compressive myelopathy due to over-drainage of CSF through a defective VP shunt valve a decade after the initial shunt was placed. One should be aware and cognizant of this complication and carefully follow the symptoms and potentially utilize brain MRI with and without contrast to look at over drainage stigmata to avoid the development of neurological complications.

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  • Antineuroinflammatory Effect of SMTP-7 in Ischemic Mice. Reviewed International journal

    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   2018.11

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    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.

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  • A case of aspergillotic orbital apex syndrome diagnosed by an additional intraorbital biopsy after nasal endoscopy

    Namiko Matsumoto, Kota Sato, Koh Tadokoro, Yoshiaki Takahashi, Taijun Yunoki, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Kentaro Fujii, Tomotsugu Ichikawa, Isao Date, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 6 )   188 - 190   2018.11

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    The prompt and accurate diagnosis of orbital apex syndrome (OAS) is very important because of its fatality. Here we report an old man with aspergillotic OAS diagnosed after two biopsies by nasal endoscopy and craniotomy. Only craniotomy leads to the appropriate diagnosis, suggesting an immediate need of additional biopsy for the accurate diagnosis and saving the patient.

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  • Congenital myopathy with fiber-type disproportion accompanied by dilated cardiomyopathy in a patient with a novel p.G48A ACTA1 mutation. Reviewed International journal

    Koh Tadokoro, Yasuyuki Ohta, Ryo Sasaki, Yoshiaki Takahashi, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Kazufumi Nakamura, Ichizo Nishino, Koji Abe

    Journal of the neurological sciences   393   142 - 144   2018.10

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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. Reviewed International journal

    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   2018.10

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    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.

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  • Protective effect of a novel sigma-1 receptor agonist is associated with reduced endoplasmic reticulum stress in stroke male mice. Reviewed International journal

    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   2018.10

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    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.

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  • Affective improvement of neurological disease patients and caregivers using an automated telephone call service. Reviewed International journal

    Yasuyuki Ohta, Toru Yamashita, Nozomi Hishikawa, Kota Sato, Noriko Hatanaka, Mami Takemoto, Shinji Doutare, Koji Abe

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia   56   74 - 78   2018.10

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    Neurological disease patients living alone or with a single caregiver need a support system to care for their psychological symptoms. We evaluated the clinical effects of a unique telephone call system that automatically called participants at their desired times once a week for 3 months. In total, 104 neurological disease patients and caregivers were evaluated by the geriatric depression scale, apathy scale and state and trait anxiety inventories (STAI) forms X-I for depression, apathy and state anxiety, respectively. High baseline STAI scores (40≥) significantly improved in the Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and spinocerebellar degeneration (SCD) + multiple system atrophy (MSA) patients (p = 0.001, p = 0.013 and p = 0.046, respectively) after patients/caregivers used the telephone call service. The baseline (pre) STAI score significantly correlated with the score change (post-pre) in PD, ALS, SCD + MSA, Alzheimer' s disease patients (ADp), and caregivers for ADp (p < 0.0001, p = 0.001, p = 0.011, p = 0.025 and p = 0.020, respectively). The geriatric depression scale and apathy scale did not significantly improve. The present study suggests that there is a positive effect of using an automated telephone call service for anxiety in neurological disease patients and caregivers, especially in ALS, SCD + MSA and PD patients with high STAI scores (40≥).

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  • Rare valiant vertical one-and-a-half syndrome without ipsilateral upward gaze palsy in a patient with thalamomesencephalic stroke Reviewed International journal

    Kota Sato, Yoshiaki Takahashi, Namiko Matsumoto, Taijun Yunoki, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 5 )   133 - 135   2018.9

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    Bilateral upward and ipsilateral downward gaze palsy due to a unilateral thalamomesencephalic stroke is called vertical one-and-a-half syndrome (VOHS). Here, we report a valiant VOHS case who presented contralateral upward and ipsilateral downward gaze palsy due to a unilateral thalamomesencephalic stroke. The neuronal fiber connections associated with vertical gaze are not completely understood, so the present case provides an important proof to obtain a better understanding of vertical gaze mechanisms.

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  • Vogt-Koyanagi-Harada case accompanied by polyneuropathy

    Keiichiro Tsunoda, Yasuyuki Ohta, Koh Tadokoro, Ryo Sasaki, Yoshiaki Takahashi, Kota Sato, Emi Nomura, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Ai Kajita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 5 )   138 - 140   2018.9

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    Vogt-Koyanagi-Harada disease (VKHD) is a systemic autoimmune disease that targets melanocyte-rich tissues such as eye, central nervous system, inner ear, and skin. Here, we report a case of VKHD accompanied by polyneuropathy. After VKHD was diagnosed, depending on the involvement of bilateral ocular, auditory, and central nervous systems, he expressed muscle weakness, pain, and numbness in bilateral lower extremities. Nerve conduction studies suggested sensorimotor polyneuropathy, while a skin, muscle, and nerve biopsy suggested vasculitis. Steroid therapy improved his symptoms. The present case might suggest a relationship between VKHD and polyneuropathy.

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

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

    Internal medicine (Tokyo, Japan)   57 ( 16 )   2399 - 2402   2018.8

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    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.

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  • A Japanese Encephalitis Patient Presenting with Parkinsonism with Corresponding Laterality of Magnetic Resonance and Dopamine Transporter Imaging Findings. Reviewed

    Koh Tadokoro, Yasuyuki Ohta, Kota Sato, Takahiro Maeki, Ryo Sasaki, Yoshiaki Takahashi, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Chang Kweng Lim, Shigeru Tajima, Koji Abe

    Internal medicine (Tokyo, Japan)   57 ( 15 )   2243 - 2246   2018.8

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    Japanese encephalitis (JE) survivors often present with nigrostriatal aftereffects with parkinsonian features. A 67-year-old woman with JE showed right-dominant clinical parkinsonism and left-dominant substantia nigra lesions after magnetic resonance imaging (MRI). Dopamine transporter (DAT) imaging using 123I-labeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane (123I-FP-CIT) revealed a corresponding left-dominant decrease. The present case is the first to reveal a clear match of laterality between clinical parkinsonism, MRI-based substantia nigra lesions, and impaired DAT in presynaptic dopaminergic neurons in JE.

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  • Therapeutic Effects of Pretreatment with Tocovid on Oxidative Stress in Postischemic Mice Brain. Reviewed International journal

    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   2018.8

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    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.

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  • Detecting spinal pyramidal tract of amyotrophic lateral sclerosis patients with diffusion tensor tractography. Reviewed International journal

    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   2018.8

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    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. Reviewed International journal

    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   2018.8

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    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.

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  • Two cases of late onset familial amyloid polyneuropathy with a Glu61Lys transthyretin variant. Reviewed International journal

    Yumiko Nakano, Koh Tadokoro, Yasuyuki Ohta, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Taro Yamashita, Yukio Ando, Koji Abe

    Journal of the neurological sciences   390   22 - 25   2018.7

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  • A new familial distal myopathy in Japan with predominant upper extremities. Reviewed International journal

    Yoshiaki Takahashi, Yasuyuki Ohta, Ryo Sasaki, Kou Tadokoro, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Ichizo Nishino, Koji Abe

    Journal of the neurological sciences   390   205 - 207   2018.7

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  • Fulminant Guillain-Barre syndrome with Takotsubo cardiomyopathy: Report of an autopsied case

    Mami Takemoto, Toru Yamashita, Yasuyuki Ohta, Nozomi Hishikawa, Kota Sato, Keiichiro Tsunoda, Jingwei Shang, Kentaro Deguchi, Takehiro Tanaka, Hirotake Nishimura, Masumi Furutani, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 4 )   117 - 119   2018.7

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    We report a case of a 77-year-old Japanese man with a fever of up to 39.0 degrees C, which subsided after 5 days. The patient showed fulminant Guillain-Barre syndrome (GBS), severe autonomic dysfunction with a labile blood pressure, an unstable heart rate from onset to death, and Takotsubo cardiomyopathy. Although Takotsubo cardiomyopathy was ameliorated by Day 14 (from admission in the hospital) with a normalized electrocardiogram, his blood pressure became markedly more variable and he died on Day 26. In the present report, we describe an autopsied case of GBS with Takotsubo cardiomyopathy.

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  • A unique telephone support system for dementia patients and their caregivers managed in Japan (Okayama Dementia Call Center, ODCC)

    Yumiko Nakano, Nozomi Hishikawa, Keiko Sakamoto, Yoko Myoraku, Yoshinori Ozaki, Mami Takemoto, Kota Sato, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 4 )   100 - 103   2018.7

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    Background: Despite a rapidly increasing prevalence of dementia, social support systems for dementia patients and their caregivers are insufficient.Aim: To investigate a telephone support system for dementia patients and their caregivers managed by a local public association, the Okayama Dementia Call Center (ODCC).Methods: A total of 1485 phone calls were retrospectively surveyed over 4 years (from June 2011 to May 2014) and were divided into four annual periods.Results: The average consulting time of each of the 1485 phone calls was 20.2 14.7 min. The chief complaint was distress related to dementia symptoms (56.2%), mainly from the children (66.7%) and spouses (17.5%) of dementia patients. With respect to management of ODCC for these clients, the proportion of providing advice has decreased (66.1 to 47.7%) as that of listening time increased (22.7 to 46.1%).Conclusion: The present unique telephone call system (ODCC) may supplement an insufficient social support, and may play an important role in the community care system, enabling people with dementia to live comfortably in their local community.

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  • Clinical predictors of Alzheimer's disease progression. Reviewed

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

    Geriatrics & gerontology international   18 ( 6 )   929 - 936   2018.6

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    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.

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  • A mild myopathy with anti-SRP plus anti-PL-12 antibodies successfully treated by oral steroid monotherapy. Reviewed International journal

    Koh Tadokoro, Yasuyuki Ohta, Ryo Sasaki, Yoshiaki Takahashi, Kota Sato, Jingwei Shang, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Keigo Hayashi, Michiko Morishita, Ichizo Nishino, Koji Abe

    Journal of the neurological sciences   388   7 - 9   2018.5

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  • Anti-MuSK Antibody-positive Myasthenia Gravis Successfully Treated with Outpatient Periodic Weekly Blood Purification Therapy. Reviewed

    Kentaro Deguchi, Kosuke Matsuzono, Yumiko Nakano, Syoichiro Kono, Kota Sato, Shoko Deguchi, Katsuyuki Tanabe, Nozomi Hishikawa, Yasuyuki Ota, Toru Yamashita, Kiyoe Ohta, Masakatsu Motomura, Koji Abe

    Internal medicine (Tokyo, Japan)   57 ( 10 )   1455 - 1458   2018.5

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    A 37-year-old man with anti-muscle-specific tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG) presented with subacute progressive dysphagia and muscle weakness of the neck and bilateral upper extremities. Conventional immune-suppressive treatments and high-dose intravenous immunoglobulin were ineffective. He then displayed repeated exacerbations and remissions over the course of two years, despite two to four sessions of plasma exchange (PE) every two months. The patient was successfully treated with outpatient periodic weekly blood purification therapy with alternative PE and double-filtration plasmapheresis using an internal shunt. This case report suggests the benefits of blood purification therapy with an internal shunt against anti-MuSK antibody-positive MG.

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  • A case of bilateral internal carotid artery dissection in young adult with cranial nerve IX and X palsies

    Ryo Sasaki, Toru Yamashita, Yoshiaki Takahashi, Jingwei Shang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 3 )   80 - 82   2018.5

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    Internal carotid artery (ICA) dissection is a major cause of cerebral infarction in young adult and usually presents cervical pain and headache, but rarely presents cranial nerve palsy. Here, we report a case of rare bilateral ICA dissections in young adult with cranial nerve IX and X palsies as initial symptom. He presented dysarthria and nasal voice at an early stage, followed by a small brain infarction. The cranial nerve palsy was improved in parallel with the improvement of ICA stenosis and dilatation. It is important to know that cranial nerve palsy can be one of the symptoms of ICA dissection for appropriate treatment.

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  • Case of acromegalic myopathy and arthropathy long after trans-sphenoidal surgery

    Ryo Sasaki, Toru Yamashita, Yoshiaki Takahashi, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 3 )   77 - 79   2018.5

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    Acromegaly patients usually show impaired vision, the enlargement of hands and feet, heart failure, and diabetes and rarely show myopathy (weakness and muscle pain) and arthropathy (joint pain). Here, we report an acromegaly patient who showed progressive myopathy and arthropathy long after a Hardy operation. The symptoms of myopathy and arthropathy occurred under normal GH and high IGF-1 levels, but these symptoms improved when the IGF-1 level was normalized by a treatment of octreotide with an increased dose of 30-40 mg. Thus, strict and immediate control of IGH-1 may be pivotally important to prevent and treat acromegalic myopathy and arthropathy.

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

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

    Journal of the neurological sciences   387   166 - 169   2018.4

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  • Familial and sporadic chronic progressive degenerative parietal ataxia. Reviewed International journal

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

    Journal of the neurological sciences   387   70 - 74   2018.4

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

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  • Accelerating Cell Therapy for Stroke in Japan: Regulatory Framework and Guidelines on Development of Cell-Based Products. Reviewed International journal

    Kiyohiro Houkin, Hideo Shichinohe, Koji Abe, Teruyo Arato, Mari Dezawa, Osamu Honmou, Nobutaka Horie, Yasuo Katayama, Kohsuke Kudo, Satoshi Kuroda, Tomohiro Matsuyama, Ichiro Miyai, Izumi Nagata, Kuniyasu Niizuma, Ken Sakushima, Masanori Sasaki, Norihiro Sato, Kenji Sawanobori, Satoshi Suda, Akihiko Taguchi, Teiji Tominaga, Haruko Yamamoto, Toru Yamashita, Toshiki Yoshimine

    Stroke   49 ( 4 )   e145-e152   2018.4

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  • Case of congenital fibrosis of the extraocular muscles type 1 with progressive cerebellar ataxia

    Toru Yamashita, Yoshiaki Takahashi, Keiichiro Tsunoda, Emi Nomura, Jingwei Shang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 2 )   48 - 50   2018.3

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    A 70-year-old women presented classical CEFOM1 phenotypes such as bilateral ptosis and external ophthalmoplegia, but also progressive cerebellar ataxia, carrying a previously reported heterozygous missense mutation of KIF21A p.Arg941Gln. The present case is the first report of CFEOM1 showing cerebellar atrophy with hypoperfusion, mainly of the vermis, indicating that cerebellar function should be carefully evaluated in CFFOM1 patients.

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  • Transarterial chemoembolization with miriplatin vs. epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial. Reviewed

    Masafumi Ikeda, Masatoshi Kudo, Hiroshi Aikata, Hiroaki Nagamatsu, Hiroshi Ishii, Osamu Yokosuka, Takuji Torimura, Manabu Morimoto, Kenji Ikeda, Hiromitsu Kumada, Tosiya Sato, Ikuko Kawai, Toru Yamashita, Hiroshi Horio, Takuji Okusaka

    Journal of gastroenterology   53 ( 2 )   281 - 290   2018.2

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    BACKGROUND: This prospective study investigated the superiority of transarterial chemoembolization (TACE) with miriplatin over TACE with epirubicin regarding overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). METHODS: Patients with unresectable HCC were randomized 1:1 to receive TACE with miriplatin or epirubicin in lipiodol. The primary endpoint was OS; secondary endpoints were percentages of patients who achieved treatment effect (TE) 4 (100% necrotizing effect or tumor reduction), duration of time to TACE failure, and adverse events (AEs). OS was compared using a stratified log-rank test adjusted for clinical stage, Child-Pugh class, and institution. RESULTS: Of 257 patients enrolled from August 2008 to August 2010, 247 were analyzed for efficacy and toxicity (miriplatin, n = 124; epirubicin, n = 123). Baseline characteristics were well balanced between the two groups. Median OS times were 1111 days for miriplatin and 1127 days for epirubicin (adjusted hazard ratio 1.01, 95% confidence interval 0.73-1.40, P = 0.946). TE4 rates were 44.4% for miriplatin and 37.4% for epirubicin. Median times to TACE failure were 365.5 days for miriplatin and 414.0 days for epirubicin. AEs of grade 3 or higher, including elevated aspartate aminotransferase (miriplatin, 39.5%; epirubicin, 57.7%) and elevated alanine aminotransferase (miriplatin, 31.5%; epirubicin, 53.7%), were less frequent in the miriplatin than the epirubicin group. CONCLUSIONS: OS after TACE with miriplatin was not superior to that after TACE with epirubicin; however, hepatic AEs were less frequent with miriplatin. CLINICAL TRIAL REGISTRATION: JapicCTI-080632.

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  • Different Associations of Plasma Biomarkers in Alzheimer's Disease, Mild Cognitive Impairment, Vascular Dementia, and Ischemic Stroke. Reviewed International journal

    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   2018.1

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    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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  • Emergency ventricular drainage plus systemic antibiotics saved an elderly patient with intraventricular rupture as a result of a pituitary abscess

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

    NEUROLOGY AND CLINICAL NEUROSCIENCE   6 ( 1 )   13 - 15   2018.1

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    A pituitary abscess is a rare intracranial infection, and direct transsphenoidal surgery is common for the therapy. Intracranial rupture of the pituitary abscess is usually fatal. Here, we report a 76-year-old woman with a pituitary abscess who showed headaches, left eyelid ptosis, periorbital swelling and external eye movement disturbances in the left eye. Although her symptoms initially improved after therapy with systemic antibiotics, the pituitary abscess suddenly developed an intraventricular rupture on admission day 27. However, emergency ventricular drainage in combination with different antibiotics gradually improved her condition. The present case suggests that the combination of emergency ventricular drainage and systemic antibiotic administration could serve as an alternative choice to manage pituitary abscesses of ventricular ruptures, especially in elderly patients.

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  • Emergency Caesarean Section Saved Both an Anti-MuSK Antibody-positive Myasthenia Gravis Mother with Pregnancy-induced Hypertension and Her Premature Baby. Reviewed

    Yoshiaki Takahashi, Toru Yamashita, Ryuta Morihara, Yumiko Nakano, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Kei Hayata, Hisashi Masuyama, Tomoka Okamura, Yosuke Washio, Koji Abe

    Internal medicine (Tokyo, Japan)   56 ( 24 )   3361 - 3364   2017.12

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    We herein report the case of a 46-year-old pregnant woman with anti-muscle specific kinase (MuSK) antibody-positive myasthenia gravis (MG) who showed pregnancy-induced hypertension and developed respiratory failure at 30 weeks and 5 days of pregnancy, and who underwent an emergency caesarean section (CS). Her MG symptoms gradually improved in the subsequent weeks. The premature baby with positive MuSK antibodies was successfully delivered, but the male baby required temporary artificial ventilation. However, his condition also gradually improved over time. The present case suggests that an emergency CS could rescue both the mother, who was in critical condition, and the prematurely born baby, even when suffering from acute respiratory insufficiency.

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  • A migration case of Kii amyotrophic lateral sclerosis/parkinsonism dementia complex with the shortest stay in the endemic area and the longest incubation to develop the disease. Reviewed International journal

    Keiichiro Tsunoda, Toru Yamashita, Hitoshi Shimada, Emi Nomura, Yoshiaki Takahashi, Jingwei Shang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Makoto Higuchi, Tetsuya Suhara, Yasumasa Kokubo, Shigeki Kuzuhara, Koji Abe

    Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia   46   64 - 67   2017.12

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    Amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) is an endemic disease observed in the Kii peninsula, Guam, and Papua. We report a case of a 76-year old man with ALS/PDC of the Kii peninsula of Japan (Kii ALS/PDC). The patient was born and grew up in the Kii peninsula. He moved out at age three, and developed symptoms 73years later. He showed pyramidal sign, parkinsonian symptoms, and mildly impaired cognitive function. 131I-metaiodobenzylguanidine myocardial scintigraphy showed decreased cardiac sympathetic nerve function, and dopamine transporter single photon emission computed tomography imaging showed decreased 123I-N-ω-fluoropropyl-2β-carbomethoxy3β-(4-iodophenyl) nortropane accumulation. Cerebral blood flow showed hypoperfusion. Positron emission tomography showed widespread tau deposition in his brain. This is a migration case of Kii ALS/PDC with the shortest stay in the endemic area and the longest delay to develop the disease, indicating a genetic factor for the disease development in a considerable degree.

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  • Therapeutic effects of drug switching between acetylcholinesterase inhibitors in patients with Alzheimer's disease. Reviewed

    Yasuyuki Ohta, Mohamed Darwish, Nozomi Hishikawa, Toru Yamashita, Kota Sato, Mami Takemoto, Koji Abe

    Geriatrics & gerontology international   17 ( 11 )   1843 - 1848   2017.11

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    AIM: To evaluate the therapeutic effects of switching from one acetylcholinesterase inhibitor (ChEI), donepezil, galantamine or rivastigmine, to another in Alzheimer's disease patients. METHODS: We retrospectively enrolled 171 Alzheimer's disease patients, whose ChEI medication was changed. The patients were evaluated on three major aspects of dementia - cognitive, affective and activities of daily living (ADL) measures - at 6 months (M) before the drug switch, at the time of drug switch (baseline), and at 3 M and 6 M after the drug switch. RESULTS: The doses of the three ChEI were significantly lower at 6 M after the switch compared with the pre-switch doses. Improvements in apathy were found at 3 M when switching from donepezil to galantamine, but not to rivastigmine, but this switch had adverse effects on ADL. Improvements in cognitive scores at 3 M were also found when switching from galantamine to rivastigmine, but not to donepezil. However, both of these changes improved Abe's Behavioral and Psychological Symptoms of Dementia scores (ABS), except ADL. Switching from rivastigmine to donepezil worsened ABS at 6 M, but preserved cognitive and ADL scores. CONCLUSIONS: The present study suggests that despite a relatively lower dose of ChEI after the switch, switching from donepezil or rivastigmine preserved cognitive functions for at least 6 M. Switching from galantamine to rivastigmine improved Mini-Mental State Examination and ABS at 3 M, but did not improve ADL scores. Geriatr Gerontol Int 2017; 17: 1843-1848.

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

    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   2017.11

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    AIM: To 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. METHODS: A 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. RESULTS: The 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 < 0.05), and galantamine at 9 months (P < 0.01). In the PVH II subgroup, the Mini-Mental State Examination showed a significant improvement from the baseline in response to galantamine (P < 0.05) at 9 months and Hasegawa Dementia Scale-Revised (P < 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 < 0.05). CONCLUSIONS: The 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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  • Type 2 Alexander disease with a novel glial fibrillary acidic protein gene mutation and its unique clinical features

    Yuko Kawahara, Toru Yamashita, Yasuyuki Ohta, Kota Sato, Emi Nomura, Mami Takemoto, Nozomi Hishikawa, Jingwei Shang, Tomokatsu Yoshida, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 6 )   183 - 185   2017.11

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    We report mother-daughter cases of type 2 Alexander disease with a novel glial fibrillary acidic protein gene mutation. The mother (proband) began to show slowly progressive gait disturbance. However, after an incidental medical checkup, it took just 9 months for the diagnosis. Different from the previous reports, she showed a unique phenotype in points of scoliosis without palatal myoclonus, decreased regional cerebral blood flow in the frontal lobe and mild cognitive impairment. Her second daughter showed mild intellectual disability. Genetic analysis of the mother and the second daughter showed the same novel glial fibrillary acidic protein gene mutation (c.371_372insAGA).

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  • Japanese sibling cases of multiple sclerosis presenting with different clinical phenotypes

    Kota Sato, Yasuyuki Ohta, Toru Yamashita, Keiichiro Tsunoda, Kentaro Deguchi, Mami Takemoto, Nozomi Hishikawa, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 6 )   186 - 188   2017.11

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    Unlike in Western countries, only a few familial multiple sclerosis cases have been reported from Asian countries. Herein, we report on the characteristics of siblings with multiple sclerosis. Their parents were consanguineous, and the siblings showed different first symptoms of gait disturbance or double vision, with a clinical phenotype of primary progressive multiple sclerosis or relapse-remitting multiple sclerosis. Their human leukocyte antigen showed unique subtypes of DPB1 (0501/0901 or 0901/0901) and DRB1 (0406/1502 or 1502/1502).

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  • Serious hyponatremia induced by a combination of angiotensin II receptor blocker and thiazide caused deterioration of cognitive functions and psychological symptoms in an elderly Alzheimer's disease patient

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

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 6 )   192 - 194   2017.11

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    As the number of elderly people increases, Alzheimer's disease and hypertension have become more common. This is an important case report that shows severe hyponatremia induced by a combination of angiotensin II receptor blocker and thiazide, causing the deterioration of cognitive functions in an elderly patient. In rapidly aging societies around the world, more attention should be paid to hyponatremia under combination therapy of angiotensin II receptor blocker plus thiazide to assist elderly patients.

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  • Behavioral and affective features of amyotrophic lateral sclerosis patients. Reviewed International journal

    Yasuyuki Ohta, Kota Sato, Mami Takemoto, Yoshiaki Takahashi, Ryuta Morihara, Yumiko Nakano, Keiichiro Tsunoda, Emi Nomura, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    Journal of the neurological sciences   381   119 - 125   2017.10

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    Evaluating the cognitive and behavioral features in amyotrophic lateral sclerosis (ALS) patients is important for therapy and care. Fifty-seven ALS, 5 ALS with the behavioral variant of frontotemporal dementia (FTD) (ALS-FTD), 12 FTD patients, and 35 control subjects were evaluated by 10 different tests for cognitive and behavioral (mini-mental state examination (MMSE), Hasegawa dementia rating scale - revised (HDS-R), frontal assessment battery (FAB), Montreal cognitive assessment (MoCA), ALS-frontotemporal dementia-Questionnaire (ALS-FTD-Q), and anosognosia scale), affective (depression, apathy, and behavioral and psychological symptoms of dementia (BPSD)), and activities of daily living (ADL) assessments. The motor functions of ALS patients were evaluated by ALS functional rating scale - revised (ALSFRS-R) and modified Norris scale. ALS-FTD-Q scores showed intermediate behavioral disturbances of ALS patients between ALS-FTD and FTD patients and control subjects, but FAB, MoCA, and anosognosia scales did not. Both FAB and MoCA scores were significantly correlated with MMSE and HDS-R in ALS patients, but ALS-FTD-Q was not. ALS-FTD-Q score was significantly correlated with ALSFRS-R, apathy, BPSD, and ADL scores in ALS patients. Thus, in ALS patients, both FAB and MoCA tests were useful to assess frontal cognitive impairments, while ALS-FTD-Q was useful to detect mild behavioral and affective disturbances.

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  • Time-dependent change of in vivo optical imaging of oxidative stress in a mouse stroke model. Reviewed International journal

    Yumiko Nakano, Toru Yamashita, Qian Li, Kota Sato, Yasuyuki Ohta, Ryuta Morihara, Nozomi Hishikawa, Koji Abe

    Journal of neuroscience research   95 ( 10 )   2030 - 2039   2017.10

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    Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a pivotal role in cellular defense against oxidative stress damage after ischemic stroke. In the present study, we examined the time-dependent change of in vivo optical imaging of oxidative stress after stroke with Keap1-dependent oxidative stress detector (OKD) mice. OKD mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 45 min, and in vivo optical signals were detected during the pre-operative period, 12 h, 1 d, 3 d, and 7 d after tMCAO. Ex vivo imaging was performed immediately after obtaining in vivo optical signals at 1 d after tMCAO. Immunohistochemical analyses and infarct volume were also examined after in vivo imaging at each period. The in vivo signals showed a peak at 1 d after tMCAO that was slightly correlated to infarct volume. The strong ex vivo signals, which were detected in the peri-ischemic area, corresponded to endogenous Nrf2 expression. Moreover, endogenous Nrf2 expression was detected mainly in neurons followed by oligodendrocytes and pericytes, but only slightly in astrocytes, microglia, endothelial cells. The present study successfully demonstrated the temporal change of in vivo imaging of oxidative stress after tMCAO, which is consistent with strong expression of endogenous Nrf2 in the peri-ischemic area with a similar time course. © 2017 Wiley Periodicals, Inc.

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  • Comprehensive effects of galantamine and cilostazol combination therapy on patients with Alzheimer's disease with asymptomatic lacunar infarction. Reviewed

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

    Geriatrics & gerontology international   17 ( 10 )   1384 - 1391   2017.10

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    AIM: The coexistence of Alzheimer's disease (AD) and cerebrovascular disease pathology increases age-dependently. We 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 (n = 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 [M] 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. Geriatr Gerontol Int 2017; 17: 1384-1391.

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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

    菱川 望, 福井 裕介, 佐藤 恒太, 太田 康之, 山下 徹, 阿部 康二

    日本老年医学会雑誌   54 ( 4 )   623 - 623   2017.10

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  • Antisense Oligonucleotides Reduce RNA Foci in Spinocerebellar Ataxia 36 Patient iPSCs. Reviewed International journal

    Kosuke Matsuzono, Keiko Imamura, Nagahisa Murakami, Kayoko Tsukita, Takuya Yamamoto, Yuishin Izumi, Ryuji Kaji, Yasuyuki Ohta, Toru Yamashita, Koji Abe, Haruhisa Inoue

    Molecular therapy. Nucleic acids   8   211 - 219   2017.9

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    Spinocerebellar ataxia type 36 is a late-onset, slowly progressive cerebellar syndrome with motor neuron degeneration that is caused by expansions of a hexanucleotide repeat (GGCCTG) in the noncoding region of NOP56 gene, with a histopathological feature of RNA foci formation in postmortem tissues. Here, we report a cellular model using the spinocerebellar ataxia type 36 patient induced pluripotent stem cells (iPSCs). We generated iPSCs from spinocerebellar ataxia type 36 patients and differentiated them into neurons. The number of RNA-foci-positive cells was increased in patient iPSCs and iPSC-derived neurons. Treatment of the 2'-O, 4'-C-ethylene-bridged nucleic acid antisense oligonucleotides (ASOs) targeting NOP56 pre-mRNA reduced RNA-foci-positive cells to ∼50% in patient iPSCs and iPSC-derived neurons. NOP56 mRNA expression levels were lower in patient iPSCs and iPSC-derived neurons than in healthy control neurons. One of the ASOs reduced the number of RNA-foci-positive cells without altering NOP56 mRNA expression levels in patient iPSCs and iPSC-derived neurons. These data show that iPSCs from spinocerebellar ataxia type 36 patients can be useful for evaluating the effects of ASOs toward GGCCTG repeat expansion in spinocerebellar ataxia type 36.

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  • Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) with Limbic Encephalitis. Reviewed

    Yasuyuki Ohta, Emi Nomura, Keiichiro Tsunoda, Toru Yamashita, Yoshiaki Takahashi, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Koji Abe

    Internal medicine (Tokyo, Japan)   56 ( 18 )   2513 - 2518   2017.9

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    Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder that mainly involves in the brainstem, basal ganglia and cerebellum. We herein report the case of a patient with CLIPPERS, which was diagnosed based on the clinical and radiological features. After initially responded to steroid treatment, the patient developed limbic encephalitis. The patient presented with memory disturbance, a delirious state and emotional incontinence. A cerebrospinal fluid study revealed interleukin-6 elevation and enhanced bilateral hippocampal lesions were observed on MRI. The patient was successfully treated with methylprednisolone pulse therapy. This is the first case of CLIPPERS with limbic encephalitis involving the bilateral hippocampus.

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  • Successful Delayed Aortic Surgery for a Patient with Ischemic Stroke Secondary to Aortic Dissection. Reviewed

    Ryuta Morihara, Toru Yamashita, Kentaro Deguchi, Keiichiro Tsunoda, Yasuhiro Manabe, Yoshiaki Takahashi, Taijun Yunoki, Kota Sato, Yumiko Nakano, Syoichiro Kono, Yasuyuki Ohta, Nozomi Hishikawa, Koji Abe

    Internal medicine (Tokyo, Japan)   56 ( 17 )   2343 - 2346   2017.9

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    The diagnosis of aortic dissection (AD) is sometimes difficult within the limited time window of recombinant tissue plasminogen activator (tPA) for ischemic stroke (IS). A 60-year-old man developed sudden left hemiparesis due to IS. During tPA infusion, his blood pressure dropped and consciousness declined. After transfer to our hospital, carotid duplex ultrasonography led to a diagnosis of AD. Emergency surgery was postponed because of the risk of hemorrhagic transformation. The patient successfully underwent aortic surgery on day 5 and was discharged with a remarkable improvement in his symptoms. Delayed surgery may avoid hemorrhagic transformation in patients with AD-induced IS who have received tPA.

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  • Reduction of intracerebral hemorrhage by rivaroxaban after tPA thrombolysis is associated with downregulation of PAR-1 and PAR-2. Reviewed International journal

    Ryuta Morihara, Toru Yamashita, Syoichiro Kono, Jingwei Shang, Yumiko Nakano, Kota Sato, Nozomi Hishikawa, Yasuyuki Ohta, Stefan Heitmeier, Elisabeth Perzborn, Koji Abe

    Journal of neuroscience research   95 ( 9 )   1818 - 1828   2017.9

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    This study aimed to assess the risk of intracerebral hemorrhage (ICH) after tissue-type plasminogen activator (tPA) treatment in rivaroxaban compared with warfarin-pretreated male Wistar rat brain after ischemia in relation to activation profiles of protease-activated receptor-1, -2, -3, and -4 (PAR-1, -2, -3, and -4). After pretreatment with warfarin (0.2 mg/kg/day), low-dose rivaroxaban (60 mg/kg/day), high-dose rivaroxaban (120 mg/kg/day), or vehicle for 14 days, transient middle cerebral artery occlusion was induced for 90 min, followed by reperfusion with tPA (10 mg/kg/10 ml). Infarct volume, hemorrhagic volume, immunoglobulin G leakage, and blood parameters were examined. Twenty-four hours after reperfusion, immunohistochemistry for PARs was performed in brain sections. ICH volume was increased in the warfarin-pretreated group compared with the rivaroxaban-treated group. PAR-1, -2, -3, and -4 were widely expressed in the normal brain, and their levels were increased in the ischemic brain, especially in the peri-ischemic lesion. Warfarin pretreatment enhanced the expression of PAR-1 and PAR-2 in the peri-ischemic lesion, whereas rivaroxaban pretreatment did not. The present study shows a lower risk of brain hemorrhage in rivaroxaban-pretreated compared with warfarin-pretreated rats following tPA administration to the ischemic brain. It is suggested that the relative downregulation of PAR-1 and PAR-2 by rivaroxaban compared with warfarin pretreatment might be partly involved in the mechanism of reduced hemorrhagic complications in patients receiving rivaroxaban in clinical trials. © 2016 Wiley Periodicals, Inc.

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  • Dynamic mislocalizations of nuclear pore complex proteins after focal cerebral ischemia in rat. Reviewed International journal

    Qian Li, Yasuyuki Ohta, Toru Yamashita, Jingwei Shang, Kentaro Deguchi, Tian Feng, Kota Sato, Nozomi Hishikawa, Yumiko Nakano, Koji Abe

    Journal of neuroscience research   95 ( 9 )   1745 - 1759   2017.9

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    Nuclear pore complexes (NPCs) play an important role in coordinating the transport of proteins and nucleic acids between the nucleus and cytoplasm, and are therefore essential for maintaining normal cellular function and liability. In the present study, we investigated the temporal immunohistochemical distribution of five representative components of NPCs-Ran GTPase-activating protein 1 (RanGap1), glycoprotein-210 (Gp210), nucleoporin 205 (Nup205), nucleoporin 107 (Nup107), and nucleoporin 50 (Nup50)-after 90 min of transient middle cerebral artery occlusion (tMCAO) up to 28 days after the reperfusion in rat brains. Single immunohistochemical analyses showed ring-like stainings along the periphery of the nucleus in sham control brains. After tMCAO, Gp210 and Nup107 immunoreactivity continuously increased from 1 day, and RanGap1, Nup205, and Nup50 increased from 2 days until 28 days, which also displayed progressive precipitations within the nucleus in the peri-ischemic area, while the ischemic core showed scarce expression with collapsed structure. Double immunofluorescent analyses revealed nuclear retention and apparent colocalization of RanGap1 with Nup205, Gp210 with Nup205, and partial colocalization of Nup205 with Nup107; most of the ischemic changes above were similar to those observed in patients with C9orf72-genetic amyotrophic lateral sclerosis. Taken together, these observations suggest that the mislocalization of these nucleoporins may be a common pathogenesis of both ischemic and neurodegenerative disease. © 2016 Wiley Periodicals, Inc.

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  • Occult chronic progressive cervical and thoracic myelopathy without evident magnetic resonance imaging lesion

    Emi Nomura, Toru Yamashita, Yoshiaki Takahashi, Keiichiro Tsunoda, Jingwei Shang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Hiroki Ueno, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 5 )   155 - 158   2017.9

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    Progressive myelopathy is caused by infectious, inflammatory, autoimmune, paraneoplastic, demyelinating, vascular, hereditary, degenerative, metabolic and toxic properties. Here, we report a case of a 53-year-old woman who showed a progressive cervical and thoracic myelopathy with muscle weakness in all limbs, and hypoesthesia in all limbs and trunk below the Th8 level without any evident magnetic resonance imaging lesions. She displayed rheumatoid factor, anti-double stranded DNA antibody and hepatitis B surface antigen, as well as an elevated cerebrospinal fluid protein level. The paraneoplastic antibodies that we examined were negative. Our treatments (plasma exchange, steroid pulse therapy and immunoglobulin therapy) were slightly effective, but the symptoms did not improve completely. The present case suggests that the presence of a cervical and thoracic lesion without evident magnetic resonance imaging abnormalities required a careful follow up to discover occult lesions.

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  • Non-ketotic hyperosmolar coma after percutaneous endoscopic gastrostomy in an advanced stage of progressive supranuclear palsy

    Koh Tadokoro, Kota Sato, Ryuta Morihara, Jingwei Shang, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Nozomi Hishikawa, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 5 )   162 - 164   2017.9

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    Patients with progressive supranuclear palsy often suffer from dysphagia, and percutaneous endoscopic gastrostomy is a treatment option for the advanced stage of this disease. The present percutaneous endoscopic gastrostomy patient had slightly impaired glucose tolerance, but the condition became considerably worse with normal nutrients due to limited activity and an infection after percutaneous endoscopic gastrostomy, resulting in a non-ketotic hyperosmolar coma. After receiving supplementary fluid, intravenous insulin, antibiotics and endotracheal intubation, the patient recovered from the non-ketotic hyperosmolar coma state. Percutaneous endoscopic gastrostomy placement at an advanced stage of a neurodegenerative disorder, such as progressive supranuclear palsy, should have a careful follow-up, especially when glucose tolerance worsens.

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  • Dissociated recovery between dementia and parkinsonism by transvenous embolization of recurrent dural arteriovenous fistula

    Yumiko Nakano, Emi Nomura, Masafumi Hiramatsu, Mami Takemoto, Kota Sato, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Kenji Sugiu, Isao Date, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 5 )   159 - 161   2017.9

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    Dementia and parkinsonism are rarely observed in dural arteriovenous fistula. Here, we report a case of a 63-year-old man with recurrent dural arteriovenous fistula, who developed progressive dementia and parkinsonism as a result of a dural arteriovenous fistula at the torcular herophili. A sinus thrombosis induced the abnormal cortical venous reflux from the isolated straight sinus, resulting in the deep venous congestion of the thalamus and basal ganglia, which led to dementia and parkinsonism. However, the third endovascular embolization ameliorated memory disturbance and apathy with a slight improvement of parkinsonism. Although recoveries from dural arteriovenous fistula-associated neurological deficits are variable depending on the severity, duration and, furthermore, selective vulnerability of the responsible ischemic lesions, early treatment should be essential for better recovery.

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  • Case of myasthenia gravis and Lambert-Eaton myasthenic syndrome overlap syndrome accompanied by autoimmune encephalitis and cerebellar ataxia with multiple neuronal antibodies

    Yumiko Nakano, Emi Nomura, Toru Yamashita, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 5 )   152 - 154   2017.9

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    A 72-year-old woman developed a subacute series of encephalitis, cerebellar ataxia, and combined symptoms of both myasthenia gravis and Lambert-Eaton myasthenic syndrome. Seven different neuronal antibodies were detected for Hu, glutamic acid decarboxylase, acetylcholine receptor, P/Q-type voltage-gated calcium-channels, Zic4, Titin and SOX1 in her serum with intrathecal synthesis of glutamic acid decarboxylase antibodies. Although she showed classical manifestations with onconeural antibodies, she was diagnosed with not paraneoplastic but autoimmune neurological syndrome because of no underlying tumor and good response to immunotherapies. The present case is very unique and rare for complex neurological disorders including myasthenia gravis and Lambert-Eaton myasthenic syndrome overlap syndrome with multiple neuronal antibodies.

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  • Different Characteristics of Anterior and Posterior Branch Atheromatous Diseases with or without Early Neurologic Deterioration. Reviewed International journal

    Yoshiaki Takahashi, Toru Yamashita, Ryuta Morihara, Yumiko Nakano, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Yasuhiro Manabe, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   26 ( 6 )   1314 - 1320   2017.6

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    BACKGROUND: Among several types of ischemic stroke (IS), branch atheromatous disease (BAD) is known to be the leading cause of disability. METHODS: A total of 1919 patients with acute IS were retrospectively analyzed, and BAD patients were classified into anterior or posterior BAD, depending on the responsible vascular territories. These patients were further subcategorized with or without early neurologic deterioration (END or no-END). RESULTS: Of all IS patients, 14.3% had BAD, and 202 patients (73.7%) were further classified as anterior BAD and 72 patients (26.3%) as posterior BAD. The prevalence of diabetes mellitus and END was significantly higher in posterior than in anterior BAD (44.4% vs 26.4%, P < .01; 18.1% vs 5.4%, P < .01, respectively). Posterior BAD showed a higher proportion of female patients and an older age (69.2% vs 39.0%, P < .05; 79.1 ± 7.7 vs 70.5 ± 10.7, P < .01, respectively) in END than in no-END. The modified Rankin Scale was worse in posterior BAD at 90 days (2.5 ± 1.6, P < .01) than in anterior BAD (1.6 ± 1.4). CONCLUSIONS: Our present study shows that posterior BAD is a worse clinical outcome than anterior BAD, with more vascular risk factors. Older female patients with posterior BAD showed a higher risk of END, leading to a worse clinical outcome.

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  • Neuroprotective Effects of a Novel Antioxidant Mixture Twendee X in Mouse Stroke Model. Reviewed International journal

    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 and cerebrovascular diseases : the official journal of National Stroke Association   26 ( 6 )   1191 - 1196   2017.6

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    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 Nε-(carboxymethyl) lysine (one of advanced glycation end products), as well as inflammatory markers such as ionized calcium binding adapter molecule-1, tumor necrosis factor-α, 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.

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  • Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. Reviewed International journal

    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   2017.5

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    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 18weeks (W). Double immunofluorescent analysis showed abnormal nuclear retention and apparent co-localizations of RanGAPl with NUP205 and NUP205 with NUPl07, 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.

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  • Factors related to continuous and discontinuous attendance at memory clinics Reviewed

    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   2017.5

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    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 &lt
    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 &lt
    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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  • Clinical features of incidental mild cognitive impairment and dementia in a population-based study. Reviewed

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

    Geriatrics & gerontology international   17 ( 5 )   722 - 729   2017.5

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    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 for metabolic 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. Geriatr Gerontol Int 2017; 17: 722-729.

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  • Familial amyotrophic lateral sclerosis of the G37V-superoxide dismutase 1 mutation with a slow disease progression

    Koh Tadokoro, Yasuyuki Ohta, Yoshiaki Takahashi, Toru Yamashita, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   5 ( 3 )   96 - 98   2017.5

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    The majority of amyotrophic lateral sclerosis patients have the sporadic form, but 5-10% of those have familial amyotrophic lateral sclerosis. A total of 15-20% of familial amyotrophic lateral sclerosis patients have genetic mutations in the superoxide dismutase 1 gene. In 2012, Kobayashi et al. reported the first case of a familial amyotrophic lateral sclerosis patient carrying a G37V superoxide dismutase 1 mutation, who showed rapid progression and died within 1.2 years of onset from respiratory failure. In contrast, here we report the second case of familial amyotrophic lateral sclerosis carrying the G37V superoxide dismutase 1 mutation, showing a very slow progression, and his father and aunt also had longer disease durations from 4 to 6 years. Further clinical and biological studies will clarify the detailed pathological role of the G37V superoxide dismutase 1 mutation for amyotrophic lateral sclerosis.

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  • Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype. Reviewed International journal

    Toru Yamashita, Jun Mitsui, Nobuyuki Shimozawa, Shigeo Takashima, Hiroshi Umemura, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Takashi Matsukawa, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji, Koji Abe

    Journal of the neurological sciences   375   424 - 429   2017.4

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    Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild). Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement. All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C (p.M1T), and a novel mutation, c.920G>A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10. The present cases suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems including pupillary autonomic, pyramidal and extrapyramidal systems.

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  • Flow-metabolism uncoupling in the cervical spinal cord of ALS patients. Reviewed International journal

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

    Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology   38 ( 4 )   659 - 665   2017.4

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    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 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) PET and 11C-flumazenil (11C-FMZ) PET. On the ipsilateral side of C5 and T1 levels, 18F-FDG uptake increased significantly (*p < 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 11C-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. Reviewed International journal

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

    Neurological research   39 ( 4 )   331 - 336   2017.4

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    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 (AIS ≤3 and AIS ≥4) and compared cognitive, affective, and ADL functions by sex and age. RESULTS: Subjective insomnia (AIS ≥4) 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 AIS ≥4 subgroup than the AIS ≤3 subgroup. Apathy Scale scores were significantly higher in males in the AIS ≥4 subgroup. Of the AIS subscales, 'sleepiness during the day' was significantly higher in females than males (**p < 0.01), especially in those aged  ≥75 years (**p < 0.01). This group of older females also showed a significantly lower Trail Making Test scores (*p < 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  ≥75 years was a high frequency of daytime sleepiness, possibly related to a decline in attention and executive function.

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  • Novel Therapeutic Transplantation of Induced Neural Stem Cells for Stroke. Reviewed International journal

    Toru Yamashita, Wentao Liu, Yoshiaki Matsumura, Ryosuke Miyagi, Yun Zhai, Momoko Kusaki, Nozomi Hishikawa, Yasuyuki Ohta, Sung Min Kim, Tae Hwan Kwak, Dong Wook Han, Koji Abe

    Cell transplantation   26 ( 3 )   461 - 467   2017.3

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    Somatic cells can be directly converted into induced neural stem cells (iNSCs) by defined transcription factors. However, the therapeutic effect of undifferentiated iNSCs on ischemic stroke has not been demonstrated. In this study, we used a mouse model of transient middle cerebral artery occlusion (tMCAO). iNSCs (5 × 105) were injected directly into the ipsilateral striatum and cortex 24 h after tMCAO. Histological analysis was performed at 7 days, 28 days, and 8 months after tMCAO. We found that iNSC transplantation successfully improved the survival rate of stroke model mice with significant functional recovery from the stroke. The fate of engrafted iNSCs was that the majority of iNSCs had differentiated into astroglial cells but not into neural cells in both the sham-operated brain and the poststroke brain without forming a tumor up to 8 months after tMCAO. Our data suggest that the directly converted iNSCs can be regarded as a candidate of safe cell resource for transplantation therapy in patients suffering from ischemic stroke.

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  • A patient with slowly progressive adult-onset nemaline myopathy and novel compound heterozygous mutations in the nebulin gene. Reviewed International journal

    Keiichiro Tsunoda, Toru Yamashita, Emi Motokura, Yoshiaki Takahashi, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Atsuko Nishikawa, Ichizo Nishino, Koji Abe

    Journal of the neurological sciences   373   254 - 257   2017.2

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  • A case of very long longitudinally extensive transverse myelitis (LETM) with necrotizing Vasculitis. Reviewed International journal

    Kota Sato, Keiichiro Tsunoda, Toru Yamashita, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toshiyuki Takahashi, Ichiro Nakashima, Takao Yasuhara, Isao Date, Koji Abe

    Journal of the neurological sciences   373   152 - 154   2017.2

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  • Potential multisystem degeneration in Asidan patients. Reviewed International journal

    Yasuyuki Ohta, Toru Yamashita, Nozomi Hishikawa, Kota Sato, Kosuke Matsuzono, Keiichiro Tsunoda, Noriko Hatanaka, Mami Takemoto, Toshihiko Takemi, Kazuhiro Takamatsu, Koji Abe

    Journal of the neurological sciences   373   216 - 222   2017.2

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    OBJECTIVE: To evaluate a potential multisystem involvement of neurodegeneration in Asidan, in addition to cerebellar ataxia and signs of motor neuron disease. METHODS: We compared the new Asidan patients and those identified in previous studies with Parkinson's disease (PD, n=21), and progressive supranuclear palsy (PSP, n=13) patients using 123I-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy (Asidan, DAT: n=10; MIBG: n=15). RESULTS: Both the PD and PSP groups served as positive controls for DAT decline. The PD and PSP groups served as a positive and negative control, respectively, of MIBG decline in the early phase H/M ratio. Of the Asidan patients, 60.0% showed DAT decline without evident parkinsonian features and 6.7% showed impaired MIBG in only the delayed phase H/M ratio. Combined with a normal range of the early phase H/M ratio, this phenotype was newly named Declined DAT Without Evident Parkinsonism (DWEP). INTERPRETATION: The results of present study including DWEP suggest a wider spectrum of neurodegeneration for extrapyramidal and autonomic systems in Asidan patients than expected, involving cerebellar, motor system and cognitive functioning.

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  • Marked hypertriglyceridemia induced by interferon-beta 1a therapy in a clinically isolated syndrome patient Reviewed International journal

    Yuko Kawahara, Toru Yamashita, Yasuyuki Ohta, Kota Sato, Keiichiro Tsunoda, Mami Takemoto, Nozomi Hishikawa, Jun Eguchi, Koji Abe

    JOURNAL OF THE NEUROLOGICAL SCIENCES   373   144 - 146   2017.2

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  • An AOA2 patient with a novel compound heterozygous SETX frame shift mutations. Reviewed International journal

    Emi Motokura, Toru Yamashita, Yoshiaki Takahashi, Keiichiro Tsunoda, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Akihiro Hashiguchi, Hiroshi Takashima, Koji Abe

    Journal of the neurological sciences   372   294 - 296   2017.1

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  • iPS cells and iN cells Reviewed

    Toru Yamashita, Koji Abe

    Cell Therapy against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials   39 - 46   2017.1

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    The discovery of iPS indicated that overexpression of master transcriptional factors might change cell fate. Recent developments in reprogramming methods have shown that somatic cells can be directly reprogrammed to various kinds of neuronal cells directly. Moreover, overexpression of a neuron-specific transcriptional factor with a viral vector can change the fate of endogenous glial cells to neuronal cells in vivo. In this chapter, we discuss the advantages, issues, and possibility for clinical application of these reprogramming methods for cell transplantation/replacement therapy.

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  • Neuromyelitis Optica Spectrum Disorder Coinciding with Spinocerebellar Ataxia Type 31

    Yoshiaki Takahashi, Yasuhiro Manabe, Ryuta Morihara, Hisashi Narai, Toru Yamashita, Koji Abe

    CASE REPORTS IN NEUROLOGY   9 ( 2 )   127 - 130   2017

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    We report the unusual case of a 63-year-old man with spinocerebellar ataxia (SCA) type 31 who developed neuromyelitis optica spectrum disorder (NMOSD) 14 years after the onset of cerebellar symptoms. In addition to cerebellar atrophy, magnetic resonance imaging showed multiple high-intensity areas in the brain and a long thoracic cord lesion from Th1/2 to Th11. The combination of NMOSD and SCA31 is accidental. However, our case suggests that inflammatory processes could be involved in the pathogenesis of NMOSD and SCA31. (C) 2017 The Author(s) Published by S. Karger AG, Basel.

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  • [Recent Progress in Cerebroprotective Therapy]. Reviewed

    Toru Yamashita, Koji Abe

    No shinkei geka. Neurological surgery   44 ( 12 )   1001 - 1008   2016.12

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  • Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis. Reviewed International journal

    Yasuyuki Ohta, Genevieve Soucy, Daniel Phaneuf, Jean-Nicolas Audet, François Gros-Louis, Guy A Rouleau, Hélène Blasco, Philippe Corcia, Peter M Andersen, Frida Nordin, Toru Yamashita, Koji Abe, Jean-Pierre Julien

    Human molecular genetics   25 ( 21 )   4771 - 4786   2016.11

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    Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)P413L allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHGBP413L variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGBL413 protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGBL413 transgene in SOD1G37R mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGBL413 variant also slowed down disease progression in SOD1G37R mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1D90A alleles and two variant CHGBP413L and CHGBR458Q alleles. In contrast, overexpression of the common CHGBP413 allele in SOD1G37R mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGBP413L allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGBL413 allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.

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  • An autopsy case of intravascular large B-cell lymphoma with subcortical U-fiber sparing and unique lymphocyte markers. Reviewed International journal

    Kota Sato, Emi Motokura, Kentaro Deguchi, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Junya Itakura, Koji Abe

    Journal of the neurological sciences   369   273 - 275   2016.10

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  • Differences between the behavioral and psychological symptoms of Alzheimer's disease and Parkinson's disease. Reviewed International journal

    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   2016.10

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    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 288AD patients and 189 PD patients (mean age, 74.6±5.9 and 73.0±8.7years 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 1 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.

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  • Temporal Profiles of Stress Protein Inductions after Focal Transient Ischemia in Mice Brain. Reviewed International journal

    Qian Li, Yumiko Nakano, Jingwei Shang, Yasuyuki Ohta, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   25 ( 10 )   2344 - 51   2016.10

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    BACKGROUND: Stress proteins have been found to play important protective roles against ischemic brain injury under hypoxic, oxidative, heat shock, and proteasome stresses. METHODS: In the present study, we investigated the temporal profiles of the major stress proteins including hypoxia-inducible factor-1α (HIF-1α), glutathione (GSH), heat shock protein 72 (HSP72), constitutive heat shock cognate protein 73 (HSC73), and ubiquitin after 45 minutes of transient middle cerebral artery occlusion (tMCAO) in the mice brain up to 7 days after reperfusion. RESULTS: Immunohistochemical analyses of HIF-1α, GSH, HSP72, and ubiquitin showed little immunoreactivity of neural cells in sham control brain, whereas HSC73 showed a constitutive immunoreactivity. After tMCAO, HSC73 showed the fastest increase at 12 hours in the peri-ischemic area, followed by HIF-1α with a peak at 24 hours, GSH, HSP72, and ubiquitin with a peak at 72 hours. All these stress proteins returned toward the baseline levels until 7 days. In the ischemic core, these stress proteins showed a similar change with less reaction compared to the peri-ischemic area. CONCLUSIONS: These data showed temporal expressions of HIF-1α, GSH, HSP72, HSC73, and ubiquitin in the mice brain after tMCAO, which might provide a better understanding of neuroprotective mechanisms and novel targets for therapeutic intervention of brain ischemic disease.

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  • Different clinical features in siblings with identical mutations of the Parkin gene (PARK2). Reviewed International journal

    Kota Sato, Toru Yamashita, Noriko Hatanaka, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

    Journal of the neurological sciences   368   147 - 9   2016.9

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  • Autophagic down-regulation in motor neurons remarkably prolongs the survival of ALS mice. Reviewed International journal

    Kuo-Wei Hsueh, Tzyy-Wen Chiou, Shu-Fen Chiang, Toru Yamashita, Koji Abe, Cesar V Borlongan, Paul R Sanberg, Angela Yu Hsuan Huang, Shinn-Zong Lin, Horng-Jyh Harn

    Neuropharmacology   108   152 - 60   2016.9

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    Amyotrophic lateral sclerosis (ALS) is a lethal degenerating disease, characterized by progressive muscular atrophy without any effective treatment. Here, we demonstrated the efficacy of abrograting autophagy in motor neurons (MN) by treatment with n-butylidenephthalide (n-BP) in ALS transgenic mice (SOD1(G93A)). Pre-symptomatic oral administration of 250 mg/kg/bid n-BP significantly prolonged the survival period (203.9 ± 18.3 days), improved motor function, and attenuated MN loss compared to vehicle control (126.4 ± 7.2 days). This prolonged survival of ALS mice is much more robust than that reported with riluzole (140 days), which is an approved clinical therapy for ALS. The therapeutic mechanism targeted by n-BP involved the autophagic pathway as evidenced by decreased LC3-II expression (a biomarker of autophagy), enhanced mTOR levels, and attenuated autophagic activity, altogether increasing MN survival in a dose-dependent manner. This result was also confirmed by double transgenic mice (SOD1(G93A):LC3-GFP) which showed that oral administration of n-BP reduced GFP density and decreased caspase-3 expression. In addition, electron microscopy revealed that n-BP administration not only decreased autophagosome number but also reduced morphological dysfunction of mitochondria. In summary, these results indicate that down-regulation of autophagy activation via n-BP may pose as a therapeutic regimen for ALS and relevant neurodegenerative diseases.

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

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

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   25 ( 8 )   1997 - 2003   2016.8

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    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: Pre-treatment 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. Reviewed International journal

    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   2016.7

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    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 (123)I-MIBG scintigraphy (MIBG). The RHI of ALS and PD, but not of PSP, MSA or SCA, were significantly lower than normal controls (p<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 (∆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.

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  • Age-dependent cognitive and affective differences in Alzheimer's and Parkinson's diseases in relation to MRI findings. Reviewed International journal

    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   2016.6

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    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 >88% and >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.

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  • Recurrent cervical internal carotid artery vasospasm relating to menstruation with endothelial dysfunction. Reviewed International journal

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

    Journal of the neurological sciences   365   72 - 3   2016.6

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  • Chronic Cerebral Hypoperfusion Accelerates Alzheimer's Disease Pathology with Cerebrovascular Remodeling in a Novel Mouse Model. Reviewed International journal

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

    Journal of Alzheimer's disease : JAD   53 ( 3 )   893 - 905   2016.6

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    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-β (Aβ) 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 Aβ 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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  • Phase II Trial of Intravenous Low-Dose Granulocyte Colony-Stimulating Factor in Acute Ischemic Stroke. Reviewed International journal

    Atsushi Mizuma, Toru Yamashita, Syoichiro Kono, Taira Nakayama, Yasuhiko Baba, Shinji Itoh, Kunihiko Asakura, Yoshiki Niimi, Takashi Asahi, Kazuya Kanemaru, Tatsuro Mutoh, Satoshi Kuroda, Hiroyuki Kinouchi, Koji Abe, Shunya Takizawa

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   25 ( 6 )   1451 - 7   2016.6

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    BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) has shown neuroprotective and neurogenerative activities in experimental studies, and our previous phase I clinical study suggested the safety and potential efficacy of low-dose G-CSF in acute ischemic stroke patients. The present phase II trial is aimed to evaluate the effect of G-CSF administration on neurological function and infarct volume, compared with a placebo group. METHODS: Forty-nine acute ischemic stroke patients (29 males, 20 females; 71 ± 10 years) within 24 hours after onset were recruited. Eligible patients were randomized 2:2:1 to receive G-CSF 150 µg/body/day, G-CSF 300 µg/body/day, and placebo, respectively. We evaluated clinical outcome in terms of the National Institutes of Health Stroke Scale, the modified Rankin Scale, and the Barthel Index at 90 days after onset, together with changes in infarct volume on magnetic resonance imaging. RESULTS: We found no serious adverse event, including change in leukocyte levels, which remained below 31,000/µL, at 150 and 300 µg G-CSF/body/day. Clinical outcome scores did not show any significant difference among the 3 groups. Chronological changes in infarct volume also showed no significant difference. CONCLUSIONS: G-CSF was well-tolerated at 150 and 300 µg/body/day in patients with acute ischemic stroke. However, administration of G-CSF at both 150 and 300 µg/body/day neither contributed to functional recovery nor reduced infarct volume at 3 months after onset, compared with the control group. The apparent lack of effectiveness may have been due to the small sample size. A trial of combination therapy with recombinant tissue plasminogen activator and G-CSF is planned.

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  • ADとPDにおける認知機能、情動機能ならびにMRI画像の加齢性変化に関する検討

    徳地 亮, 菱川 望, 佐藤 恒太, 太田 康之, 山下 徹, 阿部 康二

    日本老年医学会雑誌   53 ( Suppl. )   166 - 166   2016.5

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  • Disruption of White Matter Integrity by Chronic Cerebral Hypoperfusion in Alzheimer's Disease Mouse Model. Reviewed International journal

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

    Journal of Alzheimer's disease : JAD   52 ( 4 )   1311 - 9   2016.4

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    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 Nav1.6 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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  • New susceptible variant of COQ2 gene in Japanese patients with sporadic multiple system atrophy Reviewed International journal

    Zhuoran Sun, Yasuyuki Ohta, Toru Yamashita, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Koji Abe

    NEUROLOGY-GENETICS   2 ( 2 )   e54   2016.4

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    OBJECTIVE: The aim of this study was to analyze the association between the variations of coenzyme Q2 4-hydroxybenzoate polyprenyltransferase gene (COQ2) and Japanese patients with multiple system atrophy (MSA). METHODS: We investigated the genetic variations in exons 1, 2, 6, and 7 of the COQ2 gene in 133 Japanese patients with MSA and 200 controls and analyzed the association between the variations and MSA. RESULTS: Six DNA variations (G21S, L25V, V66L, P157S, V393A, and X422K) were found in the 133 patients with MSA, and G21S and X422K were new variations that had never been reported. V66L was a common variation that was found in all 133 patients with MSA. G21S, P157S, V393A, and X422K did not show gene frequency differences between patients with MSA and controls. On the other hand, L25V was newly proven to be the only risk factor of sporadic MSA with predominant olivopontocerebellar ataxia. CONCLUSIONS: The present study suggests L25V variant of COQ2 gene as a genetic risk factor in Japanese patients with MSA with cerebellar ataxia.

    DOI: 10.1212/NXG.0000000000000054

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  • [Regenerative therapy for post-stroke patients]. Reviewed

    Toru Yamashita, Koji Abe

    Nihon rinsho. Japanese journal of clinical medicine   74 ( 4 )   661 - 5   2016.4

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    Cell replacement therapy is attractive as a novel strategy for stroke patients. To realize this therapy, safer and more effective cell resources are now required. Since both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can retain high replication competence and pluripotency when they differentiate into various kinds of cells, they are regarded as a promising cell source for cell replacement therapy. Recent progress includes the combination of novel transcriptional factors that can convert somatic cells to various kinds of mature neuronal cells and neural stem cells without requiring embryonic stem fate. In this paper, we would like to discuss the advantage, issues, and possibility of clinical application of these cells for cell replacement therapy for post-stroke patient.

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  • Thrombolysis with Low-Dose Tissue Plasminogen Activator 3-4.5 h After Acute Ischemic Stroke in Five Hospital Groups in Japan. Reviewed International journal

    Ryuta Morihara, Syoichiro Kono, Kota Sato, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Yasuhiro Manabe, Yoshiki Takao, Kenichi Kashihara, Satoshi Inoue, Hideki Kiriyama, Koji Abe

    Translational stroke research   7 ( 2 )   111 - 9   2016.4

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    Clinical data from Japan on the safety and real-world outcomes of alteplase (tPA) thrombolysis in the extended therapeutic window are lacking. The aim of this study was to assess the safety and real-world outcomes of tPA administered within 3-4.5 h of stroke onset. The study comprised consecutive acute ischemic stroke patients (n = 177) admitted across five hospitals between September 2012 and August 2014. Patients received intravenous tPA within <3 or 3-4.5 h of stroke onset. Endovascular therapy was used for tPA-refractory patients. In the 3-4.5 h subgroup (31.6 % of patients), tPA was started 85 min later than the <3 h group (220 vs. 135 min, respectively). However, outcome measures were not significantly different between the <3 and 3-4.5 h subgroups for recanalization rate (67.8 vs. 57.1 %), symptomatic intracerebral hemorrhage (2.5 vs. 3.6 %), modified Rankin Scale score of 0-1 at 3 months (36.0 vs. 23.4 %), and mortality (6.9 vs. 8.3 %). We present data from 2005 to 2012 using a therapeutic window <3 h showing comparable results. tPA following endovascular therapy with recanalization might be superior to tPA only with recanalization (81.0 vs. 59.1 %). Compared with administration within 3 h of ischemic stroke onset, tPA administration within 3-4.5 h of ischemic stroke onset in real-world stroke emergency settings at multiple sites in Japan is as safe and has the same outcomes.

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  • Cognitive and affective benefits of combination therapy with galantamine plus cognitive rehabilitation for Alzheimer's disease. Reviewed

    Ryo Tokuchi, Nozomi Hishikawa, Kosuke Matsuzono, Yoshiki Takao, Yosuke Wakutani, Kota Sato, Syoichiro Kono, Yasuyuki Ohta, Kentaro Deguchi, Toru Yamashita, Koji Abe

    Geriatrics & gerontology international   16 ( 4 )   440 - 5   2016.4

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    AIM: The aim of the present study was to compare the effects of a galantamine only therapy and a combination therapy with galantamine plus ambulatory cognitive rehabilitation for Alzheimer's disease patients. METHODS: For this retrospective cohort study, we enrolled 86 patients with Alzheimer's disease, dividing them into two groups - a galantamine only group (group G, n = 45) and a combination with galantamine plus ambulatory rehabilitation group (group G + R, n = 41). The present cognitive rehabilitation included a set of physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week. We compared the Mini-Mental State Examination and Frontal Assessment Battery for cognitive assessment, and Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia score for affective assessment in two groups over 6 months. RESULTS: The baseline Mini-Mental State Examination score was 20.2 and 18.7 in groups G and G + R, respectively. Other baseline data (Frontal Assessment Battery, Geriatric Depression Scale, Apathy Scale, and Abe's Behavioral and Psychological Symptoms of Dementia) were not different between the two groups. Although group G kept all the scores stable until 6 months of the treatment, the Apathy Scale score showed a significant improvement in group G + R as early as 3 months, followed by the Mini-Mental State Examination and Frontal Assessment Battery improvements at 6 months (*P = 0.04 and *P = 0.02, respectively). The Geriatric Depression Scale and Abe's Behavioral and Psychological Symptoms of Dementia did not show any changes. CONCLUSION: The combination therapy of galantamine plus ambulatory cognitive rehabilitation showed a superior benefit both on cognitive and affective functions than galantamine only therapy in Alzheimer's disease patients.

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

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

    Geriatrics & gerontology international   16 ( 4 )   458 - 65   2016.4

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    AIMS: The 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: These 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.

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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. Reviewed International journal

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

    Journal of Alzheimer's disease : JAD   52 ( 1 )   113 - 26   2016.3

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    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 α7 subunit of nicotinic acetylcholine receptors (α7-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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  • Two young stroke patients associated with regular intravenous immunoglobulin (IVIg) therapy. Reviewed International journal

    Yumiko Nakano, Takeshi Hayashi, Kentaro Deguchi, Kota Sato, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Yoshiki Takao, Tomohiro Morio, Koji Abe

    Journal of the neurological sciences   361   9 - 12   2016.2

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    We recently experienced 2 young adult patients who developed ischemic stroke after regular intravenous immunoglobulin (IVIg) therapy for agammaglobulinemia with diagnosis of common variable immunodeficiency (CVID) in their childhood. Patient 1 was 26-year-old woman, who developed Wallenberg's syndrome 6 days after the last IVIg therapy, but had no further stroke recurrence with cilostazol later. Patient 2 was 37-year-old man, who developed recurrent cerebral infarction in the territory of bilateral lenticulostriate branches like branch atheromatous disease (BAD) several days after the IVIg therapy. However, he had no further stroke recurrence after bone marrow transplantation (BMT) therapy for his lymphoproliferative disorder. It was suggested that IVIg therapy was associated to these different types of ischemic stroke in our 2 young adult patients with minimal vascular risk factors. Although IVIg therapy is widely used as a relatively safe medication for immunodeficiency disorders or autoimmune diseases, we need to pay more attention to stroke occurrence with regular IVIg therapy.

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  • Cognitive and affective functions in Alzheimer's disease patients with metabolic syndrome Reviewed

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

    European Journal of Neurology   23 ( 2 )   339 - 345   2016.2

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    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. Click here to view the accompanying paper in this issue.

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  • Combination benefit of cognitive rehabilitation plus donepezil for Alzheimer's disease patients. Reviewed

    Kosuke Matsuzono, Nozomi Hishikawa, Yoshiki Takao, Yosuke Wakutani, Toru Yamashita, Kentaro Deguchi, Koji Abe

    Geriatrics & gerontology international   16 ( 2 )   200 - 4   2016.2

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    OBJECTS: Alzheimer's disease (AD) is one of the most important diseases in aging society, and non-drug therapy might be an alternative therapeutic approach. Thus, we evaluated the add-on effect of cognitive rehabilitation on AD patients under donepezil treatment. METHODS: We retrospectively analyzed 55 AD patients with a Mini-Mental State Examination score of 15-25, dividing them into two groups depending on whether they were receiving ambulatory cognitive rehabilitation (group D + R, n = 32) or not (group D, n = 23) in Kurashiki Heisei Hospital over 1 year. The present cognitive rehabilitation included physical therapy, occupational therapy and speech therapy for 1-2 h once or twice a week. RESULTS: Between group D and group D + R, there was no significant difference in baseline data, such as age, Mini-Mental State Examination score, periventricular hyperintensity on magnetic resonance imaging, deep white matter hyperintensity on magnetic resonance imaging or donepezil dose (4.1 mg/day). At 1 year later, however, the Mini-Mental State Examination score improved only in group D + R from 21.7 to 24.0 (**P < 0.001), whereas that of group D remained at 21.5 with both groups of donepezil 5.0 mg/day. CONCLUSION: The combination of cognitive rehabilitation plus a choline esterase inhibitor donepezil showed a better effect for the cognitive function of AD patients than drug only therapy at 1 year.

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  • 'PrP systemic deposition disease': Clinical and pathological characteristics of novel familial prion disease with 2-bp deletion in codon 178 Reviewed

    K. Matsuzono, H. Honda, K. Sato, R. Morihara, K. Deguchi, N. Hishikawa, T. Yamashita, S. Kono, Y. Ohta, T. Iwaki, K. Abe

    European Journal of Neurology   23 ( 1 )   196 - 200   2016.1

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    Background and purpose: A novel TYPE of prion disease associated mainly with autonomic-sensory polyneuropathy was reported by us previously. Methods: Here the autopsy pathology for patient 1 (the sister) and the clinical characteristics of her younger brother (patient 2) are newly reported. Polymerase chain reaction based restriction fragment length polymorphism analysis of the prion protein gene (PRNP) was performed on both patients and their father (normal control). Results: Polymerase chain reaction based restriction fragment length polymorphism analysis revealed a 2-bp deletion (CT) in codon 178 that causes an additional variable 25 amino acids at the C terminal, from the mutation site to the premature stop codon at codon 203, in both patients 1 and 2 but not in their father. The autopsy of patient 1 showed remarkable prion protein (PrP) deposits in the sympathetic ganglion and peripheral nerves, correlated to her severe autonomic sensory failure. PrP deposits were also found in the central nervous system and peripheral organs such as the heart, lung, stomach, jejunum, ileum, colon, urinary bladder and adrenal gland. The symptoms and biopsy findings of patient 2 were nearly the same as those reported previously for patient 1. His cognitive function was well preserved, but autonomic functions were severely impaired. His biopsied samples showed PrP deposits in the sural nerve and nerve plexuses of the stomach and colon. Conclusion: The present unique 2-bp deletion (CT) in codon 178 induced a 'PrP systemic deposition disease' such as pan-autonomic failure, sensory neuropathy and mild cognitive impairment with a specific pathology.

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  • Characteristic diffusion tensor tractography in multiple system atrophy with predominant cerebellar ataxia and cortical cerebellar atrophy. Reviewed International journal

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

    Journal of neurology   263 ( 1 )   61 - 7   2016.1

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    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 ± 8.1 years old, mean ± SD) and age- and gender-matched 15 CCA patients (63.0 ± 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<0.01, respectively) and a significant increase of the radial diffusivity (RD) value in afferent 1 (p<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<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<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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  • Recent Progress in Therapeutic Strategies for Ischemic Stroke. Reviewed International journal

    Toru Yamashita, Koji Abe

    Cell transplantation   25 ( 5 )   893 - 8   2016

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    Possible strategies for treating stroke include neuroprotection in the acute phase of cerebral ischemia and stem cell therapy in the chronic phase of cerebral ischemia. Previously, we have studied the temporal and spatial expression patterns of c-fos, hypoxia inducible factor-1α (HIF-1α), heat shock protein 70 (HSP70), and annexin V after 90 min of transient middle cerebral occlusion in rats and concluded that there is a time window for neuroprotection from 12 to 48 h after ischemia. In addition, we have estimated the neuroprotective effect of glial cell line-derived neurotrophic factor (GDNF) by injecting Sendai viral vector containing the GDNF gene into the postischemic brain. This Sendai virus-mediated gene transfer of GDNF showed a significant neuroprotective effect in the ischemic brain. Additionally, we have administered GDNF and hepatocyte growth factor (HGF) protein into the postischemic rat brain and estimated the infarct size and antiapoptotic and antiautophagic effects. GDNF and HGF significantly reduced infarct size, the number of microtubule-associated protein 1 light chain 3 (LC3)-positive cells, and the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick-end labeling (TUNEL)-positive cells, indicating that GDNF and HGF were greatly associated with not only the antiapoptotic effect but also the antiautophagic effects. Finally, we have previously transplanted undifferentiated iPSCs into the ipsilateral striatum and cortex at 24 h after cerebral ischemia. Histological analysis was performed at 14 and 28 days after cell transplantation, and we found that iPSCs could supply a great number of doublecortin-positive neuroblasts but also formed tridermal teratoma in the ischemic brain. Our results suggest that iPSCs have a potential to provide neural cells after ischemic brain injury if tumorigenesis is properly controlled. In the future, we will combine these strategies to develop more effective therapies for the treatment of strokes.

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  • Recent Progress in Cell Reprogramming Technology for Cell Transplantation Therapy. Reviewed

    Toru Yamashita, Koji Abe

    Neurologia medico-chirurgica   56 ( 3 )   97 - 101   2016

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    The discovery of induced pluripotent stem (iPS) cells opened the gate for reprogramming technology with which we can change the cell fate through overexpression of master transcriptional factors. Now we can prepare various kinds of neuronal cells directly induced from somatic cells. It has been reported that overexpression of a neuron-specific transcriptional factors might change the cell fate of endogenous astroglia to neuronal cells in vivo. In addition, some research groups demonstrated that chemical compound can induce chemical-induced neuronal cells, without transcriptional factors overexpression. In this review, we briefly review recent progress in the induced neuronal (iN) cells, and discuss the possibility of application for cell transplantation therapy.

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  • Characteristics of audiogram configuration in multiple-system atrophy C and cortical cerebellar atrophy Reviewed International journal

    Ryotaro Omichi, Yukihide Maeda, Akiko Sugaya, Yuko Kataoka, Shin Kariya, Rie Nagayasu, Atsuko Nakagawa, Toru Yamashita, Koji Abe, Kazunori Nishizaki

    ACTA OTO-LARYNGOLOGICA   136 ( 3 )   266 - 270   2016

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    CONCLUSION: The prevalence of low-tone hearing loss (LTHL) is significantly high in spinocerebellar degeneration (SCD) with cerebellar predominance, including multiple-system atrophy C (MSA-C) and cortical cerebellar atrophy (CCA). OBJECTIVE: This study aimed to test the hypothesis that SCD with cerebellar predominance, MSA-C and CCA may cause auditory symptoms. METHODS: The shape and threshold of pure-tone audiograms were evaluated for MSA-C (n = 47; mean (± SD) age, 61.6 ± 8.9 years), CCA (n = 16; 62.8 ± 9.5 years), and age-matched controls (n = 169; 62.5 ± 10.7 years). To differentiate specific hearing loss for MSA-C and CCA from presbycusis, the shape of audiograms was examined based on previously established audiological criteria. RESULTS: When audiogram shape was defined according to audiological criteria, the odds ratio for LTHL in SCD compared to controls was 2.492 (95% confidence interval (CI) = 1.208-5.139; p < 0.05, Pearson's Chi-square test) in MSA-C and 2.194 (95% CI = 0.709-6.795) in CCA. When the selection of audiogram shape according to these criteria was verified by three certified audiologists, odds ratios for LTHL in MSA-C and CCA were 3.243 (95% CI = 1.320-7.969) and 3.692 (95% CI = 1.052-12.957), respectively, significantly higher than in controls.

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  • Comparative Gait Analysis in Progressive Supranuclear Palsy and Parkinson's Disease. Reviewed International journal

    Noriko Hatanaka, Kota Sato, Nozomi Hishikawa, Mami Takemoto, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    European neurology   75 ( 5-6 )   282 - 9   2016

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    BACKGROUND: Although changes to gait are an important clinical feature of progressive supranuclear palsy (PSP), systematic analyses have not been well examined, especially in comparison to Parkinson's disease (PD). METHODS: The characteristics of gait in 20 PSP patients (14 males and 6 females) were evaluated in comparison to 124 PD patients (64 males and 60 females) and 24 controls, that is, healthy age-matched adults (5 males and 19 females). Gait in patients was recorded in a 10-m walking test at a self-selected speed. During this time, patients felt most comfortable while wearing a new portable triaxial accelerometer rhythmogram device. Gait variables among the 3 groups were compared. RESULTS: Both PSP and PD patients shared the following similar hypokinetic gait characteristics: decreased velocity, step length, cadence and mean acceleration. Step time and variability in step time were mutually related. However, among the 3 groups, PSP patients showed characteristically low vertical displacement and a higher acceleration than PD patients at the same cadence. CONCLUSION: Although PSP and PD patients showed similar hypokinetic gait, a reduced vertical displacement characterized walking in PSP patients, differing substantially from the characteristics of walking displayed by PD patients.

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  • Different Clinical and Neuroimaging Characteristics in Early Stage Parkinson's Disease with Dementia and Dementia with Lewy Bodies. Reviewed International journal

    Mami Takemoto, Kota Sato, Noriko Hatanaka, Toru Yamashita, Yasuyuki Ohta, Nozomi Hishikawa, Koji Abe

    Journal of Alzheimer's disease : JAD   52 ( 1 )   205 - 11   2016

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    Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) both commonly exhibit brain Lewy body pathology and similar end-stage symptoms, but early symptoms differ. To clarify these differences, we compared the demographic characteristics, symptoms, cognitive and affective functioning, activities of daily life, and neuroimaging results between PDD (n = 52) and DLB (n = 46) patients. In measures of cognitive functioning, PDD patients had worse Hasegawa dementia scale-revised (HDS-R) scores (11.2±4.8) and better frontal assessment battery (FAB) scores (11.3±4.1) compared with DLB (17.0±6.4, p = 0.013 and 8.6±4.7, p = 0.039, respectively). DLB patients performed worse than PDD patients in "orientation to place" tasks. In affective functions, DLB patients had worse GDS (7.6±3.4) and ABS (9.9±5.3) scores than PDD patients (5.1±4.1 and 4.8±3.0, respectively). 99mTc-ECD images showed greater CBF in the whole cingulate gyrus and a lower CBF in the precuneus area in DLB than in PDD. These results suggest that PDD patients' lower average scores for "repetition" (MMSE), "recent memory" (HDS-R), and "lexical fluency" (FAB) were related to lower CBF in the cingulate gyrus than in DLB. Furthermore, DLB patients' poorer average subscale scores of "orientation to place" (MMSE) and "similarities", "conflicting instructions", and "go-no go" (FAB) tasks may be related to the lower CBF in the precuneus area in DLB than PDD.

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  • Prospective surveillance data of human prion disease in the Chugoku and Shikoku regions of Japan

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

    PRION   10   S90 - S91   2016

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  • Differentiating progressive supranuclear palsy from Parkinson's disease by MRI-based dynamic cerebrospinal fluid flow. Reviewed International journal

    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   2015.10

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    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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  • 軽度認知機能障害の知的機能・情動機能の特徴

    福井 裕介, 菱川 望, 山下 徹, 佐藤 恒太, 河野 祥一郎, 太田 康之, 出口 健太郎, 阿部 康二

    日本老年医学会雑誌   52 ( 4 )   451 - 451   2015.10

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  • Cognitive and affective functions of aged subacute myelooptico neuropathy patients in Japan

    Yuko Kawahara, Kentaro Deguchi, Nozomi Hishikawa, Tomoko Kurata, Kota Sato, Syoichiro Kono, Yoshio Omote, Yasuyuki Ohta, Toru Yamashita, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   3 ( 5 )   173 - 178   2015.9

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    Background: Subacute myelo-optico neuropathy was the first epidemic drug intoxication that affected many people in Japan in the 1970s. Aim: More than 40 years later, we assessed the real conditions of subacute myelooptico neuropathy patients. Methods: The present study examined current cognitive and affective functions, activities of daily living, and vascular endothelial function in aged subacute myelooptico neuropathy patients (n = 28) compared with age-,sex-,body mass indexand years of schooling-matched normal controls (n = 141).Results: Mini-Mental State Examination, Hasegawa Dementia Scale-Revised, Montreal Cognitive Assessment and Frontal Assessment Battery scores were not significantly lower in subacute myelo-optico neuropathy patients, but the Geriatric Depression Scale was significantly higher without apathy. Computerized touchpanel tests showed poor performance in the flipping cards game, arranging pictures game and beating devils game, whereas activities of daily living and vascular endothelial function were within normal limits.Conclusion: The present study shows that subacute myelo-optico neuropathy patients showed essentially normal cognitive function using standard cognitive assessments, although the touch- panel tests detected some decline in subacute myelo- optico neuropathy patients. Subacute myelo- optico neuropathy patients presented a higher depression score without evident apathy, activities of daily living decline or vascular endothelial dysfunction.

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  • Polyneuritis and refractory headache overlap with synovitis, acne, pustulosis, hyperostosis and osteitis syndrome

    Kosuke Matsuzono, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   3 ( 5 )   182 - 184   2015.9

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    The primary clinical manifestations of synovitis, acne, pustulosis, hyperostosis and osteitis syndrome are skin lesions and osteitis. We describe a 53-year-old woman patient suffering from overlapping refractory headache and polyneuritis (cranial nerves I, II and VII). She complained of headaches, which recurred every month, followed by bilateral anosmia and left vision loss approximately 1 year later. Prednisolone therapy improved her symptoms; however, her refractory headache, pain in the right shoulder and left hip joint, and rash recurred 1 year after prednisolone withdrawal. Also, the patient presented with left sensorineural deafness and extensive acne on her body, and bone scintigraphy and bone biopsy showed synovitis, acne, pustulosis, hyperostosis and osteitis syndrome. After treatment, her symptoms improved without recurrence. Although synovitis, acne, pustulosis, hyperostosis and osteitis syndrome induced by polyneuritis is rare, it should be considered when clinicians encounter patients presenting with headache and polyneuritis of unknown cause.

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  • Aggressive Garcin's syndrome by acquired cystic disease of kidney-related renal cell carcinoma in a long-term hemodialytic patient. Reviewed International journal

    Yuko Kawahara, Kentaro Deguchi, Kota Sato, Nozomi Hishikawa, Syoichiro Kono, Yasuyuki Ohta, Toru Yamashita, Eiko Hayashi, Yasuharu Sato, Koji Abe

    Journal of the neurological sciences   355 ( 1-2 )   216 - 8   2015.8

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  • Cerebrospinal blood flow and its regulation Reviewed

    Toru Yamashita, Kazunori Miyazaki, Koji Abe

    Neuroanesthesia and Cerebrospinal Protection   25 - 29   2015.8

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    The human brain utilizes large amounts of O2, which means that the rate of blood flow has to be maintained at a consistently high level. This is made possible by "cerebral autoregulation," the process by which the cerebral and spinal blood vessels keep cerebral blood flow constant, even under change in systemic blood pressure. In addition, cerebral and spinal blood flow and its regulation appear to be closely related not only to vascular disease phenotype but also the pathophysiology of various neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. In this review, we briefly highlight cerebral and spinal blood flow and its autoregulation and show its relationship to neurological diseases.

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  • High Incidence of Dementia Conversion than Stroke Recurrence in Poststroke Patients of Late Elder Society. Reviewed International journal

    Yumiko Nakano, Kentaro Deguchi, Toru Yamashita, Ryuta Morihara, Kosuke Matsuzono, Yuko Kawahara, Kota Sato, Syoichiro Kono, Nozomi Hishikawa, Yasuyuki Ohta, Yasuto Higashi, Yoshiki Takao, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   24 ( 7 )   1621 - 8   2015.7

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    BACKGROUND: This study investigated the incidence of current poststroke dementia (PSD), the annual conversion ratio into PSD, and the risk factors for conversion. METHODS: In a 4.8-year follow-up period, 112 poststroke patients (ischemic stroke and intracerebral hemorrhage) were retrospectively investigated in cognitive examinations. They were categorized into 3 subgroups: converters into PSD, nonconverters who maintained their normal cognitive functions, and reverters who recovered to the normal mentality range. The clinical and demographic characteristics of these 3 subgroups were analyzed. RESULTS: Among all 112 poststroke patients (61.6% male, 73.6 ± 10.4 years old), 16.1% had PSD. During the follow-up period, a part of the normal baseline mentality group (83.9% of 112 original patients) newly developed PSD (subdivided into converters) with an annual conversion rate of 7.6%. The reversion rate from the baseline PSD group was 11.3%. There were significant differences in age (P < .05), baseline mini-mental state examination scores (P < .05), body mass index (P < .05), and periventricular and deep white matter hyperintensity grades (P < .05 and P = .01, respectively) between converters and nonconverters. The annual rate of stroke recurrence was only 2.2% in all stroke subtypes. CONCLUSIONS: In comparison with stroke recurrence (2.2%), 7.6% of the annual PSD conversion rate was very high. Therefore, prevention of direct conversion into PSD without stroke recurrence may be another important aspect of poststroke clinics, especially in late elder society.

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  • Protective effect of telmisartan on neurovascular unit and inflammasome in stroke-resistant spontaneously hypertensive rats. Reviewed International journal

    Wentao Liu, Toru Yamashita, Tomoko Kurata, Syoichiro Kono, Nozomi Hishikawa, Kentaro Deguchi, Yun Zhai, Koji Abe

    Neurological research   37 ( 6 )   491 - 501   2015.6

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    OBJECTIVES: Hypertension is a crucial risk factor for both stroke and dementia, including Alzheimer's disease (AD). We inspected the effect of telmisartan on the neurovascular unit (NVU) and related inflammatory responses in spontaneously hypertensive rat stroke resistant (SHR-SR) by observing the components of NVU such as N-acetyl glucosamine oligomer (NAGO), collagen IV, astrocytes, and matrix metalloproteinase-9 (MMP-9), as well as inflammasome NOD-like receptors family protein 3 (NLRP3). METHODS: In the present study, we examined the effect of a highly selective angiotensin type 1 (AT-1) antagonist of angiotensin 2 receptor with high lipid solubility, telmisartan, on NVU and related inflammatory responses in SHR-SR with a low dose (0.3 mg/kg/day) only for improving metabolic syndrome, and a high dose (3 mg/kg/day) for improving both metabolic syndrome and SHR-SR hypertension. RESULTS: Compared to normotensive Wistar rats, long-lasting hypertension in SHR-SR disrupted NVU by changing immunohistological components such as NAGO, collagen IV, astrocytes, and MMP-9. SHR-SR also strongly induced AD-related inflammasome NLRP3 in neuronal cells with age. However, such NVU disruption and inflammasome activation were greatly improved with dose-dependent telmisartan treatments. DISCUSSION: These results suggest that telmisartan comprehensively protected the NVU components by reducing inflammatory reactions relative to AD in hypertensive rats, which could also preclude the risk of AD under hypertension.

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  • Simultaneous assessment of cognitive and affective functions in multiple system atrophy and cortical cerebellar atrophy in relation to computerized touch-panel screening tests. Reviewed International journal

    Yuko Kawahara, Yoshio Ikeda, Kentaro Deguchi, Tomoko Kurata, Nozomi Hishikawa, Kota Sato, Syoichiro Kono, Taijun Yunoki, Yoshio Omote, Toru Yamashita, Koji Abe

    Journal of the neurological sciences   351 ( 1-2 )   24 - 30   2015.4

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    Cognitive impairment and affective dysfunction of multiple system atrophy (MSA) and cortical cerebellar atrophy (CCA) have not been simultaneously examined comparing standard test batteries and a sensitive tool to detect subtle cognitive decline in patients. In the present study, we simultaneously examined cognitive and affective ability in MSA with predominant cerebellar ataxia (MSA-C, n=25), MSA with predominant parkinsonism (MSA-P, n=8), and CCA (n=14) patients using computerized touch panel screening tests. Mini-mental state examination (MMSE), Hasegawa dementia scale-revised (HDS-R), frontal assessment battery (FAB), and Montreal cognitive assessment (MoCA) scores were significantly lower in MSA-C patients than in age-and gender-matched normal controls. One MSA-C patient showed a decrease in the regional cerebral blood flow (rCBF) of the frontal lobe. MSA-P patients showed no such cognitive decline. Only FAB and MoCA scores were significantly lower in the CCA patients. MSA and CCA patients also showed a mild to moderate depressive state. Touch-panel screening tests demonstrated a significant decline of beating devils game in all three disease groups including MSA-P patients, and a significant extension of the flipping cards game only in MSA-C patients. The present study demonstrated different cognitive and affective functions among MSA-C, MSA-P, and CCA patients, and a sensitive screening method for cognitive assessment using touch-panel tests.

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  • Long-term effect of telmisartan on Alzheimer's amyloid genesis in SHR-SR after tMCAO. Reviewed International journal

    Tomoko Kurata, Violeta Lukic, Miki Kozuki, Daisuke Wada, Kazunori Miyazaki, Nobutoshi Morimoto, Yasuyuki Ohta, Kentaro Deguchi, Toru Yamashita, Nozomi Hishikawa, Kosuke Matsuzono, Yoshio Ikeda, Tatsushi Kamiya, Koji Abe

    Translational stroke research   6 ( 2 )   107 - 15   2015.4

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    Telmisartan is expected to reduce not only the level of blood pressure but also neuroinflammation and neurotoxicity via pleiotrophic effects as a metabo-sartan. We examined the effects of telmisartan on Alzheimer's disease (AD) pathology in spontaneously hypertensive rat stroke resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO) by giving either telmisartan at 0 (vehicle), 0.3 mg/kg/day (low dose, with no reduction of blood pressure), or 3 mg/kg/day (high dose, with a significant reduction of blood pressure) p.o. from 3 months (M) of age, and performed immunohistological analysis at 6, 12, and 18 M of age. The numbers of amyloid β (Aβ)-positive neurons in the cerebral cortex and hippocampus and senile plaque (SP) in the ipsilateral cerebral cortex progressively increased with age until 18 M in the SHR-SR after tMCAO. On the other hand, low-dose telmisartan significantly reduced the number of Aβ-positive neuron as well as SP at 6, 12, and 18 M. High-dose telmisartan showed further reductions of the above AD pathology. The present study suggests that telmisartan reduced both intracellular Aβ and extracellular SP accumulations after tMCAO in SHR-SR, with a further improvement by combined BP lowering. Such a strong effect of telmisartan could provide a preventative approach for AD in post-stroke patients with hypertension.

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  • Neurovascular protection by telmisartan via reducing neuroinflammation in stroke-resistant spontaneously hypertensive rat brain after ischemic stroke. Reviewed International journal

    Syoichiro Kono, Tomoko Kurata, Kota Sato, Yoshio Omote, Nozomi Hishikawa, Toru Yamashita, Kentaro Deguchi, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   24 ( 3 )   537 - 47   2015.3

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    Telmisartan is a highly lipid-soluble angiotensin receptor blocker (ARB), which improves insulin sensitivity and reduces triglyceride levels and, thus, is called metabo-sartan. We examined the effects of telmisartan on neurovascular unit (N-acetylglucosamine oligomer [NAGO], collagen IV, and glial fibrillary acidic protein [GFAP]) and neuroinflammation (matrix metalloproteinase-9 [MMP-9] and inflammasome) in brain of stroke-resistant spontaneously hypertensive rat (SHR-SR). At 12 weeks of age, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups, that is, vehicle group, low-dose telmisartan group (.3 mg/kg/d), and high-dose telmisartan group (3 mg/kg/d, postoral). Immunohistologic analysis at ages 6, 12, and 18 months showed progressive decreases of NAGO-positive endothelium and collagen IV-positive basement membrane and progressive increases of MMP-9-positive neurons, GFAP-positive astrocytes, and NLRP3-positive inflammasome in the cerebral cortex of vehicle group. Low-dose telmisartan reduced such changes without lowering blood pressure (BP), and high-dose telmisartan further improved such changes with lowering BP. The present findings suggest that a persistent hypertension caused a long-lasting inflammation after tMCAO in SHR-SR, which accelerated neurovascular disruption and emergent inflammasome, and that telmisartan greatly reduced such inflammation and protected the neurovascular unit via its pleiotropic effects in living hypertensive rat brain after ischemic stroke.

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  • Tumefactive demyelinating disease mimicking malignant tumor in positron emission tomography with C-11-methionine

    Kosuke Matsuzono, Kentaro Deguchi, Nozomi Hishikawa, Toru Yamashita, Tomotsugu Ichikawa, Isao Date, Koji Abe

    NEUROLOGY AND CLINICAL NEUROSCIENCE   3 ( 2 )   81 - 83   2015.3

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    Tumefactive demyelination is sometimes difficult differentiate from malignant tumors. Positron emission tomography with C-11-methionine is useful for diagnosing cerebral malignant tumors, but there are previous reports for tumefactive demyelination. We experienced a 32-year-old man who suffered from subacute onset dysarthria and left hemiparesis with magnetic resonance image of a large lesion (5.3 x 4.2 cm) in the right frontal lobe. Positron emission tomography with F-18-fluorodeoxyglucose showed a high ring-shaped glucose uptake in the lesion and C-11-methionine showed a remarkable methionine uptake in the whole lesion. Although a malignant tumor was suspected, the patient was finally diagnosed with tumefactive demyelinating disease based on brain biopsy results, and was treated completely by methylpredonisolone therapy. Although C-11-methionine uptake with positron emission tomography commonly suggests a malignant tumor, there can still be a possibility of tumefactive demyelinating disease.

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  • Cognitive and affective functions in diabetic patients associated with diabetes-related factors, white matter abnormality and aging Reviewed

    N. Hishikawa, T. Yamashita, K. Deguchi, J. Wada, K. Shikata, H. Makino, K. Abe

    European Journal of Neurology   22 ( 2 )   313 - 321   2015.2

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    Diabetes mellitus (DM) is associated with a decline in cognitive and affective functions. Methods: In all, 182 outpatients with DM were investigated for associations of cognitive and affective functions with diabetes-related factors and cerebral white matter abnormalities. In addition, the difference in cognitive decline of age-matched late elderly normal subjects and DM patients was investigated. Results: The present study revealed that cognitive and affective functions declined in some DM patients. Furthermore, the decline in these functions was unrelated to fasting blood sugar level but was related to glycosylated hemoglobin (HbA1c) and insulin resistance. Poor HbA1c control was associated with a significant decline in the 'calculation' subscale and insulin resistance for 'naming', 'read list of letters' and 'delayed recall' Montreal Cognitive Assessment (MoCA) subscale scores. Magnetic resonance imaging scans showed that both periventricular hyperintensity (PVH) and deep white matter hyperintensity were associated with Mini Mental State Examination (MMSE) and MoCA scores, but only PVH was related to homeostasis model assessment of insulin resistance scores. Compared with age-matched late elderly normal subjects, 'orientation to time' and 'registration' MMSE subscales declined in late elderly DM patients. Conclusions: These results suggest that cognitive and affective decline in DM patients was mostly related to glucose control and insulin resistance, whilst amongst late elderly subjects the impairment of 'attention' and 'orientation' were characteristic features of DM patients.

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  • Comprehensive Clinical Evaluations of Frontotemporal Dementia Contrasting to Alzheimer's Disease (oFTD Study). Reviewed International journal

    Kosuke Matsuzono, Nozomi Hishikawa, Toru Yamashita, Yasuyuki Ohta, Kota Sato, Shoichiro Kono, Kentaro Deguchi, Ryuta Morihara, Koji Abe

    Journal of Alzheimer's disease : JAD   48 ( 1 )   279 - 86   2015

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    BACKGROUND/OBJECTIVE: To examine comprehensive clinical evaluations of frontotemporal dementia (FTD) patients compared with Alzheimer's disease (AD) patients. METHODS: We used eight batteries and the touch panel test to retrospectively analyze 41 FTD patients compared with 121 AD patients. Furthermore, 34 FTD and all 121 AD patients were evaluated with a frontotemporal dementia-Alzheimer's disease index (FA index), which we developed for novel diagnosis with magnetic resonance imaging. RESULTS: Frontal assessment battery, geriatric depression scale, and Abe's behavioral and psychological symptom of dementia score were significantly worse in FTD patients than in AD patients ( **p <  0.01 in FAB,  **p <  0.01 in the geriatric depression scale, and  ***p <  0.001 in Abe's behavioral and psychological symptom of dementia score), although there was no significant difference in the other five scores. The finding mistakes game score of the touch panel test was worse in FTD than in AD ( *p <  0.05). The receiver operating characteristic curve of the FA index showed 91.4% sensitivity and 89.3% specificity with the FA index ≤0.6015 to discriminate FTD from AD. CONCLUSION: Combining clinical scores, a computerized touch panel test, and the FA index will help to provide a more accurate diagnosis of FTD in contrast to AD.

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  • Telmisartan promotes potential glucose homeostasis in stroke-resistant spontaneously hypertensive rats via peroxisome proliferator-activated receptor γ activation. Reviewed International journal

    Yoshio Omote, Kentaro Deguchi, Tomoko Kurata, Toru Yamashita, Kota Sato, Nozomi Hishikawa, Koji Abe

    Current neurovascular research   12 ( 1 )   91 - 7   2015

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    An angiotensin 2 type 1 receptor blocker (ARB) telmisartan possesses not only an anti-hypertensive effect but also an anti-metabolic syndrome effect due to peroxisome proliferator-activated receptor γ (PPAR-γ) activation. In the present study, we examined the effects of telmisartan on the angiotensin 2 type 1 receptor (AT1R), PPAR-γ, and insulin receptor (IR) in stroke-resistant spontaneously hypertensive rats (SHR-SR), comparing them with Wistar rats. Three-months-old SHR-SR rats were divided into three treatment groups, i.e., vehicle (SHR/Ve), low-dose telmisartan (0.3 mg/kg/day, SHR/Low), and high-dose telmisartan (3 mg/kg/day, SHR/High). Compared with Wistar rats, SHR/Ve increased the staining of AT1R, PPAR-γ and IR in the cerebral cortical neurons. On the other hand, telmisartan dose-dependently suppressed the excessive expression of AT1R and IR, but enhanced PPAR-γ activation. Low-dose telmisartan showed these effects even without lowering blood pressure (BP), while high-dose telmisartan lowered BP and showed further effects. The present study suggests that even a low dose of telmisartan decreased AT1R and IR, and increased PPAR-γ in the cerebral cortex of SHR-SR without lowering BP, probably by improving glucose homeostasis. The high dose of telmisartan showed further decreases in AT1R and IR, and further PPAR-γ activation while lowering BP, suggesting an additive benefit to lowering BP, namely the improvement of glucose homeostasis.

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  • Combination Therapy of Cholinesterase Inhibitor (Donepezil or Galantamine) plus Memantine in the Okayama Memantine Study. Reviewed International journal

    Kosuke Matsuzono, Nozomi Hishikawa, Yasuyuki Ohta, Toru Yamashita, Kentaro Deguchi, Yumiko Nakano, Koji Abe

    Journal of Alzheimer's disease : JAD   45 ( 3 )   771 - 80   2015

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    BACKGROUND/OBJECTIVE: To compare the effectiveness of combination therapy with cholinesterase inhibitors (ChEI) plus memantine in all AD patients and in older AD patients (age >75 years). METHODS: The Okayama Memantine Study was used to compare the clinical effects of combination therapy of donepezil plus memantine (n = 61) or galantamine plus memantine (n = 53) in all AD patients, and in older AD patients separately, with six batteries at baseline, at 6 months with ChEI only monotherapy, and at 3, 6, and 12 months after addition of memantine to the treatment schedule (18 months total). RESULTS: The addition of memantine resulted in stabilization of the Mini-Mental State Examination scores and Hasegawa dementia rating for 6 months, and then significantly declined at 12 months in both subgroups. Frontal assessment battery (FAB) declined significantly at 12 months after memantine addition in the donepezil subgroup, while the galantamine subgroup significantly improved at 6 months. Affective functions were well preserved after memantine addition until 12 months, except for the apathy scale at 12 months after memantine addition in the galantamine subgroup. The combination therapy of donepezil plus memantine was better for apathy in older AD patients, and galantamine plus memantine was better for cognitive functions. CONCLUSIONS: The addition of memantine stabilized cognitive scores for 6 months and affective scores for 12 months in the donepezil subgroup. Additionally, memantine significantly improved FAB at 6 months in the galantamine subgroup although apathy scale became significantly worse at 12 months.

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  • Computerized touch-panel screening tests for detecting mild cognitive impairment and Alzheimer's disease. Reviewed

    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 (Tokyo, Japan)   54 ( 8 )   895 - 902   2015

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    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<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<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<0.01) and the apathy scale (AS) (* p<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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  • [SCA6 presenting parkinsonism without ataxia--A case report]. Reviewed

    Shinichi Takeshima, Ikuko Takeda, Keitaro Kobatake, Toru Yamashita, Koji Abe, Masaru Kuriyama

    Rinsho shinkeigaku = Clinical neurology   55 ( 4 )   243 - 7   2015

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    A 57-year-old man was admitted to our hospital because of bradykinesia. He was diagnosed with Parkinson disease (Hoehn and Yahr grade 2) and administered levodopa at the maximum dose of 800 mg. However, his condition did not improve. While his symptoms were responsive to levodopa therapy, the sensitivity to the drug was poor. Brain MRI revealed atrophy of the upper vermis and cerebral hemispheres, and brain SPECT revealed low perfusion in both parietal lobes. I(123)-metaiodobenzylguanidine scintigraphy showed a decrease in the heart/mediastinum ratio. Striatal dopamine transporter (DAT) density was evaluated using I(123)-FP-CIT. The patient showed moderately reduced DAT density, which suggested nigrostriatal dopaminergic damage. His mother was found to have pure cerebellar ataxia without parkinsonism, and her two siblings also had celebellar type of multiple system atrophy (MSA-C) and progressive supranuclear palsy, respectively. Genetic testing revealed that the patient, his mother and the uncle with MSA-C had spinocerebellar ataxia type 6 (SCA6). SCA6 presenting parkinsonism without ataxia is very rare and important for the pathomechanism of disease.

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  • Time-dependent profiles of microRNA expression induced by ischemic preconditioning in the gerbil hippocampus. Reviewed International journal

    Miao Sun, Toru Yamashita, Jingwei Shang, Ning Liu, Kentaro Deguchi, Juan Feng, Koji Abe

    Cell transplantation   24 ( 3 )   367 - 76   2015

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    MicroRNAs (miRNAs) are critically important in both normal neuronal development and neurological diseases. Although cerebral ischemia has been shown to alter the miRNA profiles of rats, the role of miRNA in the cornu ammonis 1 region of the gerbil hippocampus under ischemic tolerance has not been studied. In the present study, Mongolian gerbils were subjected to one or three times the nonlethal dose of 2-min transient common carotid artery occlusion (tCCAO). miRNA microarray technology detected 251 miRNAs and the expression of seven of these in terms of ischemic tolerance. They were compared at different time points: 1 day, 7 days, 1 month, and 6 months. mmu-miR-15a-5p, related to neurogenesis, showed increased expression after one dose of 2-min tCCAO and was much higher after three doses. An increase in sha-miR-24 and oan-let-7b-3p, related to transactivation response DNA-binding protein (TDP43), was observed after one dose of 2-min tCCAO, but the peak was accelerated to an earlier period of reperfusion after three doses. In contrast, mmu-miR-125b-5p and mmu-miR-132-5p, related to fused in sarcoma/translocated in liposarcoma (FUS/TLS), showed similar increases at both doses. mmu-miR-181c-5p and mmu-miR-378a-5p, related to heat shock protein 70 (HSP70), also showed accelerated expression after three doses. This data set provides new insight about miRNA expression during neurogenesis, and related to TDP43, FUS/TLS, and HSP70, which may be useful when pursuing further studies on the possible use of miRNAs as biomarkers in cerebral ischemic tolerance and neuroregeneration.

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  • Single photon emission computed tomography (SPECT) findings of a patient with a novel prion mutation. Reviewed

    Kosuke Matsuzono, Ryuta Morihara, Kota Sato, Nozomi Hishikawa, Toru Yamashita, Kentaro Deguchi, Koji Abe

    Internal medicine (Tokyo, Japan)   54 ( 1 )   79 - 82   2015

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    We experienced a unique case of familial prion disease with a prion gene mutation that caused pan-autonomic failure, sensory neuropathy and mild cognitive impairment. No abnormal sites of intensity were observed on diffusion-weighted magnetic resonance image (MRI) over six to 11 years or fluid attenuated inversion recovery MRI at six or nine years. However, (99m)Tc-ethylcysteinate dimer single photon emission computed tomography (SPECT) showed a decreased cerebral blood flow in the bilateral parietal and occipital lobes at nine years, which then expanded at 11 years, corresponding to mild atrophy in these areas on MRI. In some cases of prion mutations, particularly the slowly progressive type, SPECT may show abnormalities, while MRI does not.

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  • Clinical Benefits of Memantine Treatment for Alzheimer's Disease in the Okayama Memantine Study II (OMS II). Reviewed International journal

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

    Journal of Alzheimer's disease : JAD   47 ( 2 )   487 - 93   2015

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    The clinical benefits of memantine, depending on the baseline cognitive and affective conditions in real world dementia clinics, have not been completely examined. We performed the "Okayama Memantine Study II (OMS II)" to retrospectively evaluate the clinical effects of memantine monotherapy (n = 38) in Alzheimer's disease (AD) patients using seven batteries to assess dementia at the baseline, at 3, 6, and 12 months. Additionally, we divided 163 AD patients treated with memantine into two subgroups depending on the baseline cognitive score of the Mini-Mental State Examination (MMSE): the MMSE <15 group (n = 36) and the baseline MMSE ≥15 group (n = 127). We also analyzed 71 AD patients based on the baseline behavioral and psychological symptoms of dementia (BPSD) severity using Abe's BPSD score (ABS). Memantine monotherapy maintained cognitive functions until 6 months of treatment, but showed a decrease at 12 months ( *p <  0.05 versus baseline). However, memantine monotherapy greatly improved BPSD symptoms until 12 months ( *p <  0.05,  **p <  0.01) and maintained other affective functions as well as the activity of daily living. Memantine treatment showed similar effects, regardless of the baseline cognitive functions, but showed better effects on ABS for higher baseline cognitive functions. Memantine treatment greatly improved ABS depending on baseline BPSD severity. Our present OMS II showed that memantine monotherapy improved BPSD until 12 months. The higher baseline cognitive subgroup (MMSE ≥15) and the worse baseline BPSD subgroup were expected to show better effects with memantine.

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  • Long-Term Efficacy of Galantamine in Alzheimer's Disease: The Okayama Galantamine Study (OGS). Reviewed International journal

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

    Journal of Alzheimer's disease : JAD   47 ( 3 )   609 - 17   2015

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    BACKGROUND: Alzheimer's disease (AD) is one of the most significant diseases affecting an increasingly aging society. OBJECTIVE: To determine the long-term efficacy of galantamine treatment in a Japanese population. METHODS: We performed "Okayama Galantamine Study (OGS)" to retrospectively analyze the clinical effects of galantamine in 279 AD patients using 7 batteries for assessing dementia at baseline, 3, 6, 12, and 24 months. We further analyzed the effects of galantamine based on gender and the severity of their baseline cognitive, affective, and activity of daily living (ADL) functions. RESULTS: In all 279 AD patients (80.6 ± 7.2 years old, MMSE 20.0 ± 4.5), cognitive functions were well preserved until 12 months and even frontal assessment battery improved after 12 months although Hasegawa dementia scale-revised finally worsened at 24 months ( *p <  0.05) with galantamine treatment. Affective and ADL functions were also well maintained after galantamine treatment with significant improvement of Geriatric Depression Scale scores at 3 months ( *p <  0.05). Subanalyses showed the better response to galantamine for male and lower baseline function subgroups. CONCLUSIONS: Our present study (OGS) revealed a long-term efficacy of galantamine in very elderly AD patients, and suggested a better efficacy for male and baseline lower cognitive, affective, and ADL functions.

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  • Selective disappearance of medial back muscles in a case of myotonic dystrophy type 1. Reviewed International journal

    Ryuta Morihara, Nozomi Hishikawa, Toru Yamashita, Kentaro Deguchi, Tomoko Kurata, Koji Abe

    Journal of the neurological sciences   353 ( 1-2 )   185 - 6   2015

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    Here, we report a unique case of late-onset myotonic dystrophy type 1 in a 64-year-old woman, with selective disappearance of the medial lower back muscles. We compared the clinical features of this patient with those of a cohort of 29 patients with myotonic dystrophy type 1 to clarify the correlation between clinical features and lower back muscle atrophy. After classification into three subgroups according to muscle atrophy pattern, medial muscle atrophy was present in 17.2% of the patients. Affected patients were older at onset than non-affected patients, and limb muscle power and respiratory function decreased with atrophy progression.

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

    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

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    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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  • Clinical Benefits of Rivastigmine in the Real World Dementia Clinics of the Okayama Rivastigmine Study (ORS). Reviewed International journal

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

    Journal of Alzheimer's disease : JAD   48 ( 3 )   757 - 63   2015

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    BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) is one of the most important diseases in an aging society, but the clinical effects of rivastigmine have not been fully examined in real world domestic clinics. METHODS: We performed the "Okayama Rivastigmine Study (ORS)" to retrospectively analyze the clinical effects of rivastigmine (n = 75) or donepezil (n = 71) on AD patients with seven dementia assessment batteries at the baseline, 3, 6, and 12 months. In addition, we divided the rivastigmine group into two subgroups at the baseline: the mild behavioral and psychological symptoms of dementia (BPSD) group (Abe's BPSD score (ABS) <6) and the severe BPSD group (6≤ABS). In these two subgroups, baseline scores and changes were also retrospectively analyzed until 12 months. RESULTS: Rivastigmine significantly improved the Mini-Mental State Examination score at 3 months (*p <  0.05 versus baseline) and at 6 months (*p <  0.05), the Frontal Assessment Battery (FAB) at 6 months (*p <  0.05), and ABS at 3 months (**p <  0.01) while donepezil only stabilized the three cognitive scores. On the other hand, the Geriatric Depression Scale and the Apathy Scale were stable until 12 months in both groups. Baseline BPSD severity-dependent analysis showed a small improvement of FAB at 6 months in the mild BPSD subgroup (*p <  0.05) and a great improvement of ABS at 3 months in the severe BPSD subgroup (**p <  0.01) in the rivastigmine group. CONCLUSIONS: Our present study showed that rivastigmine improved both cognitive and affective functions at 3 and 6 months, and suggested an advantage at 3 and 6 months compared to donepezil in real world dementia clinics.

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  • Clinical Benefits for Older Alzheimer's Disease Patients: Okayama Late Dementia Study (OLDS). Reviewed International journal

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

    Journal of Alzheimer's disease : JAD   46 ( 3 )   687 - 93   2015

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    BACKGROUND/OBJECTIVE: There are few reports on the effects of anti-Alzheimer's disease (AD) drugs on older AD patients, and possible differences based on gender in a real world setting. METHODS: "Okayama Late Dementia Study (OLDS)" is a retrospective clinical cohort study focusing on older AD patients (n = 373; age≥75 years) treated with monotherapy donepezil (n = 55), galantamine (n = 222), rivastigmine (n = 63), or memantine (n = 33). The patients were evaluated as an entire group and separated by gender, using seven batteries for dementia assessment at baseline and at 3, 6, and 12 months of drug therapy. RESULTS: All four drugs preserved cognitive and affective functions until 12 months, except for Frontal Assessment Battery (FAB) with memantine ( *p <  0.05 versus baseline). Donepezil monotherapy significantly improved Hasegawa Dementia Rating Scale-Revised (HDS-R) at 3 months ( *p <  0.05), and memantine (3 and 6 months, *p <  0.05) and rivastigmine (3 months, **p <  0.01) improved Abe's Behavior and Psychological Symptom of Dementia Score (ABS), respectively. Activities of daily living (ADL) became significantly worse with galantamine at 12 months ( *p <  0.05). Male Mini-Mental State Examination scores became worse at 12 months with donepezil ( *p <  0.05), as did female Geriatric Depression Scale scores at 6 months ( *p <  0.05). Male HDS-R and ABS scores were preserved in the galantamine group until 12 months. Female ABS scores with memantine improved at 6 months ( *p <  0.05), while male ADL scores became worse with rivastigmine at 12 months ( *p <  0.05). CONCLUSION: OLDS revealed that anti-AD drugs were effective even for older AD patients, and the clinical benefits of each drug showed a small difference with regard to gender.

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  • A new simple score (ABS) for assessing behavioral and psychological symptoms of dementia Reviewed

    K. Abe, T. Yamashita, N. Hishikawa, Y. Ohta, K. Deguchi, K. Sato, K. Matsuzono, Y. Nakano, Y. Ikeda, Y. Wakutani, Y. Takao

    Journal of the Neurological Sciences   350 ( 1-2 )   14 - 17   2015

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    In addition to cognitive impairment, behavioral and psychological symptoms of dementia (BPSD) are another important aspect of most dementia patients. This studywas designed for a newsimple assessment of BPSD. Wefirst employed a clinical survey for the local community with sending an inquiry letter to all members (n= 129) of dementia caregiver society, and then attempted to create a new BPSD score for dementia with 10 BPSD items. This new simple BPSD score was compared to a standard-detailed BPSD score neuropsychiatric inventory (NPI) for a possible correlation (n=792) and a time to complete (n=136). Inter-rater reliabilitywas examined comparing scores between main and second caregivers (n = 70) for AD. Based on the clinical survey for local caregivers, a new BPSD score for dementia (ABS, Abe's BPSD score) was newly created, in which each BPSD item was allotted by an already-weighted score (maximum 1-9) based on the frequency and severity, and was finalized with taking temporal occurrences into account. ABS was filled by the main caregiver with a full score of 44, was well correlated with NPI (r = 0.716,p &lt
    0.01) in 792 AD patients (age 78.6 ± 7.0 years, MMSE 19.0 ± 5.9), and took a shorter time as only 56.8 ± 38.8 s (p &lt
    0.01) than NPI score (132.7 ± 94.0 s) with 136 AD patients. A high inter-rater reliability was obtained (r = 0.964,p &lt
    0.01) with a little smaller score (0.877 time) of ABS in secondary than the main caregivers. ABS provides a new simple and quick test for BPSD assessment, with a good correlation to NPI but a shorter time, and with a high inter-rater reliability. Thus ABS is useful for evaluating BPSD for mild to moderate dementia patients.

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  • Clinical and demographic predictors of mild cognitive impairment for converting to Alzheimer's disease and reverting to normal cognition. Reviewed International journal

    Ryo Tokuchi, Nozomi Hishikawa, Tomoko Kurata, Kota Sato, Syoichiro Kono, Toru Yamashita, Kentaro Deguchi, Koji Abe

    Journal of the neurological sciences   346 ( 1-2 )   288 - 92   2014.11

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    OBJECTIVE: To identify clinical and demographic predictors for mild cognitive impairment (MCI) conversion to Alzheimer's disease (AD) or reversion to normal cognition, and sustained MCI. METHODS: In total, 74 baseline MCI subjects were retrospectively investigated and categorized into three subgroups: conversion to AD, sustained MCI, or reversion to normal cognition during one year. The clinical and demographic characteristics assessed were age, gender, educational attainment, vascular risk factors, white matter lesions (WMLs), and parahippocampal gyrus atrophy (PGA), analyzed by magnetic resonance imaging (MRI) using the voxel-based specific regional analysis system for AD (VSRAD). RESULTS: Of the 74 MCI subjects, 29 (39.2%) were classified as "converters", 39 (52.7%) as "sustained MCI", and 6 (8.1%) as "reverters". Among the three subgroups, there were significant differences in educational attainment (years) (*p = 0.03), baseline mini-mental state examination (MMSE) scores (***p<0.001), and periventricular and deep white matter hyperintensity grades (*p = 0.02 and *p = 0.03, respectively). Baseline PGA showed a significant increasing trend among the three subgroups (reverters<sustained MCI<converters, (###)p<0.001). MCI subjects with higher educational attainment and low VSRAD Z-scores without WMLs were associated with reversion to normal cognitive function. CONCLUSIONS: Risk factors for MCI conversion to AD were low educational attainment, low baseline MMSE scores, high grade WMLs, and high VSRAD Z-scores. High educational attainment, low VSRAD Z-scores, and no WMLs characterized reversion to normal cognition.

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  • Characteristic RNA foci of the abnormal hexanucleotide GGCCUG repeat expansion in spinocerebellar ataxia type 36 (Asidan) Reviewed

    W. Liu, Y. Ikeda, N. Hishikawa, T. Yamashita, K. Deguchi, K. Abe

    European Journal of Neurology   21 ( 11 )   1377 - 1386   2014.11

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    Background and purpose: Spinocerebellar ataxia type 36 (SCA36), also called Asidan, is an autosomal-dominant neurodegenerative disorder identified as a hexanucleotide GGCCTG repeat expansion in the first intron 1 of the NOP56 gene. In the present study, for the first time an autopsy sample from an Asidan patient was examined and cytoplasmic inclusions and (GGCCUG)n repeat RNA foci were detected. Methods: Hematoxylin and eosin staining, immunohistochemical staining, as well as fluorescence in situ hybridization were used to investigate the cytoplasmic inclusions of ubiquitin and p62 and the (GGCCUG)n repeat RNA foci. Results: The present study showed both ubiquitin- and p62-positive inclusions in the cytoplasm of the inferior olivary nucleus of the Asidan patient, (GGCCUG)n RNA foci in neuronal nuclei of the cerebrum, cerebellum, inferior olive, spinal cord and temporal muscle, and three types of RNA foci, i.e. single small, multiple small and giant. Of interest is that the giant RNA foci, nearly 10 μm in diameter, that were detected in Purkinje cells, spinal motor neurons and most frequently in the inferior olivary nucleus, may be responsible for pivotal clinical symptoms of Asidan. Conclusions: The present study is the first report to show neuronal cytoplasmic inclusion bodies and giant RNA foci in an Asidan patient. The relationships between the giant RNA foci and neurodegeneration have yet to be studied.

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  • Pericyte protection by edaravone after tissue plasminogen activator treatment in rat cerebral ischemia. Reviewed International journal

    Kentaro Deguchi, Ning Liu, Wentao Liu, Yoshio Omote, Syoichiro Kono, Taijun Yunoki, Shoko Deguchi, Toru Yamashita, Yoshio Ikeda, Koji Abe

    Journal of neuroscience research   92 ( 11 )   1509 - 19   2014.11

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    Pericytes play a pivotal role in contraction, mediating inflammation and regulation of blood flow in the brain. In this study, changes of pericytes in the neurovascular unit (NVU) were examined in relation to the effects of exogenous tissue plasminogen activator (tPA) and a free radical scavenger, edaravone. Immunohistochemistry and Western blot analyses showed that the overlap between platelet-derived growth factor receptor β-positive pericytes and N-acetylglucosamine oligomers (NAGO)-positive endothelial cells increased significantly at 4 days after 90 min of transient middle cerebral artery occlusion (tMCAO). The number of pericytes and the overlap with NAGO decreased with tPA but recovered with edaravone 4 days after tMCAO with proliferation. Thus, tPA treatment damaged pericytes, resulting in the detachment from astrocytes and a decrease in glial cell line-derived neurotrophic factor secretion. However, treatment with edaravone greatly improved tPA-induced damage to pericytes. The present study demonstrates that exogenous tPA strongly damages pericytes and destroys the integrity of the NVU, but edaravone treatment can greatly ameliorate such damage after acute cerebral ischemia in rats.

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  • Anti-oxidative nutrient-rich diet protects against acute ischemic brain damage in rats. Reviewed International journal

    Taijun Yunoki, Kentaro Deguchi, Yoshio Omote, Ning Liu, Wentao Liu, Nozomi Hishikawa, Toru Yamashita, Koji Abe

    Brain research   1587   33 - 9   2014.10

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    We evaluated the neuroprotective effects of an anti-oxidative nutrient rich enteral diet (AO diet) that contained rich polyphenols (catechins and proanthocyanidins) and many other anti-oxidative ingredients. Wistar rats were treated with either vehicle, normal AO diet (containing 100kcal/100mL, catechin 38.75mg/100mL and proanthocyanidin 19mg/100mL, 1mL/day), or high AO diet (containing 10 times the polyphenols of the normal AO diet) for 14 days, and were subjected to 90min of transient middle cerebral artery occlusion. The AO diet improved motor function, reduced cerebral infarction volume, and decreased both peroxidative markers such as 4-hydroxynonenal, advanced glycation end products, 8-hydroxy-2-deoxyguanosine and inflammatory markers such as monocyte chemotactic protein-1, ionized calcium-binding adapter molecule-1, and tumor necrosis factor-α. Our study has shown that an AO diet has neuroprotective effects through both anti-oxidative and anti-inflammatory mechanisms, indicating that nutritional control with polyphenols could be useful for patients with acute ischemic stroke.

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  • Strong improvement of apolipoprotein E/low-density lipoprotein receptor signals by telmisartan in poststroke spontaneously hypertensive stroke resistant. Reviewed International journal

    Toru Yamashita, Yun Zhai, Tomoko Kurata, Nozomi Hishikawa, Nobutoshi Morimoto, Yasuyuki Ohta, Kentaro Deguchi, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   23 ( 9 )   2240 - 9   2014.10

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    BACKGROUND: Telmisartan, an angiotensin receptor blocker also called metabosartan, is a promising solution for preventing cognitive decline or the incidence of dementia. METHODS: We examined the effects of telmisartan on cholesterol transport-related proteins (apolipoprotein E [ApoE]/low-density lipoprotein receptor [LDL-R]) and microtubule-associated protein 2 (MAP2) in the brain of spontaneously hypertensive stroke resistant (SHR-SR). SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes at 12 weeks of age and then was divided into 3 experiment groups including a vehicle, low-dose telmisartan (.3 mg/kg/day), and high-dose telmisartan (3 mg/kg/day). RESULTS: The low dose served to improve the metabolic syndrome of SHR-SR without lowering the blood pressure (BP) whereas the high dose was used to improve metabolic syndrome while lowering BP. Immunohistologic analysis showed that ApoE expression of cortical neurons was strong in the vehicle group at 6, 12, and 18 months of age, and that this ApoE expression pattern was very similar between the ipsilateral and contralateral sides of cerebral ischemia. On the other hand, LDL-R expression of cortical neurons was transiently increased at 6 months of age only on the ipsilateral side. Telmisartan dramatically suppressed the expression of ApoE/LDL-R at both doses. There was no remarkable difference in neuronal MAP2 staining between the 3 groups. CONCLUSIONS: These findings suggest that both low and high doses of telmisartan prevented the activation of ApoE/LDL-R in SHR-SR after tMCAO, and that the antimetabolic effect was regarded as the most important mechanism with few additional benefits by lowering BP in this transient stroke model.

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  • Ketogenic diet therapy is effective in encephalitis with refractory seizures. Reviewed International journal

    Kosuke Matsuzono, Tomoko Kurata, Shoko Deguchi, Toru Yamashita, Kentaro Deguchi, Koji Abe

    Neurological research   36 ( 10 )   906 - 10   2014.10

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    OBJECTIVE AND IMPORTANCE: Although ketogenic diet therapy is effective in refractory seizures in childhood, its effect on adult encephalitis with similar refractory seizures and prolonged encephalopathy has not been well reported. CLINICAL PRESENTATION: We report here a case of a 22-year-old man with acute encephalitis with refractory repetitive partial seizures (AERRPS). INTERVENTION: Partial seizures of the face developed to repeated generalized convulsions, which were refractory against anti-epileptic drugs and a high dose of propofol. After struggling for 9 months, he dramatically recovered after ketogenic diet therapy. CONCLUSION: Ketogenic diet therapy may be an important tool to help cure AERRPS.

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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. Reviewed International journal

    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 and cerebrovascular diseases : the official journal of National Stroke Association   23 ( 9 )   2350 - 61   2014.10

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    BACKGROUND: Telmisartan is a unique angiotensin II type 1 receptor blocker with a partial peroxisome proliferator-activated receptor-γ (PPARγ) 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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  • Synergistic neuroprotective effects of combined treatment with olmesartan plus azelnidipine in stroke-prone spontaneously hypertensive rats. Reviewed International journal

    Yoshio Omote, Kentaro Deguchi, Syoichiro Kono, Wentao Liu, Tomoko Kurata, Nozomi Hishikawa, Toru Yamashita, Yoshio Ikeda, Koji Abe

    Journal of neuroscience research   92 ( 10 )   1330 - 7   2014.10

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    An angiotensin 2 type 1 receptor blocker, olmesartan, and a calcium channel blocker, azelnidipine, possess not only an antihypertensive effect but also an antioxidative effect and other beneficial effects. In the present study, we examined the efficacy of olmesartan and azelnidipine monotherapy (2 mg/kg or 10 mg/kg each) and their combination therapy (1 mg/kg each) on stroke-prone spontaneously hypertensive rats (SHR-SP) in relation to oxidative stress, inflammation, and the neurovascular unit. In comparison with the vehicle group, body weight, regional cerebral blood flow, and motor function were preserved, whereas systolic blood pressure and diastolic blood pressure decreased in the five drug-treatment groups. Spontaneous infarct volume decreased with the low-dose combination of olmesartan plus azelnidipine and with the high-dose olmesartan, with a further decrease in the high-dose azelnidipine group. In addition, these drugs dose-dependently reduced oxidative stresses, proinflammatory molecules, and well-preserved components of the neurovascular unit. The low-dose combination of olmesartan plus azelnidipine showed a better effect than the low-dose olmesartan or azelnidipine monotherapy. The present study shows that the low-dose combination of olmesartan plus azelnidipine demonstrates a greater synergistic benefit than monotherapy with a low-dose of olmesartan or azelnidipine in SHR-SP for preventing spontaneous infarct volume, reducing oxidative stresses and proinflammatory molecules, and imparting neurovascular protection. In addition, a high-dose of olmesartan showed a greater benefit without the lowering of blood pressure, probably because of the antioxidative and anti-inflammatory effects. A high dose of azelnidipine showed the best benefit, probably because of the two effects mentioned above related to the lowering of blood pressure.

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  • Rivaroxaban and apixaban reduce hemorrhagic transformation after thrombolysis by protection of neurovascular unit in rat. Reviewed International journal

    Syoichiro Kono, Toru Yamashita, Kentaro Deguchi, Yoshio Omote, Taijun Yunoki, Kota Sato, Tomoko Kurata, Nozomi Hishikawa, Koji Abe

    Stroke   45 ( 8 )   2404 - 10   2014.8

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    BACKGROUND AND PURPOSE: This study aimed to assess the risk and benefit of tissue-type plasminogen activator treatment after oral anticoagulation with rivaroxaban or apixaban compared with warfarin or placebo. METHODS: Pretreatment with warfarin (0.2 mg/kg per day), rivaroxaban (2 mg/kg per day), apixaban (10 mg/kg per day), or vehicle (0.5% carboxymethyl cellulose sodium salt) was performed for 7 days. Transient middle cerebral artery occlusion was then induced for 120 minutes, followed by reperfusion with tissue-type plasminogen activator (10 mg/kg per 10 mL). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. Twenty-four hours after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and matrix metalloproteinase-9 activity was measured by zymography. RESULTS: The paraparesis score was significantly improved in the rivaroxaban-pretreated group compared with the warfarin-pretreated group. Intracerebral hemorrhage was observed in the warfarin-pretreated group, and this was reduced in the rivaroxaban and apixaban-pretreated groups compared with the vehicle group. Marked dissociation of astrocyte foot processes and the basal lamina or pericytes was observed in the warfarin-pretreated group, and this was improved in the rivaroxaban and apixaban-pretreated groups. Furthermore, activation of matrix metalloproteinase-9 in the ipsilateral warfarin-pretreated brain was greatly reduced in rivaroxaban- and apixaban-pretreated rats. CONCLUSIONS: This study shows a lower risk of intracerebral hemorrhage after tissue-type plasminogen activator treatment in rats with ischemic stroke that are pretreated with rivaroxaban and apixaban compared with pretreatment with warfarin. Reducing neurovascular dissociation by rivaroxaban and apixaban compared with warfarin could partly explain a reduction in hemorrhagic complications reported in clinical studies.

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  • Protective effect of telmisartan against progressive oxidative brain damage and synuclein phosphorylation in stroke-resistant spontaneously hypertensive rats. Reviewed International journal

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

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   23 ( 6 )   1545 - 53   2014.7

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    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 α-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 α-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.

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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. Reviewed International journal

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

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   23 ( 6 )   1554 - 63   2014.7

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    Telmisartan is an angiotensin receptor blocker with high lipid solubility, also called metabosartan, which exerts a special protective effect on both acute brain damage and chronic neurodegeneration. We examined the effects of telmisartan on oxidative stress by advanced glycation end product (AGE) and 4-hydroxynonenal (4-HNE) assays and the accumulation of phosphorylated α-synuclein (pSyn) in the brain of stroke-resistant spontaneously hypertensive rats (SHR-SR). At the age of 12 weeks, SHR-SR received transient middle cerebral artery occlusion (tMCAO) for 90 minutes and were divided into the following 3 groups: the vehicle group, the low-dose telmisartan group (.3 mg/kg/day), and the high-dose telmisartan group (3 mg/kg/day, postoperatively). Immunohistologic analysis was performed when rats were 6, 12, and 18 months old. AGE, 4-HNE, and pSyn-positive cells (per square millimeter) increased with age in the cerebral cortex and hippocampus of the vehicle group, in the low-dose telmisartan group, these parameters decreased without lowering blood pressure (BP), and in the high-dose telmisartan group, these parameters increased with lowering BP. The present study suggests that a persistent hypertension after tMCAO caused a progressive oxidative stress with the abnormal accumulation of pSyn, and that telmisartan reduced oxidative stress and the accumulation of pSyn without lowering BP (low dose) or improved these conditions with a reduction in BP (high dose) via its pleiotropic effects through a potential peroxisome proliferator-activated receptor gamma stimulation in the brain of SHR-SR.

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  • Neurovascular protection of cilostazol in stroke-prone spontaneous hypertensive rats associated with angiogenesis and pericyte proliferation. Reviewed International journal

    Yoshio Omote, Kentaro Deguchi, Syoichiro Kono, Ning Liu, Wentao Liu, Tomoko Kurata, Toru Yamashita, Yoshio Ikeda, Koji Abe

    Journal of neuroscience research   92 ( 3 )   369 - 74   2014.3

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    Stroke is the major cause of death and decrease in the activities of daily living. This study sought to evaluate the effects of commonly used antiplatelet drugs on spontaneous cerebral infarction in relation to neurovascular protection associated with angiogenesis and pericyte proliferation. Stroke-prone spontaneously hypertensive rats (SHR-SP) were treated with vehicle, aspirin, clopidogrel, or cilostazol from 8 to 10 weeks of age. The interaction of neurovascular components among endothelial cells, pericytes, and astrocytic endfeet were immunohistochemically examined in brain sections. Angiogenesis associated with vascular endothelial growth factor receptor 2 (VEGFR2) and pericyte proliferation were also examined immunohistochemically. The expression and activity of matrix metalloproteinase 9 (MMP-9) were assessed immunohistochemically and by gelatin zymography. Among the antiplatelet drugs, cilostazol preserved the neurovascular unit (NVU) by preventing astrocytic endfeet or pericytes from pathological detachment found in the vehicle and aspirin treatment. Cilostazol also inhibited the expression and activity of MMP-9, which led to protection of the NVU. Furthermore, in the periinfarct area, cilostazol increased VEGFR2 expression, promoting angiogenesis through proliferation of pericytes. The present study showed a strong protection of NVU integrity by cilostazol and the promotion of angiogenesis by stimulating both endothelial VEGFR2 expression and pericyte proliferation. In addition to the antioxidative effect, these pleiotropic effects of cilostazol contribute to reduce spontaneous infarct volume and preserve motor and cognitive function in SHR-SP.

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  • Acceleration of TDP43 and FUS/TLS protein expressions in the preconditioned hippocampus following repeated transient ischemia. Reviewed International journal

    Miao Sun, Toru Yamashita, Jingwei Shang, Ning Liu, Kentaro Deguchi, Wentao Liu, Yoshio Ikeda, Juan Feng, Koji Abe

    Journal of neuroscience research   92 ( 1 )   54 - 63   2014.1

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    The 43-kDa transactivation response DNA binding protein (TDP43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), heat shock protein 70 (HSP70), and β-amyloid (Aβ) are induced and involved in cerebral ischemia, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), but their relationships in ischemic tolerance have never been examined, although they could be involved in endogenous neuroprotection under ischemic preconditioning. In the present study, Mongolian gerbils were subjected to one or three incidents of basically nonlethal 2-min transient common carotid arteries occlusion (tCCAO). Hippocampal CA1 neurons were lost only in the 2-min three times group at 3 and 7 days, which then gradually recovered from 1 to 6 months. Inductions of TDP43 and FUS/TLS were accelerated from 3 months to 7 days or from 7 days to 1 day, respectively, after 2-min three times ischemia compared with once. The cytoplasmic stainings of TDP43 and FUS/TLS showed a further acceleration of the peaks from 1 months to 3 days or from 1 months to 7 days, respectively, after 2-min three times ischemia compared with once. In contrast, HSP70 was induced only at 7 days after 2-min tCCAO for three times, with no expression for Aβ. These data show that ischemic preconditioning offers a way to induce endogenous neuroprotection and neurogenesis in gerbils, with TDP43, FUS/TLS, and HSP70 involved in this function.

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  • Reducing hemorrhagic complication by dabigatran via neurovascular protection after recanalization with tissue plasminogen activator in ischemic stroke of rat. Reviewed International journal

    Syoichiro Kono, Kentaro Deguchi, Yoshio Omote, Taijun Yunoki, Toru Yamashita, Tomoko Kurata, Yoshio Ikeda, Koji Abe

    Journal of neuroscience research   92 ( 1 )   46 - 53   2014.1

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    This study assesses the risks and benefits of tissue plasminogen activator (tPA) treatment under oral anticoagulation with dabigatran compared with warfarin or vehicle control in transient middle cerebral artery occlusion (tMCAO). After pretreatment with warfarin (0.2 mg/kg/day), dabigatran (20 mg/kg/day), or vehicle (0.5% carboxymethyl cellulose sodium salt) for 7 days, tMCAO was induced for 120 min, followed by reperfusion and tPA (10 mg/kg/10 ml). Clinical parameters, including cerebral infarction volume, hemorrhagic volume, and blood coagulation, were examined. At 24 hr after reperfusion, markers for the neurovascular unit at the peri-ischemic lesion were immunohistochemically examined in brain sections, and MMP-9 activity was measured by zymography. Paraparesis and intracerebral hemorrhage volume were significantly improved in the dabigatran-pretreated group compared with the warfarin-pretreated group. A marked dissociation between astrocyte foot processes and the basal lamina or pericyte was observed in the warfarin-pretreated group, which was greatly improved in the dabigatran-pretreated group. Furthermore, a remarkable activation of MMP-9 in the ipsilateral warfarin-pretreated rat brain was greatly reduced in dabigatran-pretreated rats. The present study reveals that the mechanism of intracerebral hemorrhage with warfarin-pretreatment plus tPA in ischemic stroke rats is the dissociation of the neurovascular unit, including the pericyte. Neurovascular protection by dabigatran, which was first shown in this study, could partially explain the reduction in hemorrhagic complication by dabigatran reported from clinical study.

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  • [Impact of combined medial temporal atrophy and white matter lesions on the cognitive and emotional functions in Alzheimer's disease patients]. Reviewed

    Ryou Tokuchi, Kentaro Deguchi, Toru Yamashita, Koji Abe

    Nihon Ronen Igakkai zasshi. Japanese journal of geriatrics   51 ( 4 )   342 - 9   2014

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    AIM: The purpose of this study was to determine the relationship between the combined presence of medial temporal atrophy (MTA) and white matter lesions (WMLs: periventricular hyperintensity (PVH) and deep white matter hyperintensity) and the cognitive/emotional function in Alzheimer's disease (AD) patients. METHODS: The subjects included 193 patients with AD and 30 normal elderly controls. On MRI, MTA was rated using the Voxel-based specific regional analysis system for AD (VSRAD). WMLs was also estimated using the Fazekas scale. The MRI measurements were classified as follows: MTA=VSRAD<2 or ≥2; WML absent (-) 0/1 or present (+) 2/3. A total of five groups were assessed, including four groups with AD and a control group. The cognitive and emotional functions were evaluated with neuropsychological tests (Mini-Mental State Examination (MMSE), Frontal Assessment Battery (FAB), Geriatric Depression Scale (GDS) and Apathy scale). RESULTS: Four AD groups showed significant declines in the both the MMSE and FAB scores compared to that observed in the control group ((***)p<0.001, (**)p<0.01, (*)p<0.05). Among these four AD groups, the MMSE and FAB scores of in the VSRAD<2 and WML (-) groups significantly declined to VSRAD≥2 and WML (+), respectively group ((*)p<0.05). VSRAD≥2 and WML (+) groups showed demonstrated significantly higher scores than the control group on the GDS ((*)p<0.05), and the PVH (+) group exhibited significantly higher scores than the control group on the apathy scale ((*)p<0.05). Multiple regression analysis identified a VSRAD score of ≥2 and the presence of WMLs to be most significantly associated with the cognitive and emotional functions. CONCLUSIONS: Combined presence of MTA and WML is associated with lower MMSE and FAB scores. Furthermore, depression is also associated with MTA and WML, while PVH independently affects the degree of apathy.

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  • Telmisartan ameliorates inflammatory responses in SHR-SR after tMCAO Reviewed

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

    Journal of Stroke and Cerebrovascular Diseases   23 ( 10 )   2511 - 2519   2014

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    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-a, and ionized calcium-binding adapter molecule 1 cells (/mm2) 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.

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  • Direct reprogrammed neuronal cells as a novel resource for cell transplantation therapy. Reviewed International journal

    Toru Yamashita, Koji Abe

    Cell transplantation   23 ( 4-5 )   435 - 9   2014

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    Cell transplantation/replacement therapy is attractive as a novel strategy for neurological diseases such as Parkinson's disease, Alzheimer's disease, and stroke. To realize this therapy, safer and more therapeutic effective cell resources are now required. Since induced pluripotent stem cells (iPSCs) can retain high replication competence and pluripotency when they differentiate into various kinds of cells, they are regarded as a promising cell source for cell transplantation therapy. However, high tumorigenesis of iPSCs has to be overcome for clinical applications. Recent progress includes the combination of novel transcriptional factors that can convert somatic cells to various kinds of mature neuronal cells and neural stem cells without requiring iPSC fate. Some evidence indicates that these directly induced neuronal cells have little tumorigenic potential. In this article, we discuss the advantage, issues, and possibility of clinical application of these cells for cell transplantation therapy.

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  • Cognitive and affective assessments of multiple sclerosis (MS) and neuromyelitis optica (NMO) patients utilizing computerized touch panel-type screening tests. Reviewed

    Yuko Kawahara, Masami Ikeda, Kentaro Deguchi, Nozomi Hishikawa, Syoichiro Kono, Yoshio Omote, Kosuke Matsuzono, Toru Yamashita, Yoshio Ikeda, Koji Abe

    Internal medicine (Tokyo, Japan)   53 ( 20 )   2281 - 90   2014

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    OBJECTIVE: Cognitive and affective dysfunctions are important aspects for patients with multiple sclerosis (MS) and neuromyelitis optica (NMO). METHODS: We herein examined the cognitive and affective ability in MS (n=35) and NMO (n=10) patients using computerized touch panel-type screening tests. RESULTS: While MS patients and normal controls (NC1, n=40) did not significantly differ in their scores from the Hasegawa dementia scale-revised (HDS-R) or the frontal assessment battery, MS patients did score significantly lower on the mini-mental state examination (MMSE). In contrast, NMO patients did not differ from the normal control group 2 (NC2, n=15) in any of the three cognitive assessments. We also examined the affective ability and found that MS patients scored significantly higher on the apathy scale (AS) compared with the NC1 group, while NMO patients scored significantly higher on the geriatric depression scale (GDS) compared with the NC2 group. Although the GDS and AS scores did not correlate with any of the cognitive assessments among MS patients, the AS scores did correlate with the MMSE and HDS-R among NMO patients. Compared with normal controls, the times to complete the flipping cards and arranging pictures games were significantly longer for MS patients but not for NMO patients. CONCLUSION: These results indicate differences between some features of cognitive and affective dysfunctions between MS and NMO patients. Computerized touch panel-type screening tests may be a more useful and sensitive tool for the cognitive assessment of MS patients than NMO patients.

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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 Reviewed

    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 and Cerebrovascular Diseases   23 ( 10 )   2646 - 2653   2014

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    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 proliferatoractivated receptor gamma (PPAR-g), 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-g-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.

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  • In vivo optical imaging correlates with improvement of cerebral ischemia treated by intravenous bone marrow stromal cells (BMSCs) and edaravone. Reviewed International journal

    FengFeng Tian, Toru Yamashita, Kentaro Deguchi, Yoshio Omote, Hiromi Kawai, Yasuyuki Ohta, Koji Abe

    Neurological research   35 ( 10 )   1051 - 8   2013.12

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    OBJECTIVE: Recent studies show that modern In vivo optical imaging can detect matrix metallopeptidase (MMP) activation in the ischemic brain. In this study, we analyze the protective effects of bone marrow stromal cells (BMSCs) and edaravone (EDA) against tissue plasminogen activator (tPA) risk in the ischemic brain with In vivo optical fluorescence MMP imaging. METHODS: At 48 hours after 60 minutes of transient middle cerebral artery occlusion (tMCAO) with tPA, C57BL/6J mice were subjected to motor function analysis, In vivo and ex vivo optical imaging for MMP activation, gelatin zymography, and double immunofluorescent analyses with or without intravenous BMSC transplantation and the intravenous free radical scavenger EDA. RESULTS: In vivo fluorescent signals for MMP were detected over the heads of living mice 48 hours after tMCAO; the strongest were in the tPA group, which were reduced by BMSC or EDA treatment. These In vivo data were confirmed by ex vivo fluorescence imaging. While massive intracerebral hemorrhages were observed in the ischemic hemispheres of the tPA group, only slight hemorrhages were found in the tPA/BMSC, tPA/EDA, and EDA groups. Gelatin zymography showed the strongest MMP-9 activation in the tPA group after tMCAO, which was reduced by BMSC or EDA treatment. CONCLUSION: The present study provides a correlation between In vivo optical imaging of MMP activation and the improvement of ischemic brain damage caused by tPA after tMCAO and treated by BMSC and EDA.

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  • Cerebral embolic stroke after disappearing takotsubo cardiomyopathy. Reviewed International journal

    Kosuke Matsuzono, Yoshio Ikeda, Shoko Deguchi, Toru Yamashita, Tomoko Kurata, Kentaro Deguchi, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   22 ( 8 )   e682-3   2013.11

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    Takotsubo cardiomyopathy can induce cerebral embolic stroke because of intracardiac thrombosis, but the timing of cardiogenic embolism relating to takotsubo cardiomyopathy has not been well described. We evaluated a 71-year-old woman with takotsubo cardiomyopathy, who developed cardiogenic cerebral embolism after recovery of cardiac wall motion. Nevertheless, we treated her with anticoagulation therapy. The present clinical observation suggests that attention should be paid to the timing when takotsubo cardiomyopathy resolves against risk of cardiogenic cerebral embolism.

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  • Intravenous thrombolysis with neuroprotective therapy by edaravone for ischemic stroke patients older than 80 years of age. Reviewed International journal

    Syoichiro Kono, Kentaro Deguchi, Nobutoshi Morimoto, Tomoko Kurata, Toru Yamashita, Yoshio Ikeda, Hisashi Narai, Yasuhiro Manabe, Yoshiki Takao, Sanami Kawada, Kenichi Kashihara, Yasushi Takehisa, Satoshi Inoue, Hideki Kiriyama, Koji Abe

    Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association   22 ( 7 )   1175 - 83   2013.10

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    BACKGROUND: Alteplase, a recombinant tissue plasminogen activator (tPA), was approved for patients with acute ischemic stroke within 3 hours of stroke onset in Japan in October 2005 at a dose of 0.6 mg/kg. The aim of this study was to assess the safety and efficacy of alteplase in elderly patients in Japan. METHODS: One hundred twenty-nine consecutive patients who were admitted to our 5 hospital groups and who received intravenous tPA within 3 hours of stroke onset between January 2010 and December 2011 were divided into 2 groups by age (<80 years of age [younger group] and >80 years of age [older group]) and by treatment with or without edaravone. Clinical backgrounds and outcomes were investigated. RESULTS: The National Institutes of Health Stroke Scale score on admission was not different in both groups, but the National Institutes of Health Stroke Scale scores 7 days after stroke onset were significantly higher in the older group (score 8; P < .05) than in the younger group (score 4), and the ratio of patients with a modified Rankin Scale score of 4 to 6 was significantly greater in the older group (41.7%; P < .05) than in the younger group (22.2%). However, there was no difference in asymptomatic and symptomatic intracerebral hemorrhage rates between the younger and older groups (asymptomatic 20.2% v 18.8%; symptomatic 2.6% v 2.1%). Patients with edaravone showed a higher recanalization rate (61.9%; P < .01) and a better modified Rankin Scale score at 3 months poststroke (P < .01) than the nonedaravone group. CONCLUSIONS: These data suggest that intravenous alteplase (0.6 mg/kg) within 3 hours of stroke onset was safe and effective, even for very old patients (≥ 80 years of age), but resulted in poor outcomes relating not to tPA but to aging. In addition, edaravone may be a good partner for combination therapy with tPA to enhance recanalization and reduce hemorrhagic transformation.

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  • Early and selective reduction of NOP56 (Asidan) and RNA processing proteins in the motor neuron of ALS model mice. Reviewed International journal

    Kazunori Miyazaki, Toru Yamashita, Nobutoshi Morimoto, Kota Sato, Takafumi Mimoto, Tomoko Kurata, Yoshio Ikeda, Koji Abe

    Neurological research   35 ( 7 )   744 - 54   2013.9

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    OBJECTIVE: There is increasing evidence to support that altered RNA processing is implicated in the pathogenesis of motor neuron degeneration of amyotrophic lateral sclerosis (ALS). We evaluate the expression of three RNA processing-related proteins in ALS model mice in this study. METHODS: We analyzed expression and distribution patterns of three RNA processing-related proteins, nucleolar protein (NOP) 56 (identified as causative gene for spinocerebellar ataxia (SCA) 36, nicknamed Asidan), TDP-43, and fused in sarcoma/translocated in liposarcoma (FUS) in lumbar and cervical cords, hypoglossal nucleus, cerebral motor cortex, and cerebellum of transgenic (Tg) SOD1 G93A ALS model mice throughout the course of motor neuron degeneration. RESULTS: Compared to age-matched wild type (WT) mice, Tg mice showed progressive reduction of NOP56 levels in the large motor neurons of lumbar and cervical cords from the early-symptomatic stage (14 weeks of age) to the end stage of the disease (18 weeks). TDP-43 and FUS protein levels showed a later decrease in the nucleus of large motor neuron at 18 weeks (end stage of the disease). These changes were not observed in the primary motor cortex of the cerebrum as well as molecular and granular layers and Purkinje cells in the cerebellum. DISCUSSION: The present study suggests a progressive loss of these three nuclear proteins and subsequent RNA processing problems including a novel gene relating to ALS (NOP56) under the motor neuron degeneration.

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  • Mitochondrial fusion and fission proteins expression dynamically change in a murine model of amyotrophic lateral sclerosis. Reviewed International journal

    Wentao Liu, Toru Yamashita, Fengfeng Tian, Nobutoshi Morimoto, Yoshio Ikeda, Kentaro Deguchi, Koji Abe

    Current neurovascular research   10 ( 3 )   222 - 30   2013.8

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    Mitochondria dynamically change their shape through frequent fusion and fission to continuously perform their function in the cell. Although a change in mitochondrial morphology was reported in amyotrophic lateral sclerosis (ALS), detailed changes of mitochondrial fusion and fission proteins have not been reported in ALS model mice. In transgenic (Tg) mice with the G93A human SOD1 mutation (G93ASOD1), both mitochondrial fusion proteins (Mfn1 and Opal) and fission proteins (Drp1 and Fis1) showed a significant increase in the anterior half of the lumbar spinal cord. Such changes in Tg mice were already noticeable at presymptomatic 10 week (W) compared with wildtype (WT) mice, detected through immunohistochemical as well as Western blot analyses. Furthermore, fusion protein levels of Mfn1 and Opa1 showed a progressive decrease from 10 to 18 W in Tg mice while fission protein levels of P-Drp1 and Fis1 maintained a high level of expression in Tg mice from 10 to 18 W. These data suggest that abnormal changes in mitochondrial morphology began before the onset of ALS and that the balanced mitochondrial morphology becomes altered by fissions in motor neurons (MNs) in this ALS model.

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  • Combination benefit of amlodipine plus atorvastatin treatment on carotid atherosclerosis in Zucker metabolic rats. Reviewed International journal

    Hiromi Kawai, Tomoko Kurata, Kentaro Deguchi, Shoko Deguchi, Toru Yamashita, Yasuyuki Ohta, Yoshio Omote, Syoichiro Kono, Koji Abe

    Neurological research   35 ( 2 )   181 - 6   2013.3

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    OBJECTIVES: Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases. METHODS: We studied effects of amlodipine, atorvastatin, and their combination on carotid arteriosclerotic processes in a metabolic syndrome model of Zucker fatty rats. Zucker fatty rats were treated with vehicle, amlodipine, atorvastatin, or combination amlodipine plus atorvastatin for 28 days. RESULTS: Compared with the single treatment with amlodipine or atorvastatin, the combination of amlodipine plus atorvastatin treatment prevented arteriosclerotic processes, and induced a strong recovery of Sirtuin1 (Sirt1) expression and a marked reduction in p53, p21, and monocyte chemoattractant protein-1 (MCP-1). DISCUSSION: As Sirt1 is a longevity gene that prevents endothelial atherosclerotic processes, and p53, p21, and MCP-1 play pivotal roles in the initiation and development of atherosclerosis, these data suggest a strong synergistic benefit of combination therapy with amlodipine and atorvastatin for preventing atherosclerotic processes, and potentially reducing the clinical risk of cerebrovascular events in metabolic obesity patients.

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  • Neuroleptic malignant syndrome associated with risperidone long-acting injection: a case report. Reviewed International journal

    Toru Yamashita, Yasuo Fujii, Fuminari Misawa

    Journal of clinical psychopharmacology   33 ( 1 )   127 - 9   2013.2

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  • Assessment of swallowing in motor neuron disease and Asidan/SCA36 patients with new methods. Reviewed International journal

    Nobutoshi Morimoto, Toru Yamashita, Kota Sato, Tomoko Kurata, Yoshio Ikeda, Toshimasa Kusuhara, Naomichi Murata, Koji Abe

    Journal of the neurological sciences   324 ( 1-2 )   149 - 55   2013.1

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    BACKGROUND: We report on a unique complication of cerebellar ataxia and motor neuron disease named Asidan/SCA36 with a high frequency of tongue atrophy. We aimed to elucidate dysphagia in amyotrophic lateral sclerosis (ALS) and spinal, bulbar muscular atrophy (SBMA), and Asidan/SCA36 patients with new methods. METHODS: Patients diagnosed with ALS (n=20), SBMA (n=6), and Asidan (n=12) were included. A videofluoroscopic swallow study (VFS), an assessment of maximal tongue pressure (MTP), and impedance pharyngography (IPG) were applied. RESULTS: The frequencies of VFS abnormalities were 70%, 50%, and 33% in ALS, SBMA, and Asidan/SCA36, respectively. Compared with control subjects (31.6 ± 6.3 kPa, mean ± SD), MTP was significantly decreased in ALS patients and SBMA patients, but was relatively preserved in Asidan patients. ALS patients performed more swallowing actions (Ns) detected by IPG than did control subjects, but SBMA and Asidan/SCA36 patients performed similar Ns to control subjects. CONCLUSIONS: VFS showed a higher frequency of swallowing abnormalities in ALS patients. MTP and IPG measurements showed the most severe involvement in ALS patients and a relatively preserved swallowing function in SBMA and Asidan/SCA36 patients.

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  • Synchronized Babinski and Chaddock signs preceded the MRI findings in a case of repetitive transient ischemic attack. Reviewed

    Kosuke Matsuzono, Takao Yoshiki, Yosuke Wakutani, Yasuhiro Manabe, Toru Yamashita, Kentaro Deguchi, Yoshio Ikeda, Koji Abe

    Internal medicine (Tokyo, Japan)   52 ( 18 )   2127 - 9   2013

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    We herein report a 53-year-old female with repeated transient ischemic attack (TIA) symptoms including 13 instances of right hemiparesis that decreased in duration over 4 days. Two separate examinations using diffusion weighted image (DWI) in magnetic resonance imaging (MRI) revealed normal findings, but we observed that both Babinski and Chaddock signs were completely synchronized with her right hemiparesis. We were only able to diagnose this case of early stage TIA using clinical signs. This diagnosis was confirmed 4 days after the onset by the presence of abnormalities on the MRI. DWI-MRI is generally useful when diagnosing TIA, but a neurological examination may be more sensitive, especially in the early stages.

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  • Two Unique Cases with Anti-GluR Antibody-Positive Encephalitis. Reviewed International journal

    Kosuke Matsuzono, Tomoko Kurata, Shoko Deguchi, Toru Yamashita, Kentaro Deguchi, Yoshio Ikeda, Koji Abe

    Clinical medicine insights. Case reports   6   113 - 7   2013

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    We report two cases of anti-glutamic acid receptor (anti-GluR) antibody-positive encephalitis in males with symptoms such as Parkinsonism, urinary retention, and paralytic ileus. Although non-herpetic encephalitis typically shows magnetic resonance imaging (MRI) lesions in the limbic system during early stages, the present cases showed MRI lesions during later stages in the bilateral claustrum and pons. In both cases, anti-GluRɛ2 and δ2 antibodies were later shown to be positive in the cerebrospinal fluid but negative in the serum. Although early detection of anti-GluR antibodies is essential, early treatment may be significantly more important.

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  • Prevention of hyperglycemic signal pathways in metabolic syndrome carotid artery of rats. Reviewed International journal

    Hiromi Kawai, Fengfeng Tian, Tomoko Kurata, Kentaro Deguchi, Toru Yamashita, Yoshio Omote, Syoichiro Kono, Koji Abe

    Translational stroke research   3 ( 4 )   466 - 72   2012.12

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    Obesity is the major risk factor for metabolic syndrome and atherosclerotic cardiocerebrovascular diseases and induces insulin resistance characterized by a dysfunction of insulin to activate insulin receptor /insulin receptor substrate 1(IRS-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Zucker fatty rats (8 weeks) were treated with vehicle (0.5 % methyl cellulose in physiological saline, p.o.), amlodipine (3 mg/kg/day, p.o.), atorvastatin (10 mg/kg/day, p.o.), or the combination of amlodipine plus atorvastatin (3 + 10 mg/kg/day, p.o.) for 28 days, and anti-insulin-like growth factor 1 (IGF-1)/IRS-1/PI3K/Akt pathways were evaluated. Our present immunohistochemical study first demonstrated that a combination of amlodipine plus atorvastatin treatment prevented an arteriosclerotic process compared to the single treatment with amlodipine or atorvastatin with strong recoveries of pTyr IRS-1, pPI3K, and pAkt expressions and with remarkable restraints of IGF-1 and pSer IRS-1. As a result, combination therapy with amlodipine plus atorvastatin showed a strong synergistic effect to prevent atherosclerotic processes. The present study newly suggests a synergistic benefit of combination therapy with amlodipine plus atorvastatin for strong prevention of atherosclerotic processes, which could reduce the clinical risk of cerebrovascular events for obesity patients.

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  • Intracerebral transplantation of bone marrow stromal cells ameliorates tissue plasminogen activator-induced brain damage after cerebral ischemia in mice detected by in vivo and ex vivo optical imaging. Reviewed International journal

    Ning Liu, Kentaro Deguchi, Toru Yamashita, Wentao Liu, Yoshio Ikeda, Koji Abe

    Journal of neuroscience research   90 ( 11 )   2086 - 93   2012.11

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    Detection and protection of the neurovascular unit (NVU) are essential for treatment of acute stroke patients, especially the use of tissue plasminogen activator (tPA). In the present study, we conducted in vivo and ex vivo optical imaging for detecting activation of matrix metalloproteinases (MMPs) and evaluated the protective effect of intracerebral transplantation of bone marrow stromal cells (BMSCs) obtained from green fluorescent protein (GFP) transgenic (Tg) mice on the NVU in tPA-mediated brain damage after transient middle cerebral artery occlusion (tMCAO) in mice. Compared with the tMCAO group, the tMCAO plus BMSC group showed significant reductions of in vivo and ex vivo fluorescent signals for MMPs at 48 hr after tMCAO, with a partial colocalization of BMSC-GFP signals. Intracerebrally transplanted BMSCs ameliorated MMP-9 activation by immunohistochemistry and Western blot with differentiation into microglial and astroglial cells. Double-immunofluorescence study revealed improved NVU disruption in the tMCAO plus BMSC group. The present study suggests that intracerebral BMSC transplantation reduced MMP activation and subsequent NVU disruption caused by tPA after tMCAO and that this MMP activation and BMSC effect were detectable with in vivo and ex vivo optical imaging.

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  • Strong neuroprotection with a novel platinum nanoparticle against ischemic stroke- and tissue plasminogen activator-related brain damages in mice Reviewed

    M. Takamiya, Y. Miyamoto, T. Yamashita, K. Deguchi, Y. Ohta, K. Abe

    Neuroscience   221   47 - 55   2012.9

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    Reactive oxygen species (ROS) are major exacerbation factor in acute ischemic stroke, and thrombolytic agent tissue plasminogen activator (tPA) may worsen motor function and cerebral infarcts. The platinum nanoparticle (nPt) is a novel ROS scavenger, and thus we examined the clinical and neuroprotective effects of nPt in ischemic mouse brains. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60. min and divided into the following four groups by intravenous administration upon reperfusion, vehicle, tPA, tPA. +. nPt, and nPt. At 48. h after tMCAO, motor function, infarct volume, immunohistochemical analyses of neurovascular unit (NVU), in vivo imaging of matrix metalloproteinase (MMP), and zymography for MMP-9 activity were examined. Superoxide anion generation at 2. h after tMCAO was also examined with hydroethidine (HEt). As a result, administration of tPA deteriorated the motor function and infarct volume as compared to vehicle. In vivo optical imaging of MMP showed strong fluorescent signals in affected regions of tMCAO groups. Immunohistochemical analyses revealed that tMCAO resulted in a minimal decrease of NAGO and occludin, but a great decrease of collagen IV and a remarkable increase of MMP-9. HEt stain showed increased ROS generation by tMCAO. All these results became pronounced with tPA administration, and were greatly reduced by nPt. The present study demonstrates that nPt treatment ameliorates neurological function and brain damage in acute cerebral infarction with neuroprotective effect on NVU and inactivation of MMP-9. The strong reduction of ROS production by nPt could account for these remarkable neurological and neuroprotective effects against ischemic stroke. © 2012 IBRO.

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  • Alternative alpha-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology Reviewed International journal

    Herve Rhinn, Liang Qiang, Toru Yamashita, David Rhee, Ari Zolin, William Vanti, Asa Abeliovich

    NATURE COMMUNICATIONS   3   1084 - 1084   2012.9

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    α-Synuclein is implicated both in physiological functions at neuronal synaptic terminals as well as in pathological processes in the context of Parkinson's disease. However, the molecular mechanisms for these apparently diverse roles are unclear. Here we show that specific RNA transcript isoforms of α-synuclein with an extended 3' untranslated region, termed aSynL, appear selectively linked to pathological processes, relative to shorter α-synuclein transcripts. Common variants in the aSynL 3' untranslated region associated with Parkinson's disease risk promote the accumulation and translation of aSynL transcripts. The presence of intracellular dopamine can further enhance the relative abundance of aSynL transcripts through alternative polyadenylation site selection. We demonstrate that the presence of the extended aSynL transcript 3' untranslated region impacts accumulation of α-synuclein protein, which appears redirected away from synaptic terminals and towards mitochondria, reminiscent of Parkinson's disease pathology. Taken together, these findings identify a novel mechanism for aSyn regulation in the context of Parkinson's disease-associated genetic and environmental variations.

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  • Early-stage epigenetic modification during somatic cell reprogramming by Parp1 and Tet2. Reviewed International journal

    Claudia A Doege, Keiichi Inoue, Toru Yamashita, David B Rhee, Skylar Travis, Ryousuke Fujita, Paolo Guarnieri, Govind Bhagat, William B Vanti, Alan Shih, Ross L Levine, Sara Nik, Emily I Chen, Asa Abeliovich

    Nature   488 ( 7413 )   652 - 5   2012.8

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    Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by using the pluripotency factors Oct4, Sox2, Klf4 and c-Myc (together referred to as OSKM). iPSC reprogramming erases somatic epigenetic signatures—as typified by DNA methylation or histone modification at silent pluripotency loci—and establishes alternative epigenetic marks of embryonic stem cells (ESCs). Here we describe an early and essential stage of somatic cell reprogramming, preceding the induction of transcription at endogenous pluripotency loci such as Nanog and Esrrb. By day 4 after transduction with OSKM, two epigenetic modification factors necessary for iPSC generation, namely poly(ADP-ribose) polymerase-1 (Parp1) and ten-eleven translocation-2 (Tet2), are recruited to the Nanog and Esrrb loci. These epigenetic modification factors seem to have complementary roles in the establishment of early epigenetic marks during somatic cell reprogramming: Parp1 functions in the regulation of 5-methylcytosine (5mC) modification, whereas Tet2 is essential for the early generation of 5-hydroxymethylcytosine (5hmC) by the oxidation of 5mC (refs 3,4). Although 5hmC has been proposed to serve primarily as an intermediate in 5mC demethylation to cytosine in certain contexts, our data, and also studies of Tet2-mutant human tumour cells, argue in favour of a role for 5hmC as an epigenetic mark distinct from 5mC. Consistent with this, Parp1 and Tet2 are each needed for the early establishment of histone modifications that typify an activated chromatin state at pluripotency loci, whereas Parp1 induction further promotes accessibility to the Oct4 reprogramming factor. These findings suggest that Parp1 and Tet2 contribute to an epigenetic program that directs subsequent transcriptional induction at pluripotency loci during somatic cell reprogramming.

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  • Stem cell therapy for cerebral ischemia: from basic science to clinical applications. Reviewed International journal

    Koji Abe, Toru Yamashita, Shunya Takizawa, Satoshi Kuroda, Hiroyuki Kinouchi, Nobutaka Kawahara

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism   32 ( 7 )   1317 - 31   2012.7

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    Recent stem cell technology provides a strong therapeutic potential not only for acute ischemic stroke but also for chronic progressive neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis with neuroregenerative neural cell replenishment and replacement. In addition to resident neural stem cell activation in the brain by neurotrophic factors, bone marrow stem cells (BMSCs) can be mobilized by granulocyte-colony stimulating factor for homing into the brain for both neurorepair and neuroregeneration in acute stroke and neurodegenerative diseases in both basic science and clinical settings. Exogenous stem cell transplantation is also emerging into a clinical scene from bench side experiments. Early clinical trials of intravenous transplantation of autologous BMSCs are showing safe and effective results in stroke patients. Further basic sciences of stem cell therapy on a neurovascular unit and neuroregeneration, and further clinical advancements on scaffold technology for supporting stem cells and stem cell tracking technology such as magnetic resonance imaging, single photon emission tomography or optical imaging with near-infrared could allow stem cell therapy to be applied in daily clinical applications in the near future.

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  • Clinical and pathological improvement in stroke-prone spontaneous hypertensive rats related to the pleiotropic effect of cilostazol. Reviewed International journal

    Yoshio Omote, Kentaro Deguchi, FengFeng Tian, Hiromi Kawai, Tomoko Kurata, Toru Yamashita, Yasuyuki Ohta, Koji Abe

    Stroke   43 ( 6 )   1639 - 46   2012.6

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    BACKGROUND AND PURPOSE: Cerebral infarction is a major cause of death or decreasing activities of daily living. This study aimed to investigate the efficacy of commonly used antiplatelet drugs on stroke and motor and cognitive functions in relation to oxidative stress markers and insulin-like growth factor 1 receptor (IGF-1R). METHODS: Stroke-prone spontaneously hypertensive rats were treated with vehicle, aspirin, clopidogrel, and cilostazol from 8 to 10 weeks of age. Physiological parameters, regional cerebral blood flow, and serum lipids were examined. Motor and cognitive functions were evaluated weekly by the Rotorod and water maze task. Spontaneous infarct volume, oxidative stress markers for lipid, protein, and DNA at the ischemic boundary zone of spontaneous infarction, and the IGF-1R-positive cell ratio in the hippocampus were immunohistochemically examined in brain sections. IGF-1Rβ expression in the hippocampus was assessed by Western blotting. RESULTS: The antiplatelet drugs, cilostazol and clopidogrel, reduced the spontaneous infarct volume more than aspirin. Only cilostazol improved motor and cognitive functions with a significant increase (P<0.05) in the memory-related IGF-1R-positive ratio and IGF-1Rβ expression in the hippocampus. Cilostazol reduced the 4 oxidative stress markers in affected neurons in stroke-prone spontaneously hypertensive rats regardless of blood pressure, regional cerebral blood flow, or serum lipid levels. CONCLUSIONS: The present results suggest that a possible pleiotropic effect of cilostazol resulted in the reduction of spontaneous infarct volume and preservation of motor and spatial cognitive functions. The increase of IGF-1R-positive cells in the hippocampal CA1 region could partly explain the preservation of spatial cognitive function in stroke-prone spontaneously hypertensive rats.

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  • Asymmetric Pattern of Cerebrovascular Lesions in Patients After Left Ventricular Assist Device Implantation Reviewed International journal

    Tomoko S. Kato, Takeyoshi Ota, P. Christian Schulze, Maryjane Farr, Ulrich Jorde, Hiroo Takayama, Yoshifumi Naka, Toru Yamashita, Donna M. Mancini

    STROKE   43 ( 3 )   872 - 874   2012.3

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    BACKGROUND AND PURPOSE: Stroke is a major adverse event after left ventricular assist device (LVAD) surgery. The purpose of this study was to describe differences in hemispheric distribution of stroke in LVAD patients. METHODS: We reviewed 317 consecutive patients who underwent LVAD surgery between November 2000 and July 2011. Stroke during LVAD support was analyzed. RESULTS: In total, 46 strokes occurred at 76.0±96.8 days postoperatively. Among the 46 strokes, 27 events (58.7%) occurred in right hemisphere, 13 events (28.2%) in the left hemisphere, 3 events (8.7%) occurred bilaterally, and 2 events (4.3%) were vertebrobasilar lesions. The right hemispheric stroke was significantly more common in patients with postoperative infection compared with left hemispheric events. CONCLUSIONS: Stroke after LVAD implantation has a right hemispheric predominance. This finding suggests LVAD-related thrombus in the setting of infection and/or the anatomic configuration of LVAD outflow cannula-ascending aorta anastomosis to be highly associated with stroke after LVAD surgery.

    DOI: 10.1161/STROKEAHA.111.639682

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  • Mechanisms of endogenous endothelial repair in stroke. Reviewed International journal

    Toru Yamashita, Koji Abe

    Current pharmaceutical design   18 ( 25 )   3649 - 52   2012

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    Recent evidence indicates that circulating endothelial progenitor cells can play an important role, not only in endothelium homeostasis of the pre-stroke brain, but also in angiogenesis of the post-stroke brain. Circulating endothelial progenitor cells are considered to repair endothelial cells by incorporating them into newly formed vessels, or by releasing pro-angiogenic factors. The number or function of circulating endothelial progenitor cells can be modulated by various kinds of factors. For example, elevated serum cholesterol, hypertension, diabetes and smoking decreased the number whereas vascular endothelial growth factor (VEGF), exercise, and statins can increase it. In this review, we discuss the present knowledge of endogenous mechanisms for the repair of endothelial cells, and how to enhance their possible capacity to remodel vascular units as neuronal self-repair strategies.

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  • [iPS cell transplantation for ischemic brain]. Reviewed

    Koji Abe, Toru Yamashita, Hiromi Kawai

    Rinsho shinkeigaku = Clinical neurology   52 ( 11 )   1143 - 6   2012

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    Stroke is a major neurologic disorder. Induced pluripotent stem (iPS) cells can be produced from basically any part of patients, with high reproduction ability and pluripotency to differentiate into various types of cells, suggesting that iPS cells can provide a hopeful therapy for cell transplantation. However, transplantation of iPS cells into ischemic brain has not been reported. In this study, we showed that the iPS cells fate in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells (5×10(5)) were transplanted into ipsilateral striatum and cortex at 24 h after 30 mins of transient MCAO. Behavioral and histologic analyses were performed at 28 day after the cell transplantation. To our surprise, the transplanted iPS cells expanded and formed much larger tumors in mice postischemic brain than in sham-operated brain. The clinical recovery of the MCAO+iPS group was delayed as compared with the MCAO+PBS (phosphate-buffered saline) group. iPS cells formed tridermal teratoma, but could supply a great number of Dcx-positive neuroblasts and a few mature neurons in the ischemic lesion. iPS cells have a promising potential to provide neural cells after ischemic brain injury, if tumorigenesis is properly controlled.

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  • Amlodipine and atorvastatin exert protective and additive effects via antiapoptotic and antiautophagic mechanisms after transient middle cerebral artery occlusion in Zucker metabolic syndrome rats. Reviewed International journal

    Xuemei Zhang, Shoko Deguchi, Kentaro Deguchi, Yasuyuki Ohta, Toru Yamashita, Jingwei Shang, Fengfeng Tian, Ning Liu, Wentao Liu, Yoshio Ikeda, Tohru Matsuura, Koji Abe

    Journal of neuroscience research   89 ( 8 )   1228 - 34   2011.8

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    We examined the neuroprotective effects amlodipine and/or atorvastatin in metabolic syndrome (MetS) Zucker fatty rats against transient (90 min) middle cerebral artery occlusion (MCAO). The rats were pretreated with vehicle, amlodipine, atorvastatin, or amlodipine plus atorvastatin for 28 days, and 24 hr after transient MCAO the infarct size was assessed via hematoxylin and eosin staining, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) and microtubule-associated protein 1 light chain 3 (LC3) expression were examined by immunohistochemistry to evaluate apoptosis and autophagy, respectively. Compared with the vehicle group, rats treated with amlodipine or atorvastatin alone showed a significant decrease in infarct volume (P < 0.01), which was further decreased in the amlodipine plus atorvastatin group (P < 0.001). Compared with the vehicle group, the numbers of TUNEL- and LC3-positive cells were markedly reduced by amlodipine or atorvastatin alone (P < 0.01) and further decreased by amlodipine plus atorvastatin (P < 0.001). The number of apoptotic TUNEL/autophagic LC3 double-positive cells was also significantly decreased with amlodipine or atorvastatin alone compared with vehicle (P < 0.01) and was further decreased by amlodipine plus atorvastatin (P < 0.001). These data suggest additive neuroprotective effects of combination amlodipine and atorvastatin treatment after acute ischemic stroke in MetS model Zucker rats. These effects are mediated, at least in part, via antiapoptotic and antiautophagic mechanisms. Further studies are now needed to expand these preliminary results to understand fully the mechanisms involved in the protective effects of amlodipine and atorvastatin against ischemic stroke.

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  • Therapeutic approaches to vascular protection in ischemic stroke. Reviewed

    Toru Yamashita, Koji Abe

    Acta medica Okayama   65 ( 4 )   219 - 23   2011.8

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    Reperfusion with recombinant tissue plasminogen activator (tPA) sometimes causes catastrophic hemorrhagic transformation (HT) in the ischemic brain. Consequently, the application of tPA has been strictly limited. Recent studies have indicated that matrix metalloproteinases (MMPs), especially MMP-9, play a critical role in blood brain barrier (BBB) disruption in the ischemic brain, leading to brain edema and HT. In the ischemic brain, free radicals and exogenous tPA itself can trigger MMP-9 activation through several signaling pathways containing LDL receptor-related protein (LRP) and proteinase-activated receptor 1 (PAR1). Therapeutic targeting of free radicals and MMP-9/t-PA related signaling pathways might be promising approaches to minimizing catastrophic HT in acute stroke patients. We provide an overview of the available scientific reports to improve our understanding of the mechanisms leading to HT, and highlight recent progress in the development of new therapeutic strategies for preventing HT in the post-stroke brain.

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  • Neurological and pathological improvements of cerebral infarction in mice with platinum nanoparticles. Reviewed International journal

    Motonori Takamiya, Yusei Miyamoto, Toru Yamashita, Kentaro Deguchi, Yasuyuki Ohta, Yoshio Ikeda, Tohru Matsuura, Koji Abe

    Journal of neuroscience research   89 ( 7 )   1125 - 33   2011.7

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    Ischemic stroke is a major, urgent neurologic disorder in which reactive oxygen species (ROS) are deeply involved in the detrimental effects. Platinum nanoparticle (nPt) species are a novel and strong scavenger of such ROS, so we examined the clinical and neuroprotective effects of nPts in mouse ischemic brain. Mice were subjected to transient middle cerebral artery occlusion (tMCAO) for 60 min. Upon reperfusion, nPt or vehicle was administered intravenously. At 48 hr after the tMCAO, motor function, infarct volume, immunohistochemistry of neurovascular components (endothelial NAGO, tight junctional occludin, and basal laminal collagen IV), and zymography for MMP-9 activity were examined. Superoxide anion generation at 2 hr after tMCAO was determined with oxidized hydroethidine. Compared with vehicle, treatment with nPts significantly improved the motor function and greatly reduced the infarct volume, especially in the cerebral cortex. Immunohistochemical analyses revealed that tMCAO resulted in a minimal decrease of NAGO and occludin but a great decrease of collagen IV and a remarkable increase of MMP-9. Treatment with nPts greatly reduced this decrease of collagen IV and activation of MMP-9 and, with large reductions of MMP-9 activation on zymography and superoxide production. The present study demonstrates that treatment with nPts ameliorates the neurological scores with a large reduction in infarct size as well as the preservation of outer components of the neurovascular unit (collagen IV) and inactivation of MMP-9. A strong reduction of superoxide anion production by nPts could account for such remarkable neurobehavioral and neuroprotective effects on ischemic stroke.

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  • Comparisons of acoustic function in SCA31 and other forms of ataxias. Reviewed International journal

    Yoshio Ikeda, Makiko Nagai, Tomoko Kurata, Toru Yamashita, Yasuyuki Ohta, Shoko Nagotani, Kentaro Deguchi, Yasushi Takehisa, Yoshihiko Shiro, Tohru Matsuura, Koji Abe

    Neurological research   33 ( 4 )   427 - 32   2011.5

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    OBJECTIVE: To investigate whether acoustic impairment can be one of the characteristic extracerebellar symptoms in sporadic and hereditary ataxias including spinocerebellar ataxia type 31 (SCA31). METHODS: We investigated genotypes of dominant ataxia families, and determined a frequency of each form in our cohort of 154 families. Acoustic function in the groups of various forms of ataxia with multiple system atrophy of cerebellar predominance (MSA-C), cortical cerebellar atrophy (CCA), and hereditary ataxias including SCA31 was evaluated by using audiogram and brainstem auditory evoked potentials (BAEPs). RESULTS: Genetic analysis of dominant ataxia families revealed that a frequency of SCA31 in our cohort was fewer than that reported from other areas of Japan, indicating that SCA31 is not widely distributed throughout Japan. Results of audiogram showed no significant difference of hearing levels among ataxic groups, and those of BAEPs did not support inner ear dysfunction in SCA31 in which hearing loss had initially been suggested as one of its characteristic symptoms. CONCLUSION: This study suggests that acoustic impairment is neither specific to SCA31, MSA-C and CCA nor useful in making a differential diagnosis among them.

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  • Protection against ischemic stroke damage by synergistic treatment with amlodipine plus atorvastatin in Zucker metabolic rat. Reviewed International journal

    Hiromi Kawai, Shoko Deguchi, Kentaro Deguchi, Toru Yamashita, Yasuyuki Ohta, Yoshio Omote, Tomoko Kurata, Yoshio Ikeda, Tohru Matsuura, Koji Abe

    Brain research   1382   308 - 14   2011.3

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    Ischemic stroke is a major neurologic disorder and a leading cause of disability and death in the world. We compared neuroprotective effects of single or combination therapy of amlodipine (AM) and atorvastatin (AT) in such a metabolic syndrome model Zucker rat. The animals were pretreated with vehicle, AM, AT, or the combination of AM plus AT for 28days, and physical and serum parameters were analyzed, then 90min of transient middle cerebral artery occlusion (tMCAO), was performed followed by immunohistochemical analyses at 24h. Without affecting serum levels of lipids, adiponectin, and leptin, the combination therapy of AM plus AT ameliorated the post-ischemic brain weight increase. The single treatment with AM or AT itself exerted neuroprotective effects with reducing inductions of MMP-9 and AT2R, as well as with preserving collagen IV, and the combination therapy of AM plus AT showed a further synergistic benefit against acute ischemic neural damages. Single AT was more protective on these 3 molecules than single AM at this time point of 24h after tMCAO. Thus, the combination therapy with AM plus AT extended the neuroprotectives effect of single treatment with AM or AT on a part of neurovascular unit and a hypertension-related receptor.

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  • Synergistic benefit of combined amlodipine plus atorvastatin on neuronal damage after stroke in Zucker metabolic rat. Reviewed International journal

    Hiromi Kawai, Shoko Deguchi, Kentaro Deguchi, Toru Yamashita, Yasuyuki Ohta, Jingwei Shang, Fengfeng Tian, Xuemei Zhang, Ning Liu, Wentao Liu, Yoshio Ikeda, Tohru Matsuura, Koji Abe

    Brain research   1368   317 - 23   2011.1

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    Stroke is a major neurologic disorder and a leading cause of death in the world. We compared neuroprotective effects of single or combination therapy of amlodipine (AM) and atorvastatin (AT) in such a metabolic syndrome model Zucker rat after 90 min of transient middle cerebral artery occlusion (tMCAO). The animals were pretreated with vehicle, AM, AT, or the combination of AM plus AT for 28 days, and at 24h of tMCAO, infarct volume and immunohistochemical analyses were performed. The combination of AM plus AT treatment decreased the infarct volume stronger than each single treatment with AM or AT. The numbers of positive cells of oxidative stress markers such as 8-hydroxy-2'-deoxyguanosin (8-OHdG), 4-hydroxy-2-nonenal (4-HNE), and advanced end glycation products (AGE) and inflammation markers such as tumor necrosis factor alpha (TNF-α) and monocyte chemoattractant protein-1(MCP-1) decreased dramatically in the combination-treated group compared with single AM- or AT-treated group. The present study showed that single AM or AT treatment showed neuroprotective effects both with antioxidative and anti-inflammatory mechanisms, but combination therapy of AM plus AT presented a further synergistic benefit in acute ischemic neural damages.

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  • Strong neurogenesis, angiogenesis, synaptogenesis, and antifibrosis of hepatocyte growth factor in rats brain after transient middle cerebral artery occlusion. Reviewed International journal

    Jingwei Shang, Kentaro Deguchi, Yasuyuki Ohta, Ning Liu, Xuemei Zhang, Fengfeng Tian, Toru Yamashita, Yoshio Ikeda, Tohru Matsuura, Hiroshi Funakoshi, Toshikazu Nakamura, Koji Abe

    Journal of neuroscience research   89 ( 1 )   86 - 95   2011.1

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    Hepatocyte growth factor (HGF) and glial cell line-derived neurotrophic factor (GDNF) are strong neurotrophic factors. However, their potentials in neurogenesis, angiogenesis, synaptogenesis, and antifibrosis have not been compared. Therefore, we investigated these effects of HGF and GDNF in cerebral ischemia in the rat. Wistar rats were subjected to 90 min of transient middle cerebral artery occlusion (tMCAO). Immediately after reperfusion, HGF or GDNF was given by topical application. BrdU was injected intraperitoneally twice daily 1, 2, and 3 days after tMCAO. On 14 day, we histologically evaluated infarct volume, antiapoptotic effect, neurogenesis, angiogenesis, synaptogenesis, and antifibrosis. Both HGF and GDNF significantly reduced infarct size and the number of TUNEL-positive cells, but only HGF significantly increased the number of BrdU-positive cells in the subventricular zone, and 5'-bromo-2'-deoxyuridine -positive cells differentiated into mature neurons on the ischemic side. Enhancement of angiogenesis and synaptogenesis at the ischemic boundary zone was also observed only in HGF-treated rats. HGF significantly decreased the glial scar formation and scar thickness of the brain pia mater after tMCAO, but GDNF did not. Our study shows that both HGF and GDNF had significant neurotrophic effects, but only HGF can promote the neurogenesis, angiogenesis, and synaptogenesis and inhibit fibrotic change in brains after tMCAO.

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  • Vascular protection and restorative therapy in ischemic stroke. Reviewed International journal

    Toru Yamashita, Kentaro Deguchi, Shoko Nagotani, Koji Abe

    Cell transplantation   20 ( 1 )   95 - 7   2011

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    Possible strategies for treating stroke include: 1) thrombolytic therapy with tissue plasminogen activator (tPA): restoring cerebral blood flow in the acute phase of ischemic stroke but sometimes causing hemorrhagic transformation (HT); 2) stem cell therapy: the repair of disrupted neuronal networks with newly born neurons in the chronic phase of ischemic stroke. Firstly, we estimated the vascular protective effect of a free radical scavenger, edaravone, in the tPA-treated rat model of middle cerebral artery occlusion. Edaravone prevented dramatically decreased the hemorrhagic transformation and improved the neurologic score and survival rate of tPA-treated rats. Secondly, we attempted to restore brain tissue using a novel biomaterial, polydimethysiloxane-tetraethoxysilane (PDMS-TEOS) hybrid with or without vascular endothelial growth factor (VEGF), and we could show that implantation of a PDMS-TEOS scaffold with VEGF might be effective for treating old brain infarction or trauma. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.

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  • Advances in induced Pluripotent Stem cell therapy for neurological diseases Reviewed

    Toru Yamashita, Hiromi Kawai, Koji Abe

    Japanese Journal of Neurosurgery   20 ( 8 )   585 - 588   2011

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    Induced Pluripotent Stem (iPS) cells are regarded to be potential supply source of cells for application to cell replacement therapies. Recent scientific papers indicated that human iPS cells are capable of differentiating into glutamatergic neurons, dopaminergic neurons, and motor neurons. However, tumorigenesis in iPS cells is a serious problem which should be overcome for clinical application. Recently, we evaluated the influence of ischemic condition on undifferentiated iPS cells within a transient Middle Cerebral Artery Occlusion (MCAO) using a mouse model. Undifferentiated iPS cells (5 × 105) were injected into the ipsilateral striatum and cortex, which were considered as the ischemic boundary zone at 24 hours after MCAO. Ischemic brains treated with iPS cells tended to form teratoma with larger volume compared with those in intact brains. c~Myc, Oct3/4 and Sox2 were strongly expressed in iPS-derived tumors of the ischemic brain. Above results indicated that the transcriptional factors integrated into the genome by retrovirus vectors might promote teratoma formation in the ischemic brain. Potential interaction between integrated transcriptional factors and iPS cell characteristics needs to be kept in mind, for the development of transplantation therapy.

    DOI: 10.7887/jcns.20.585

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  • Tumorigenic development of induced pluripotent stem cells in ischemic mouse brain. Reviewed International journal

    Toru Yamashita, Hiromi Kawai, Fengfeng Tian, Yasuyuki Ohta, Koji Abe

    Cell transplantation   20 ( 6 )   883 - 91   2011

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    Induced pluripotent stem (iPS) cells may provide cures for various neurological diseases. However, undifferentiated iPS cells have high tumorigenicity, and evaluation of the cells fates, especially in pathologic condition model, is needed. In this study, we demonstrated the effect of ischemic condition to undifferentiated iPS cells fates in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells were characterized with immunofluorescent staining. The iPS cells (5 × 10⁵) were injected into ipsilateral striatum and cortex after 24 h of MCAO. Histological analysis was performed from 3 to 28 days after cell transplantation. iPS cells in ischemic brain formed teratoma with higher probability (p < 0.05) and larger volume (p < 0.01) compared with those in intact brain. Among the four transcriptional factors to produce iPS cells, c-Myc, Oct3/4, and Sox2 strongly expressed in iPS-derived tumors in ischemic brain (p < 0.01). Additionally, expression of matrix metalloproteinase-9 (MMP-9) and phosphorylated vascular endothelial growth factor receptor2 (phospho-VEGFR2) were significantly increased in iPS-derived tumors in the ischemic brain (p < 0.05). These results suggest that the transcriptional factors might increase expression of MMP-9 and activate VEGFR2, promoting teratoma formation in the ischemic brain. We strongly propose that the safety of iPS cells should be evaluated not only in normal condition, but also in a pathologic, disease model.

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  • In vivo optical imaging of early-stage apoptosis in mouse brain after transient cerebral ischemia. Reviewed International journal

    Ning Liu, Kentaro Deguchi, Jingwei Shang, Xuemei Zhang, Fengfeng Tian, Toru Yamashita, Yasuyuki Ohta, Yoshio Ikeda, Tohru Matsuura, Koji Abe

    Journal of neuroscience research   88 ( 16 )   3488 - 97   2010.12

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    Apoptosis is one of the mechanisms contributing to neuronal degeneration in ischemic stroke. In vivo imaging of annexin V (A5) was performed at 12 hr, 24 hr, 48 hr, and 4 days after 90-min transient middle cerebral artery occlusion (tMCAO) in mice with a fluorescent protein Cy5.5. Immunohistochemistry for heat shock protein 70 (HSP70), A5, and TUNEL were also performed with brain sections after the tMCAO. In vivo fluorescence was strongly observed at 48 hr over the head, especially with removal of both head skin and skull bone. Zonal ex vivo fluorescent signals were surrounding the ischemic core, and double-positive cells with Cy5.5/exogenous A5 antibody were found in this area. HSP70 was observed at the peak time of 24 hr; A5 became detectable at 12 hr, with increasing numbers until 48 hr. The number of TUNEL-positive cells increased at 24 hr and retained the high level until 4 days, showing a dissociating temporal pattern with A5. Double-positive cells for A5/TUNEL reached their peak at 48 hr. All the data suggest that some cells still have a chance to be rescued for a long period after acute cerebral ischemia. The in vivo Cy5.5 fluorescence representing A5 signal spatially surrounding the ischemic core temporally detects an early-stage apoptosis after cerebral ischemia.

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  • Free radical scavenger edaravone administration protects against tissue plasminogen activator induced oxidative stress and blood brain barrier damage. Reviewed International journal

    Violeta Lukic-Panin, Kentaro Deguchi, Toru Yamashita, Jingwei Shang, Xuemei Zhang, FengFeng Tian, Ning Liu, Hiromi Kawai, Tohru Matsuura, Koji Abe

    Current neurovascular research   7 ( 4 )   319 - 29   2010.11

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    One of the therapeutics for acute cerebral ischemia is tissue plasminogen activator (t-PA). Using t-PA after 3 hour time window increases the chances of hemorrhage, involving multiple mechanisms. In order to show possible mechanisms of t-PA toxicity and the effect of the free radical scavenger edaravone, we administered vehicle, plasmin, and t-PA into intact rat cortex, and edaravone intravenously. Plasmin and t-PA damaged rat brain with the most prominent injury in t-PA group on 4-HNE, HEL, and 8-OHdG immunostainings. Such brain damage was strongly decreased in t-PA plus edaravone group. For the neurovascular unit immunostainings, occludin and collagen IV expression was decreased in single plasmin or t-PA group, which was recovered in t-PA plus edaravone group. In contrast, matrix metalloproteinase-9 intensity was the strongest in t-PA group, less in plasmin, and was the least prominent in t-PA plus edaravone group. In vitro data showed a strong damage to tight junctions for occludin and claudin 5 in both administration groups, while there were no changes for endothelial (NAGO) and perivascular (GFAP) stainings. Such damage to tight junctions was recovered in t-PA plus edaravone group with similar recovery in Sodium-Fluorescein permeability assay. Administration of t-PA caused oxidative stress damage to lipids, proteins and DNA, and led to disruption of outer parts of neurovascular unit, greater than the effect in plasmin administration. Additive edaravone ameliorated such an oxidative damage by t-PA with protecting outer layers of blood-brain barrier (in vivo) and tight junctions (in vitro).

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  • In vivo imaging of autophagy in a mouse stroke model. Reviewed International journal

    FengFeng Tian, Kentaro Deguchi, Toru Yamashita, Yasuyuki Ohta, Nobutoshi Morimoto, Jingwei Shang, Xuemei Zhang, Ning Liu, Yoshio Ikeda, Tohru Matsuura, Koji Abe

    Autophagy   6 ( 8 )   1107 - 14   2010.11

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    Recent studies have suggested that autophagy is involved in a neural death pathway following cerebral ischemia. In vivo detection of autophagy could be important for evaluating ischemic neural cell damage for human stroke patients. Using novel green fluorescent protein (GFP)-fused microtubule-associated protein 1 light chain 3 (LC3) transgenic (Tg) mice, in vivo imaging of autophagy was performed at 1, 3 and 6 d after 60 min transient middle cerebral artery occlusion (tMCAO). Ex vivo imaging of autophagy, testing of the autophagy inhibitor 3-methyladenine (3-MA), estern blot analysis, immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labeling (TUNEL) and fluorescent analyses were performed on brain sections following tMCAO. In vivo fluorescent signals were detected above the ischemic hemisphere through the skull bone at 1, 3 and 6 d after tMCAO, with a peak at 1 d. Similar results were obtained with ex vivo fluorescence imaging. western blot analysis revealed maximum LC3-I and LC3-II expression at 1 d after tMCAO and fluorescence immunohistochemistry demonstrated that GFP-LC3-positive cells were primarily neuronal, not astroglial or microglial, cells. The number of GFP-LC3/TUNEL double-positive cells was greater in the periischemic area than in the core. These results provided evidence of in vivo autophagy detection, with a peak at 1 d, in a live animal model following cerebral ischemia. This novel technique could be valuable for monitoring autophagic processes in vivo in live stroke patients, as well as for clarifying the detailed role of autophagy in the ischemic brain, as well as in other neurological diseases.

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  • Antiapoptotic and antiautophagic effects of glial cell line-derived neurotrophic factor and hepatocyte growth factor after transient middle cerebral artery occlusion in rats. Reviewed International journal

    Jingwei Shang, Kentaro Deguchi, Toru Yamashita, Yasuyuki Ohta, Hanzhe Zhang, Nobutoshi Morimoto, Ning Liu, Xuemei Zhang, Fengfeng Tian, Tohru Matsuura, Hiroshi Funakoshi, Toshikazu Nakamura, Koji Abe

    Journal of neuroscience research   88 ( 10 )   2197 - 206   2010.8

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    Glial cell line-derived neurotrophic factor (GDNF) and hepatocyte growth factor (HGF) are strong neurotrophic factors, which function as antiapoptotic factors. However, the neuroprotective effect of GDNF and HGF in ameliorating ischemic brain injury via an antiautophagic effect has not been examined. Therefore, we investigated GDNF and HGF for changes of infarct size and antiapoptotic and antiautophagic effects after transient middle cerebral artery occlusion (tMCAO) in rats. For the estimation of ischemic brain injury, the infarct size was calculated at 24 hr after tMCAO by HE staining. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) was performed for evaluating the antiapoptotic effect. Western blot analysis of microtubule-associated protein 1 light chain 3 (LC3) and immunofluorescence analysis of LC3 and phosphorylated mTOR/Ser(2448) (p-mTOR) were performed for evaluating the antiautophagic effect. GDNF and HGF significantly reduced infarct size after cerebral ischemia. The amounts of LC3-I plus LC3-II (relative to beta-tubulin) were significantly increased after tMCAO, and GDNF and HGF significantly decreased them. GDNF and HGF significantly increased p-mTOR-positive cells. GDNF and HGF significantly decreased the numbers of TUNEL-, LC3-, and LC3/TUNEL double-positive cells. LC3/TUNEL double-positive cells accounted for about 34.3% of LC3 plus TUNEL-positive cells. This study suggests that the protective effects of GDNF and HGF were greatly associated with not only the antiapoptotic but also the antiautophagic effects; maybe two types of cell death can occur in the same cell at the same time, and GDNF and HGF are capable of ameliorating these two pathways.

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  • Tridermal tumorigenesis of induced pluripotent stem cells transplanted in ischemic brain. Reviewed International journal

    Hiromi Kawai, Toru Yamashita, Yasuyuki Ohta, Kentaro Deguchi, Shoko Nagotani, Xuemei Zhang, Yoshio Ikeda, Tohru Matsuura, Koji Abe

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism   30 ( 8 )   1487 - 93   2010.8

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    Stroke is a major neurologic disorder. Induced pluripotent stem (iPS) cells can be produced from basically any part of patients, with high reproduction ability and pluripotency to differentiate into various types of cells, suggesting that iPS cells can provide a hopeful therapy for cell transplantation. However, transplantation of iPS cells into ischemic brain has not been reported. In this study, we showed that the iPS cells fate in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells (5 x 10(5)) were transplanted into ipsilateral striatum and cortex at 24 h after 30 mins of transient MCAO. Behavioral and histologic analyses were performed at 28 day after the cell transplantation. To our surprise, the transplanted iPS cells expanded and formed much larger tumors in mice postischemic brain than in sham-operated brain. The clinical recovery of the MCAO+iPS group was delayed as compared with the MCAO+PBS (phosphate-buffered saline) group. iPS cells formed tridermal teratoma, but could supply a great number of Dcx-positive neuroblasts and a few mature neurons in the ischemic lesion. iPS cells have a promising potential to provide neural cells after ischemic brain injury, if tumorigenesis is properly controlled.

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  • Temporal and spatial differences of multiple protein expression in the ischemic penumbra after transient MCAO in rats. Reviewed International journal

    Xuemei Zhang, Kentaro Deguchi, Toru Yamashita, Yasuyuki Ohta, Jingwei Shang, Fengfeng Tian, Ning Liu, Violeta Lukic Panin, Yoshio Ikeda, Tohru Matsuura, Koji Abe

    Brain research   1343   143 - 52   2010.7

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    Temporal and spatial differences and relationships of proteins relating to the ischemic penumbra were examined at 1, 3, 12, 24, and 48 h after 90 min of transient middle cerebral artery occlusion (tMCAO) in rats. 2, 3, 5-triphenyltetrazolium chloride (TTC) staining showed that the apparent infarction focus first appeared at 1h after tMCAO, which then largely matured at 24h. Immunohistochemistry and Western blot indicated no or trace levels of c-fos, hypoxia inducible factor-1 alpha (HIF-1 alpha), heat shock protein 70 (HSP70), and annexin V (A5) positive cells in the sham control brain. Expression of c-fos increased quickly and widely within and outside of the affected arterial territory (peak at 1h), and that of HIF-1 alpha reached the maximum at 12h in a smaller area than c-fos. HSP70 began to be induced during the first few hours after tMCAO, peaked at 24h, then decreased within 48 h, while A5 was slightly expressed at 3h, then gradually increased until 48 h. Double immunofluorescent analyses showed that the colocalization rates of c-fos/HIF-1 alpha, HIF-1 alpha/HSP70, HSP70/A5, and A5/TUNEL were 40.6%, 58.4%, 42.1% and 61.0%, respectively. These data suggest that multiple molecular penumbra exist after 90 min of tMCAO in the rat brain where several different proteins participate in different temporal and spatial expression patterns. Thus, there is a window for rescue of ischemic neural cells from 12 to 48 h after injury.

    DOI: 10.1016/j.brainres.2010.04.027

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  • Dissociation and protection of the neurovascular unit after thrombolysis and reperfusion in ischemic rat brain. Reviewed International journal

    Toru Yamashita, Tatsushi Kamiya, Kentaro Deguchi, Toshiki Inaba, Hanzhe Zhang, Jingwei Shang, Kazunori Miyazaki, Aiji Ohtsuka, Yasuo Katayama, Koji Abe

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism   29 ( 4 )   715 - 25   2009.4

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    In the ischemic brain, reperfusion with tissue plasminogen activator (tPA) sometimes causes catastrophic hemorrhagic transformation (HT); however, the mechanism remains elusive. Here, we show that the basement membrane, and not the endothelial cells, is vulnerable to ischemic/reperfusion injury with tPA treatment. We treated a spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) with vehicle alone, tPA alone, or a free radical scavenger, edaravone, plus tPA. Light and electron microscopic analyses of each microvascular component revealed that the basement membrane disintegrated and became detached from the astrocyte endfeet in tPA-treated animals that showed HT. On the other hand, edaravone prevented the dissociation of the neurovascular unit, dramatically decreased the HT, and improved the neurologic score and survival rate of the tPA-treated rats. These results suggest that the basement membrane that underlies the endothelial cells is a key structure for maintaining the integrity of the neurovascular unit, and a free-radical scavenger can be a viable agent for inhibiting tPA-induced HT.

    DOI: 10.1038/jcbfm.2008.164

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  • Therapeutic strategy for ischemic stroke. Reviewed International journal

    Toru Yamashita, Kentaro Deguchi, Yoshihide Sehara, Violeta Lukic-Panin, Hanzhe Zhang, Tatsushi Kamiya, Koji Abe

    Neurochemical research   34 ( 4 )   707 - 10   2009.4

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    Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.

    DOI: 10.1007/s11064-008-9842-2

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  • Gene and stem cell therapy in ischemic stroke. Reviewed International journal

    Toru Yamashita, Kentaro Deguchi, Shoko Nagotani, Tatsushi Kamiya, Koji Abe

    Cell transplantation   18 ( 9 )   999 - 1002   2009

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    Possible strategies for treating ischemic stroke include neuroprotection (preventing injured neurons from undergoing apoptosis in the acute phase of cerebral ischemia) and stem cell therapy (the repair of disrupted neuronal networks with newly born neurons in the chronic phase of cerebral ischemia). First, we estimated the neuroprotective effect of glial cell line-derived neurotrophic factor (GDNF) by administration of GFNF protein. GDNF protein showed a direct protective effect against ischemic brain damage. Pretreatment of animals with adenoviral vector containing GDNF gene (Ad-GDNF) 24 h before the subsequent transient middle cerebral artery occlusion (MCAO) effectively reduced infarcted volume. Secondly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin. Both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their antioxidative property. Lastly, we developed a restorative stroke therapy with a bioaffinitive scaffold, which is able to provide an appropriate platform for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes.

    DOI: 10.3727/096368909X471233

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  • Epigenetic regulation of neural cell differentiation plasticity in the adult mammalian brain. Reviewed International journal

    Jun Kohyama, Takuro Kojima, Eriko Takatsuka, Toru Yamashita, Jun Namiki, Jenny Hsieh, Fred H Gage, Masakazu Namihira, Hideyuki Okano, Kazunobu Sawamoto, Kinichi Nakashima

    Proceedings of the National Academy of Sciences of the United States of America   105 ( 46 )   18012 - 7   2008.11

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    Neural stem/progenitor cells (NSCs/NPCs) give rise to neurons, astrocytes, and oligodendrocytes. It has become apparent that intracellular epigenetic modification including DNA methylation, in concert with extracellular cues such as cytokine signaling, is deeply involved in fate specification of NSCs/NPCs by defining cell-type specific gene expression. However, it is still unclear how differentiated neural cells retain their specific attributes by repressing cellular properties characteristic of other lineages. In previous work we have shown that methyl-CpG binding protein transcriptional repressors (MBDs), which are expressed predominantly in neurons in the central nervous system, inhibit astrocyte-specific gene expression by binding to highly methylated regions of their target genes. Here we report that oligodendrocytes, which do not express MBDs, can transdifferentiate into astrocytes both in vitro (cytokine stimulation) and in vivo (ischemic injury) through the activation of the JAK/STAT signaling pathway. These findings suggest that differentiation plasticity in neural cells is regulated by cell-intrinsic epigenetic mechanisms in collaboration with ambient cell-extrinsic cues.

    DOI: 10.1073/pnas.0808417105

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  • Gelatin-siloxane hybrid scaffolds with vascular endothelial growth factor induces brain tissue regeneration. Reviewed International journal

    Hanzhe Zhang, Tatsushi Kamiya, Takeshi Hayashi, Kanji Tsuru, Kentaro Deguchi, Violeta Lukic, Atsushi Tsuchiya, Toru Yamashita, Satoshi Hayakawa, Yoshio Ikeda, Akiyoshi Osaka, Koji Abe

    Current neurovascular research   5 ( 2 )   112 - 7   2008.5

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    In the brain after infarction or trauma, the tissue becomes pannecrotic and forms a cavity. In such situation, a scaffold is necessary to produce new tissue. In this study, we implanted a new porous gelatin-siloxane hybrid derived from gelatin and 3-(glycidoxypropyl) trimethoxysilane (gelatin-GPTMS) scaffolds into a brain defect, and investigated whether it makes a new brain tissue. In addition, vascular endothelial growth factor (VEGF) was added on gelatin-GPTMS scaffolds and its effect on tissue regeneration was examined. At 30 days after the implantation, the marginal territory of the scaffolds became occupied by newly formed tissue. Immunohistochemical analysis revealed that the new tissue was constituted by endothelial, astroglial and microglial cells, some of which were labeled for bromodeoxyuridine (BrdU). Addition of VEGF promoted numbers of these cells. Thus, combination of gelatin-GPTMS scaffolds and VEGF is preferable for brain regeneration.

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  • Macrophage infiltration, lectin-like oxidized-LDL receptor-1, and monocyte chemoattractant protein-1 are reduced by chronic HMG-CoA reductase inhibition. Reviewed International journal

    Atsushi Tsuchiya, Shoko Nagotani, Takeshi Hayashi, Kentaro Deguchi, Yoshihide Sehara, Toru Yamashita, HanZhe Zhang, Violeta Lukic, Tatsushi Kamiya, Koji Abe

    Current neurovascular research   4 ( 4 )   268 - 73   2007.11

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    Statin reduces cerebrovascular events independent of its cholesterol lowering effect. We hypothesized that statin inhibits early atherosclerotic change in common carotid artery (CCA), and investigated its effect on lectin-like oxidized-LDL receptor-1 (LOX-1) and monocyte chemoattractant protein-1 (MCP-1) expression, both of which are early atherosclerotic markers. Stroke-prone spontaneous hypertensive rats (SHR-SP) of 8 weeks old were orally treated with vehicle or simvastatin (20mg/kg) daily. After 4 weeks of simvastatin or vehicle treatment, or 2 weeks of vehicle and 2 weeks of simvastatin treatment, CCA was removed. LOX-1 and MCP-1 expression as well as macrophage infiltration were histologically investigated. Lipid deposition was also investigated by Sudan III staining. Simvastatin groups showed significantly smaller amount of lipid deposition and LOX-1 and MCP-1 expression, independent of serum lipid levels. Macrophage infiltration was also decreased. Reduction of cerebrovascular events by statins may be brought by the direct inhibition of atherosclerotic change.

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  • beta-Catenin signaling promotes proliferation of progenitor cells in the adult mouse subventricular zone Reviewed International journal

    Kazuhide Adachi, Zaman Mirzadeh, Masanori Sakaguchi, Toru Yamashita, Tania Nikolcheva, Yukiko Gotoh, Gary Peltz, Leyi Gong, Takeshi Kawase, Arturo Alvarez-Buylla, Hideyuki Okano, Kazunobu Sawamoto

    STEM CELLS   25 ( 11 )   2827 - 2836   2007.11

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    The subventricular zone (SVZ) is the largest germinal zone in the mature rodent brain, and it continuously produces young neurons that migrate to the olfactory bulb. Neural stem cells in this region generate migratory neuroblasts via highly proliferative transit-amplifying cells. The Wnt/beta-catenin signaling pathway partially regulates the proliferation and neuronal differentiation of neural progenitor cells in the embryonic brain. Here, we studied the role of beta-catenin signaling in the adult mouse SVZ. beta-Catenin-dependent expression of a destabilized form of green fluorescent protein was detected in progenitor cells in the adult SVZ of Axin2-d2EGFP reporter mice. Retrovirus-mediated expression of a stabilized beta-catenin promoted the proliferation of Mash1+ cells and inhibited their differentiation into neuroblasts. Conversely, the expression of Dkk1, an inhibitor of Wnt signaling, reduced the proliferation of Mash1+ cells. In addition, an inhibitor of GSK3 beta promoted the proliferation of Mash1+ cells and increased the number of new neurons in the olfactory bulb 14 days later. These results suggest that beta-catenin signaling plays a role in the proliferation of progenitor cells in the SVZ of the adult mouse brain.

    DOI: 10.1634/stemcells.2007-0177

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  • Prevention of neuronal damage by calcium channel blockers with antioxidative effects after transient focal ischemia in rats. Reviewed International journal

    Violeta Lukic-Panin, Tatsushi Kamiya, Hanzhe Zhang, Takeshi Hayashi, Atsushi Tsuchiya, Yoshihide Sehara, Kentaro Deguchi, Toru Yamashita, Koji Abe

    Brain research   1176   143 - 50   2007.10

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    BACKGROUND: Cerebral ischemia is a major leading cause of death and at the first place cause of disability all over the world. There are a lot of drugs that are in experimental stage for treatment of stroke. Among them are calcium channel blockers (CCBs) that have, in animal models, different effectiveness in healing of ischemic damage in brain. Mechanism of CCBs' action in cerebral ischemia is still unclear, but antioxidative property is supposed to be implicated. In the present study, we investigated antioxidative and neuroprotective properties of two CCBs, azelnidipine and amlodipine. METHODS: Male Wistar Kyoto rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) by a nylon thread. Animals were divided into 3 groups, vehicle, azelnidipine and amlodipine group. In the azelnidipine and amlodipine groups, rats were treated with azelnidipine (1 mg/kg) and amlodipine (1 mg/kg) by gastric gavage for 2 weeks before MCAO. Vehicle group was treated by solution of methyl cellulose for 2 weeks. Rats were killed 24 h after MCAO. Physiological parameters (mean arterial pressure, heart rate, body weight), infarct volume, brain edema index, cerebral blood flow (CBF), oxidative stress markers which are HEL, 4-HNE, AGE and 8-OHdG, and evidence of apoptosis by TUNEL, were investigated. RESULTS: There were no significant differences among groups in mean arterial pressure, heart rate and body weight. Treatment with azelnidipine and amlodipine reduced infarct volume and brain edema. Azelnidipine treated group showed more marked reduction of infarct volume and cerebral edema than amlodipine group. There was no attenuation of CBF in CCBs groups. The number of HEL, 4-HNE, AGE and 8-OHdG positive cells were significantly decreased in the CCBs treated groups. These molecules were again fewer in the azelnidipine group than in the amlodipine group. In TUNEL staining, the numbers of positive cells was smaller in the CCBs treated groups, especially in the azelnidipine group. CONCLUSIONS: Pretreatment of azelnidipine and amlodipine had a neuroprotective effect in ischemic brain. Antioxidative property is one of the important profiles of CCBs that is implicated in brain protection.

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  • Decreased focal inflammatory response by G-CSF may improve stroke outcome after transient middle cerebral artery occlusion in rats. Reviewed International journal

    Yoshihide Sehara, Takeshi Hayashi, Kentaro Deguchi, Hanzhe Zhang, Atsushi Tsuchiya, Toru Yamashita, Violeta Lukic, Makiko Nagai, Tatsushi Kamiya, Koji Abe

    Journal of neuroscience research   85 ( 10 )   2167 - 74   2007.8

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    Recent studies have shown that administration of granulocyte colony-stimulating factor (G-CSF) is neuroprotective. However, the precise mechanisms of the neuroprotective effect of G-CSF are not entirely known. We carried out 90-min transient middle cerebral occlusion (tMCAO) of rats. The rats were injected with vehicle or G-CSF (50 mug/kg) immediately after reperfusion and sacrificed 8, 24, or 72 hr later. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was carried out using brain sections of 72 hr, and immunohistochemistry was carried out with those of 8, 24, and 72 hr. TTC-staining showed a significant reduction of infarct volume in the G-CSF-treated group (**P < 0.01). Immunohistochemistry showed a significant decrease of the number of cells expressing tumor necrosis factor-alpha (TNF-alpha) at 8-72 hr, transforming growth factor-beta (TGF-beta) and inducible nitric oxide synthase (iNOS) at 24 and 72 hr after tMCAO in the peri-ischemic area (*P < 0.05 each). Our data suggest that the suppression of inflammatory cytokines and iNOS expression may be one mechanism of neuroprotection by G-CSF.

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  • Expression of netrin-1 and its receptors DCC and neogenin in rat brain after ischemia. Reviewed International journal

    Atsushi Tsuchiya, Takeshi Hayashi, Kentaro Deguchi, Yoshihide Sehara, Toru Yamashita, HanZhe Zhang, Violeta Lukic, Makiko Nagai, Tatsushi Kamiya, Koji Abe

    Brain research   1159   1 - 7   2007.7

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    It is very important to investigate the mechanism of axonal growth in the ischemic brain in order to consider a novel mean of therapy for stroke. Netrins are chemotropic factors for axon with chemoattractant or chemorepellant guidance activities, and deleted in colorectal cancer (DCC) and neogenin are receptors for netrins. In this study, we examined expressions of netrin-1, DCC, and neogenin in the brain after 90 min of transient middle cerebral artery occlusion (tMCAO). Netrin-1 was expressed in neurons at the peri-ischemic area with a peak at 14 days. DCC was expressed both in neurons and astrocytic feet with a peak at 14 days, though neogenin was expressed in endothelial cells at MCA territory with a peak at the same time point. These results suggest that netrin-1 is involved in the promotion of axonal growth. The expression of netrin-1 and DCC was overlapped both in the spatial and temporal patterns, indicating that DCC plays a role in netrin-1's axonal growth promoting effects. The location of neogenin positive cells differed from that of netrin-1 positive cells, thus its angiogenic activity may not have relevance with netrin-1.

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  • Potentiation of neurogenesis and angiogenesis by G-CSF after focal cerebral ischemia in rats. Reviewed International journal

    Yoshihide Sehara, Takeshi Hayashi, Kentaro Deguchi, Hanzhe Zhang, Atsushi Tsuchiya, Toru Yamashita, Violeta Lukic, Makiko Nagai, Tatsushi Kamiya, Koji Abe

    Brain research   1151   142 - 9   2007.6

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    Recently, granulocyte colony-stimulating factor (G-CSF) is expected to demonstrate beneficial effects on cerebral ischemia. Here, we showed the potential benefit of G-CSF administration after transient middle cerebral artery occlusion (tMCAO). Adult male Wistar rats received vehicle or G-CSF (50 microg/kg) subcutaneously after reperfusion, and were treated with 5-bromodeoxyuridine (BrdU, 50 mg/kg) once daily by the intraperitoneal route for 3 days after tMCAO. Nissl-stained sections at 7 days after tMCAO showed significant reduction of the infarction area (31%, P<0.01). At 7 days after tMCAO, BrdU plus NeuN double-positive cells increased by 43.3% in the G-CSF-treated group (P<0.05), and BrdU-positive endothelial cells were increased 2.29 times in the G-CSF-treated group, to a level as high as that in the vehicle-treated group (P<0.01), in the periischemic area. Our results indicate that G-CSF caused potentiation of neuroprotection and neurogenesis and is expected to have practical therapeutic potential in treating individuals after ischemic brain injury.

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  • G-CSF enhances stem cell proliferation in rat hippocampus after transient middle cerebral artery occlusion. Reviewed International journal

    Yoshihide Sehara, Takeshi Hayashi, Kentaro Deguchi, Hanzhe Zhang, Atsushi Tsuchiya, Toru Yamashita, Violeta Lukic, Makiko Nagai, Tatsushi Kamiya, Koji Abe

    Neuroscience letters   418 ( 3 )   248 - 52   2007.5

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    Granulocyte colony-stimulating factor (G-CSF) enhances the survival and stimulates the proliferation of neutrophil progenitors. Recently, the neurogenerative effect of G-CSF has been intensely investigated. In this study, we explored the possibility that G-CSF enhanced the cell proliferation in the rat dentate gyrus (DG) after focal cerebral ischemia, using a rat transient middle cerebral artery occlusion (tMCAO) model. At 7 days after tMCAO, the number of 5-bromodeoxyuridine (BrdU)-positive cells in the G-CSF-treated group was significantly increased compared with that in the vehicle-treated group in the ipsilateral SGZ (16.6+/-5.5/mm(2) in the vehicle-treated group versus 33.0+/-7.2/mm(2) in the G-CSF-treated group, **p<0.01) and in the ipsilateral GCL (14.2+/-2.8/mm(2) in the vehicle-treated group versus 21.0+/-3.8/mm(2) in the G-CSF-treated group, *p<0.05). This result showed the possibility of a neurogenerative role of G-CSF after tMCAO in rats.

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  • Enhanced neurogenesis in the ischemic striatum following EGF-induced expansion of transit-amplifying cells in the subventricular zone. Reviewed International journal

    Mikiko Ninomiya, Toru Yamashita, Nobuo Araki, Hideyuki Okano, Kazunobu Sawamoto

    Neuroscience letters   403 ( 1-2 )   63 - 7   2006.7

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    In the subventricular zone (SVZ) of the adult mammalian brain, neural stem cells continually produce transit-amplifying precursors, which generate neuroblasts migrating into the olfactory bulb. Previous studies have suggested that SVZ cells also have the capacity to generate some striatal neurons after cerebral ischemia. The infusion of epidermal growth factor (EGF) has been demonstrated to increase the number of these regenerated neurons. However, which cell types in the SVZ are stimulated to proliferate or differentiate after EGF infusion remains unknown. In this paper, we demonstrated that cerebral ischemia results in an increase in the number of EGF receptor (EGFR)-positive transit-amplifying cells in the SVZ. EGF infusion into the ischemic brain caused the number of transit-amplifying cells to increase and the number of neuroblasts to decrease. On the other hand, after an interval of 6 days after the discontinuation of EGF infusion, a significant increase in the number of neuroblasts was found, both in the striatum and the SVZ. These results suggest that the replacement of neurons in injured striatum can be enhanced by an EGF-induced expansion of transit-amplifying cells in the SVZ.

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  • Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. Reviewed International journal

    Toru Yamashita, Mikiko Ninomiya, Pilar Hernández Acosta, Jose Manuel García-Verdugo, Takehiko Sunabori, Masanori Sakaguchi, Kazuhide Adachi, Takuro Kojima, Yuki Hirota, Takeshi Kawase, Nobuo Araki, Koji Abe, Hideyuki Okano, Kazunobu Sawamoto

    The Journal of neuroscience : the official journal of the Society for Neuroscience   26 ( 24 )   6627 - 36   2006.6

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    Recent studies have revealed that the adult mammalian brain has the capacity to regenerate some neurons after various insults. However, the precise mechanism of insult-induced neurogenesis has not been demonstrated. In the normal brain, GFAP-expressing cells in the subventricular zone (SVZ) of the lateral ventricles include a neurogenic cell population that gives rise to olfactory bulb neurons only. Herein, we report evidence that, after a stroke, these cells are capable of producing new neurons outside the olfactory bulbs. SVZ GFAP-expressing cells labeled by a cell-type-specific viral infection method were found to generate neuroblasts that migrated toward the injured striatum after middle cerebral artery occlusion. These neuroblasts in the striatum formed elongated chain-like cell aggregates similar to those in the normal SVZ, and these chains were observed to be closely associated with thin astrocytic processes and blood vessels. Finally, long-term tracing of the green fluorescent-labeled cells with a Cre-loxP system revealed that the SVZ-derived neuroblasts differentiated into mature neurons in the striatum, in which they expressed neuronal-specific nuclear protein and formed synapses with neighboring striatal cells. These results highlight the role of the SVZ in neuronal regeneration after a stroke and its potential as an important therapeutic target for various neurological disorders.

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  • Neuroprotection and neurosupplementation in ischaemic brain Reviewed

    T. Yamashita, K. Deguchi, K. Sawamoto, H. Okano, T. Kamiya, K. Abe

    Biochemical Society Transactions   34 ( 6 )   1310 - 1312   2006

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    Possible strategies for treating ischaemic stroke include: (i) neuroprotection (preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischaemia), and (ii) neurosupplementation (the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischaemia). In this paper, we review our recent progress in development of these distinct new strategies for treatment of damaged brain following a stroke. Firstly, we investigated the role of endogenous IL-6 (interleukin-6), which is one of the cytokines drastically induced by ischaemic stimuli, by administering IL-6RA (anti-IL-6 receptor monoclonal antibody) to mice.We found that endogenous IL-6 plays a critical role in neuroprotection and that its role may be mediated by STAT3 (signal transducer and activator of transcription-3) activation. Secondly, we studied the endogenous sources of the newly born neurons in the ischaemic striatum by region- and cell-type-specific cell labelling techniques. The results revealed that the SVZ (subventricular zone) is the principal source of the neuronal progenitors that migrate laterally towards the infarcted regions, and differentiate into newly born neurons. Finally, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is an appropriate poly-porous structure releasing bioactive substances such as neurotrophic factor. This bio-affinitive scaffold is able to give an appropriate environment for newly born neurons. In future, we will combine these strategies to develop more effective therapies for treatment of strokes. ©2006 Biochemical Society.

    DOI: 10.1042/BST0341310

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  • Blockade of interleukin-6 signaling aggravates ischemic cerebral damage in mice: possible involvement of Stat3 activation in the protection of neurons. Reviewed International journal

    Toru Yamashita, Kazunobu Sawamoto, Shigeaki Suzuki, Norihiro Suzuki, Kazuhide Adachi, Takeshi Kawase, Masahiko Mihara, Yoshiyuki Ohsugi, Koji Abe, Hideyuki Okano

    Journal of neurochemistry   94 ( 2 )   459 - 68   2005.7

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    Interleukin (IL)-6 expression transiently increases in the acute phase of cerebral ischemia. To investigate the physiological significance of endogenous IL-6 expression and to identify the main signal pathway for the action of IL-6, we administered anti-mouse IL-6 receptor monoclonal antibody (IL-6RA), which blocks IL-6 signaling, to mice immediately after a 45-min period of middle cerebral artery occlusion (MCAO). At 6 h after MCAO, IL-6RA administration had resulted in a significant reduction in the amount of phosphorylated signal transducer and activator of transcription-3 (Stat3) protein in the peri-infarct area of the cortex. At 24 h after MCAO, blockade of IL-6 signaling had led to an increase in number of apoptotic cells in the peri-infarct area and enlargement of the size of the infarct, and it had adversely affected neurological function. These results suggest that endogenous IL-6 plays a critical role in preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia and that its role may be mediated by Stat3 activation.

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  • Activation of cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 attenuates ischemic brain injury in rats. Reviewed International journal

    Shigeaki Suzuki, Toru Yamashita, Kortaro Tanaka, Hidenori Hattori, Kazunobu Sawamoto, Hideyuki Okano, Norihiro Suzuki

    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism   25 ( 6 )   685 - 93   2005.6

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    Cytokine signaling through leukemia inhibitory factor receptor (LIFR)/gp130 is known to exert a neurotrophic action in the central nervous system, although the role of this signaling in cerebral ischemia remains unknown. We examined the effect of intracerebral injection of LIF after focal cerebral ischemia in rats. The animals underwent a sham operation (sham group) or middle cerebral artery occlusion (MCAO) followed by direct injection of either vehicle (phosphate-buffered saline, the PBS group) or recombinant LIF (10 ng in the low-LIF group and 100 ng in the high-LIF group) into the cerebral cortex adjacent to the inner boundary zone of the infarct area, and neurologic and histologic evaluations were conducted 24 h later. Expression of LIFR, gp130, and phosphorylated Stat3, Akt, and ERK1/2 was investigated by Western blot analysis and immunohistochemistry. The neurologic deficits and ischemic damage were significantly less severe in the high-LIF group than in the PBS group and the low-LIF group. Leukemia inhibitory factor receptor and gp130 were expressed in neurons, and the ischemic damage of these proteins was rescued in the high-LIF group. Early induction of phosphorylated Stat3 was significantly detected on the ischemic side in the high-LIF group after LIF injection. Exogenous LIF attenuates ischemic brain injury by activating cytokine signaling through LIFR/gp130.

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Books

  • ダイレクトリプログラミング最前線

    山下徹 阿部康二( Role: Joint author ,  神経疾患治療へのダイレクトリプログラミングの応用)

    エヌティーエス  2020.4 

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    Responsible for pages:111-116   Language:English

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  • Stroke Revisited: Pathophysiology of Stroke

    Yamashita T, Abe K( Role: Joint author ,  Pathophysiology of Neuronal Cell Death After Stroke)

    Springer  2020.4 

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    Responsible for pages:235-241   Language:English

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  • 厚生労働科学研究補助金(難治性疾患克服研究事業)運動失調症の医療基盤に関する調査研究班平成30年度班会議(東京)

    阿部康二、表芳夫、太田康之、山下徹、武本麻美、菱川望

    厚生労働科学研究補助金(難治性疾患克服研究事業)運動失調症の医療基盤に関する調査研究班  2019.4 

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    Language:Japanese

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  • 厚生労働科学研究補助金(難治性疾患克服研究事業)スモンに関する調査研究班平成30年度班会議(東京)

    菱川望、商敬偉、武本麻美、佐藤恒太、太田康之、山下徹、坂井研一、阿部康二

    厚生労働科学研究補助金(難治性疾患克服研究事業)  2019.4 

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  • 代謝センシング

    田所 功、山下 徹、阿部 康二( Role: Joint author)

    株式会社シーエムシー出版  2018.9 

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  • 脳卒中病態学のススメ

    山下 徹( Role: Joint author)

    南山堂  2018.2 

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  • 厚生労働科学研究補助金(難治性疾患克服研究事業)「運動失調症の医療基盤に関する調査研究」班平成29年度班会議(東京)

    阿部康二、山下徹、下澤伸行、佐藤恒太、武本麻美、菱川望、商敬偉、太田康之( Role: Joint author)

    厚生労働科学研究補助金(難治性疾患克服研究事業)「運動失調症の医療基盤に関する調査研究」班  2018.1 

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  • Cell Therapy against Cerebral Stroke

    Yamashita T, Abe K( Role: Joint author ,  iPS cells and iN cells.)

    SpringerJapan  2017.1 

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    Responsible for pages:pp39-46   Language:English

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  • 厚生労働科学研究補助金(難治性疾患克服研究事業)「神経変性疾患に関する調査研究」平成24年度研究報告書

    阿部康二、佐藤恒太、山下 徹、池田佳生( Role: Joint author ,  ALSにおける低酸素ストレスセンサーの機能障害.)

    厚生労働科学研究補助金(難治性疾患克服研究事業)「神経変性疾患に関する調査研究」  2013.1 

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  • Research Advances in Cerebral Blood Flow & Metabolism

    Yamashita T, Kawai H, Abe K( Role: Joint author)

    Global Research Network  2011.1 

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MISC

  • 幹細胞移植による虚血脳のタンパク分解分子機構への影響

    田所功, 福井裕介, 山下徹, 劉夏, 角田慶一郎, 商敬偉, 表芳夫, 武本麻美, 菱川望, 太田康之, 阿部康二

    神経治療学(Web)   37 ( 6 )   2020

  • 幹細胞移植による虚血脳のタンパク分解分子機構への影響

    田所功, 福井裕介, 山下徹, 劉夏, 角田慶一郎, 商敬偉, 表芳夫, 武本麻美, 菱川望, 太田康之, 阿部康二

    脳循環代謝(Web)   32 ( 1 )   2020

  • ALS患者脊髄における低酸素ストレスを可視化する

    山下徹, 畠山哲宗, 佐藤恒太, 福井裕介, 菱川望, 武本麻美, 太田康之, 西山佳宏, 河井信行, 田宮隆, 阿部康二

    脳循環代謝(Web)   32 ( 1 )   2020

  • Vascular risk factors in Alzheimer's disease

    262 ( 3 )   227 - 230   2017.7

  • 運動ニューロン疾患274症例の検討 (特集 ALSの臨床像)

    佐藤 恒太, 山下 徹, 阿部 康二

    難病と在宅ケア   19 ( 7 )   13 - 15   2013.10

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    CiNii Article

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    Other Link: http://search.jamas.or.jp/link/ui/2014024574

  • Potential treatment strategies for enhancing neuroplasticity and regeneration after ischemic stroke

    Toru Yamashita, Koji Abe

    Future Neurology   7 ( 3 )   279 - 285   2012.5

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    Strokes are a major cause of death and result in a drastic reduction in quality of life. Novel therapeutic strategies for patients suffering from stroke are thus required. Two possible strategies can be proposed for treating ischemic stroke: enhancing neuroplasticity, allowing the surviving neuronal cells to compensate for stroke-related impairment through brain reorganization, sprouting and rewiring of neuronal cells, or regeneration of neuronal cells, including enhancement of intrinsic neurogenesis and stem cell transplantation therapy with neural stem cells, embryonic stem cells or induced pluripotent stem cells. Endogenous neurogenesis or transplanted neural stem cells, embryonic stem cells or induced pluripotent stem cell-derived cells are able to not only supply newborn neurons integrated into a damaged neuronal network, but also produce growth factors into the recovering brains. These secretory factors enhance sprouting and angiogenesis and may be important in neuroplasticity and recovery in the poststroke brain. © 2012 Future Medicine Ltd.

    DOI: 10.2217/fnl.12.12

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Presentations

  • 関節リウマチの維持治療中、Pembrolizumab投与を契機に髄膜脳炎を呈した一例

    松岡千加、表芳夫、菱川望、河原由子、武本麻美、野村恵美、山下徹、阿部 康二

    第108回日本神経学会中国四国地区地方会 (WEB)  2020 

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    Event date: 2020.12.5

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • 細菌性髄膜炎様の髄液所見を呈した、IgG4関連疾患による髄膜脳炎の一例

    平佑貴、表芳夫、菱川望、松本菜見子、佐藤恒太、河原由子、武本麻美、野村恵美、山下徹、阿部康二

    第108回日本神経学会中国四国地区地方会 (WEB)  2020 

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    Event date: 2020.12.5

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  • 80歳以上高齢者の難治性本態性振戦に対する経頭蓋MRガイド下集束超音波治療の経験

    小坂田陽介、平林秀裕、福留賢二、久我純弘、森原隆太、山下徹、阿部康二、大西英之

    第117回日本神経学会近畿地方会 (奈良)  2020 

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    Event date: 2020.12.5

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  • Effects of Pre-treatment with Tocovid on Oxidative Stress and Apoptosis in Ischemic Mouse Brain. International conference

    Asia Pacific Stroke Conference 2020 (Virtual Conference in Korea)  2020 

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    Event date: 2020.12.4 - 2020.12.6

    Language:English   Presentation type:Poster presentation  

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  • Animal models of vascular cognitive impairment International conference

    Asia Pacific Stroke Conference 2020 (Virtual Conference in Korea)  2020 

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    Event date: 2020.12.4

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

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  • 実は見逃されている血管性認知症の危険因子?新しい遺伝子変異CARASILの1家系からの考察?

    山下徹、野崎洋明、涌谷陽介、田所功、野村恵美、高橋義秋、佐藤恒太、菱川望、武本麻美、商敬偉、太田康之、小野寺理、阿部康二

    第39回日本認知症学会学術集会(名古屋)  2020 

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    Event date: 2020.11.26 - 2020.11.28

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  • PDDとDLBの認知機能、情動機能、脳血流画像の比較

    武本麻美、田所功、表芳夫、菱川望、太田康之、山下徹、阿部康二

    第39回日本認知症学会学術集会(名古屋)  2020 

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    Event date: 2020.11.26 - 2020.11.28

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  • ラット脳梗塞モデルにおける機械的血栓回収による直接的血管損傷と神経血管ユニットの破綻

    佐々木諒, 山下徹, 田所功, 松本菜見子, 表芳夫, 武本麻美, 菱川望, 阿部康二

    第63回日本脳循環代謝学会学術集会(横浜)  2020 

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    Event date: 2020.11.13 - 2020.11.14

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  • ALS患者脊髄における低酸素ストレスを可視化する

    山下徹、畠山哲宗、佐藤恒太、福井裕介、菱川望、武本麻美、太田康之、西山佳宏、河井信行、田宮隆、阿部康二

    第63回日本脳循環代謝学会学術集会(横浜)  2020 

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    Event date: 2020.11.13 - 2020.11.14

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  • 脳梗塞モデルマウスにおけるスフィンゴシン1リン酸受容体とスフィンゴシンキナーゼの時間的・空間的動態

    松本菜見子、山下徹、商敬偉、馮田、表芳夫、武本麻美、菱川望、阿部康二

    第63回日本脳循環代謝学会学術集会(横浜)  2020 

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    Event date: 2020.11.13 - 2020.11.14

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  • マウス脳梗塞モデルにおける新規サプリメントNeumentixの抗酸化効果

    平佑貴、山下徹 、卞宇? 、商敬偉 、松本菜見子 、佐々木諒、田所功 、野村恵美、角田慶一郎、表芳夫、武本麻美、菱川望、阿部康二

    第63回日本脳循環代謝学会学術集会(横浜)  2020 

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    Event date: 2020.11.13 - 2020.11.14

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  • 安全かつ高効率誘導を実現する新世代型ダイレクトリプログラミング法の開発

    山下徹、阿部康二

    第63回日本脳循環代謝学会学術集会(横浜)  2020 

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    Event date: 2020.11.13 - 2020.11.14

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

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  • 脳梗塞後に神経細胞を新たに生み出し神経再生を目指す?脳内グリア細胞から神経細胞を誘導する新技術の確立?

    山下徹、商敬偉、中野由美子、森原隆太、佐藤恒太、武本麻美、菱川望、太田康之、阿部康二

    第38回日本神経治療学会(東京)  2020 

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    Event date: 2020.10.28 - 2020.10.30

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  • FDG PET集積亢進を伴う腫大胸腺の切除により症状寛解を得たバセドウ病合併血清反応陰性重症筋無力症の一例

    松本菜見子、表芳夫、武本麻美、菱川望、山下徹、都地友紘、阿部康二

    第38回日本神経治療学会(東京)  2020 

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    Event date: 2020.10.28 - 2020.10.30

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • 経鼻的経蝶形骨洞手術(Hardy手術)後に生じたacromegalic myopathy and arthropathyに対する治療の検討

    佐々木諒、山下徹、高橋義秋、阿部康二

    第38回日本神経治療学会(東京)  2020 

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    Event date: 2020.10.28 - 2020.10.30

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  • 脳梗塞モデルマウスにおけるNeumentix(Rosmarin酸)の脳保護効果

    平佑貴、山下徹 、卞宇? 、商敬偉 、松本菜見子 、佐々木諒、田所功 、野村恵美、角田慶一郎、表芳夫、武本麻美、菱川望、阿部康二

    第2回日本脳サプリメント学会 (WEB)  2020 

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    Event date: 2020.10.24

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • 脳梗塞モデルマウスにおけるスフィンゴシン1リン酸受容体とスフィンゴシンキナーゼの時間的・空間的動態の検討

    松本菜見子、山下徹、商敬偉、馮田、表芳夫、武本麻美、菱川望、阿部康二

    第22回中国四国脳卒中研究会(高知)  2020 

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    Event date: 2020.9.5

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  • 機械的血栓回収による直接的血管損傷と神経血管ユニットの破綻 ラット脳梗塞モデルにおける評価

    佐々木諒、山下徹、田所功、松本菜見子、表芳夫、武本麻美、菱川望、阿部康二

    第22回中国四国脳卒中研究会(高知)  2020 

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    Event date: 2020.9.5

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  • Clinical characteristics of emergency patients with dementia in a local clinic

    Tadokoro K, Sasaki R, Wakutani Y, Takao Y, Omote Y, Takemoto M, Hishikawa N, Ohta Y, Yamashita T, Abe K

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

    Language:English   Presentation type:Poster presentation  

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  • Benefits of edaravone for Alzheimer’s disease with chronic hypoperfusion in a novel mouse model

    Feng T, Yamashita T, Ohta Y, Abe K

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • Chronic cerebral hypoperfusion induces Alzheimer’s pathology and mitochondrial form change in mice

    Matsumoto N, Feng T, Yamashita T, Zhai Y, Shang J, Nakano Y, Morihara R, Fukui Y, Hishikawa N, Ohta Y, Abe K

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • Acute anti-inflammatory markers ITIH4 and AHSG in a novel Alzheimer’s disease mice model

    Bian Z, Shi X, Ohta Y, Yamashita T, Abe K

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • PDDとDLBの認知機能と情動機能、脳血流画像の比較検討

    武本麻美、田所功、表芳夫、菱川望、太田康之、山下徹、阿部康二

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • トラクトグラフィーを用いた筋ALSにおける頚髄側索錐体路の損傷評価

    福井裕介、菱川望、表芳夫、武本麻美、 太田康之、山下徹、阿部康二

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • 中四国特別シンポジウム2Prion Neuropathy

    山下徹、阿部康二

    第61回日本神経学会学術大会 (岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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

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  • アルツハイマー病患者の臨床的進行予測因子についての検討

    菱川望、表芳夫、武本麻美、太田康之、山下徹、阿部康二

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • 同種骨髄移植が有用であった大脳型に進展した副腎白質ジストロフィーの1例

    表 芳夫、佐藤恒太、浦田知宏、藤井伸治、下澤伸行、山下 徹、武本麻美、菱川 望、太田康之、阿部康二

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • 認知機能正常者ならびに軽度認知障害における認知症周辺症状の出現

    角田慶一郎、山下徹、小坂田陽介、佐々木諒、田所功、松本菜見子、野村恵美、森原隆太、中野由美子、高橋義秋、幡中典子、商敬偉、佐藤恒太、武本麻美、菱川望、太田康之、阿部康二

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • 嚥下障害、構音障害を呈した若年性両側内頚動脈解離の一例

    佐々木諒、高橋義秋、山下徹、商敬偉、武本麻美、菱川望、太田康之、阿部康二

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • 新規Sigma-1受容体刺激薬による急性期脳梗塞治療効果

    佐々木諒、森原隆太、山下徹、阿部康二

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • コロナ緊急シンポジウム新型コロナによるtele-stroke連携・オンライン診療への影響

    佐々木諒、表芳夫、武本麻美、菱川望、山下徹、阿部康二

    第61回日本神経学会学術大会 (岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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

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  • Vas-Cog Asia/JapanシンポジウムAnimal models of vascular cognitive impairment

    Yamashita T, Abe K

    第61回日本神経学会学術大会 (岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • In vivo direct reprogramming method of glial linage to neuronal cells in post-stroke brain

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

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • Neuroprotective effects of SMTP-44D in mice stroke model

    Yu H, Shi X, Ohta Y, Yamashita T, Hasumi K, Abe K

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • Establishment of spinocerebellar ataxia type 36 model fly

    Taminato T, Ueyama M, Yamashita T, Ikeda Y, Abe K, Nagai Y

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • International Education Course 01Stem cell therapy for stroke and ALS

    Yamashita T, Abe K

    第61回日本神経学会学術大会 (岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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

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  • シンポジウム33: Latest Advances in the Treatment of Ischemic Stroke iN cell therapy for cerebral ischemia

    Yamashita T, Abe K

    第61回日本神経学会学術大会 (岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

    Language:English   Presentation type:Symposium, workshop panel (public)  

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  • シンポジウム56:Cerebral small vessel disease up-to-date Classification of cerebral small vessel disease

    Yamashita T, Abe K

    第61回日本神経学会学術大会 (岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • The involvement of hypoxia stress in amyotrophic lateral sclerosis: in vivo imaging of HIF-1α

    Nomura E, Ohta Y, Tadokoro K, Feng T, Liu X, Shi X, Matsumoto N, Sasaki R, Tsunoda K, Takemoto M, Hishikawa N, Yamashita T, Kuchimaru T, Kizaka-Kondoh S, Abe K

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • Strong associations of sarcopenia and frailty with cognitive functions in female mild cognitive impairment and Alzheimer’s disease

    Ohta Y, Nomura E, Hatanaka N, Osakada Y, Matsumoto N, Sasaki R, Tsunoda K, Takemoto M, Tadokoro K, Hishikawa N, Wakutani Y, Yamashita T, Sato K, Omote Y, Abe K

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

    Language:English   Presentation type:Poster presentation  

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  • Efficacy of edaravone for A-beta pathology in AD model micee with chronic cerebral hypoperfusion

    Osakada Y, Shang J, Yamashita T, Feng T, Li X, Liu X, Shi X, Nakano Y, Tsunoda K, Nomura E, Sasaki R, Tadokoro K, Sato K, Takemoto M, Hishikawa N, Ohta Y, Abe K

    第61回日本神経学会学術総会(岡山)  2020 

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    Event date: 2020.8.31 - 2020.9.2

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  • 脳内グリア細胞から神経細胞を誘導する新技術iN法の確立

    山下徹、阿部康二

    第45回日本脳卒中学会学術集会 (WEB)  2020 

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    Event date: 2020.8.23 - 2020.9.24

    Language:Japanese   Presentation type:Poster presentation  

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  • 抗酸化サプリメントTwendee X の軽度認知障害に対する効果についての検討

    松本 菜見子、田所 功、森原 隆太、太田 康之、菱川 望、川野 公子、武本 麻美、山下 徹、犬房 春彦、阿部 康二

    第62回日本老年医学会学術集会(東京)  2020 

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    Event date: 2020.8.4 - 2020.8.6

    Language:Japanese   Presentation type:Poster presentation  

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  • Touch panel screening test for early Alzheimer's disease. International conference

    The 14th ICME International Conference on Complex Medical Engineering -CME2020 (Virtual Conference in Kagawa, Japan)  2020 

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    Event date: 2020.8.1 - 2020.8.15

    Language:English   Presentation type:Symposium, workshop panel (public)  

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  • アルツハイマー病の脳画像

    山下徹、阿部康二

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

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

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  • Tractographyを用いた筋萎縮性側索硬化症における頚髄側索錐体路の損傷評価

    福井裕介、菱川望、表芳夫、武本麻美、太田康之、山下徹、阿部康二

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

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  • DTTを用いた小脳遠心路・求心路の検討 〜多系統萎縮症と皮質性小脳萎縮症の比較〜

    福井裕介、菱川望、表芳夫、武本麻美、太田康之、山下徹、阿部康二

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

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  • 多発性脳梗塞、認知機能障害に加え外傷性くも膜下血腫を呈した新しい遺伝子変異CARASILの1家系

    山下徹、野崎洋明、涌谷陽介、田所功、野村恵美、高橋義秋、佐藤恒太、菱川望、武本麻美、商敬偉、太田康之、小野寺理、阿部康二

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

    Language:Japanese   Presentation type:Poster presentation  

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  • 左正中神経生検で診断に至った末梢神経原発Cytotoxic molecule-positive peripheral T-cell lymphomaの一例

    松本 菜見子、河原 由子、武本 麻美、菱川 望、太田 康之、山下 徹、阿部 康二

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

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  • APP遺伝子変異を認め、多発性微小血種と石灰化を認めた家族性認知症の兄妹例

    太田康之、菱川望、池上憲、佐藤恒太、小坂田陽介、武本麻美、山下徹、表芳夫、池内健、阿部康二

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

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  • 筋萎縮性側索硬化症モデルマウスにおける酸化ストレスin vivo imaging

    太田康之、野村恵美、山下徹、馮田、武本麻美、菱川望、表芳夫、阿部康二

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

    Language:Japanese   Presentation type:Oral presentation (general)  

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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

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

    Language:Japanese   Presentation type:Oral presentation (general)  

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  • MPRAGE法によるプラークイメージングが診断に有用であった、第IX, X脳神経麻痺を伴う両側内頚動脈解離の一例

    佐々木諒、太田康之、高橋義秋、山下徹、商敬偉、武本麻美、菱川望、阿部康二

    第43回日本脳神経CI学会 (岡山)  2020 

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    Event date: 2020.1.24 - 2020.1.25

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  • 海綿静脈洞近傍の病変を主として、多発脳神経麻痺を呈したと考えられる神経サルコイドーシスの一例

    池上憲、菱川望、表芳夫、武本麻実、太田康之、山下徹、阿部康二

    第107回日本神経学会中国・四国地方会(岡山)  2019 

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    Event date: 2019.12.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • 体重減少が先行し髄液中抗GFAP抗体が陽性であったステロイド反応性脳脊髄炎の一例

    小坂田陽介、池上憲、菱川望、佐藤恒太、表芳夫、武本麻実、太田康之、山下徹、木村暁夫、阿部康二

    第107回日本神経学会中国・四国地方会(岡山)  2019 

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    Event date: 2019.12.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • 筋萎縮性側索硬化症患者の前頭葉機能評価

    太田康之、山下徹、菱川望、佐藤恒太、武本麻美、表芳夫、阿部康二

    第38回 日本認知症学会 学術集会(東京)  2019 

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    Event date: 2019.11.7 - 2019.11.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:東京  

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  • Clinical predictors of Alzheimer’s disease progression

    Hishikawa N, Omote Y, Shang J, Takemoto M, Yamashita T, Ohta Y, Abe K

    第38回 日本認知症学会 学術集会(東京)  2019 

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    Event date: 2019.11.7 - 2019.11.9

    Language:English   Presentation type:Poster presentation  

    Venue:東京  

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  • 多発性の大脳・脳幹病変を認め、診断及び治療に苦慮したMOG抗体関連疾患の一例

    松本菜見子、佐藤恒太、河原由子、武本麻美、菱川望、表芳夫、商敬偉、太田康之、山下徹、藤井謙太郎、黒住和彦、伊達勲、阿部康二

    第37回日本神経治療学会(横浜)  2019 

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    Event date: 2019.11.5 - 2019.11.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:横浜  

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  • 新規酸化ストレスイメージングによるALSへのエダラボン治療効果の検討

    太田康之、野村恵美、山下徹、馮田、佐藤恒太、武本麻美、菱川望、表芳夫、阿部康二

    第37回日本神経治療学会(横浜)  2019 

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    Event date: 2019.11.5 - 2019.11.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:横浜  

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  • 痙性対麻痺と末梢神経障害を合併したKleinfelter症候群に対する治療の検討

    佐々木諒、太田康之、田所功、佐藤恒太、菱川望、武本麻美、山下徹、阿部康二

    第37回日本神経治療学会(横浜)  2019 

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    Event date: 2019.11.5 - 2019.11.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:横浜  

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  • 胃瘻増設後に高浸透圧高血糖症候群を発症した進行性核上性麻痺の一例

    田所功、佐藤恒太、森原隆太、商敬偉、武本麻美、表芳夫、太田康之、山下徹、菱川望、阿部康二

    第37回日本神経治療学会(横浜)  2019 

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    Event date: 2019.11.5 - 2019.11.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:横浜  

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  • 抗酸化サプリメントTwendee Xの認知症発症予防効果:多施設共同前向き無作為化プラセボ対照二重盲検比較試験

    田所功、森原隆太、菱川望、山下徹、真邊泰宏、涌谷陽介、高尾芳樹、森本 展年、久徳弓子、垰本勝司、犬房春彦、楊馥華、吉川敏一、Markus Matuschka、阿部康二

    第40回日本臨床栄養協会総会(名古屋)  2019 

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    Event date: 2019.10.26 - 2019.10.27

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋  

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  • 抗酸化サプリメントTwendee Xによる認知機能低下予防効果:多施設共同前向き無作為化プラセボ対照二重盲検比較試験

    田所功、森原隆太、菱川望、山下徹、真邊泰宏、涌谷陽介、高尾芳樹、森本展年、久徳弓子、垰本勝司、犬房春彦、楊馥華、吉川敏一、Markus Matuschka、阿部康二

    第13回日本薬局学会学術総会(神戸)  2019 

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    Event date: 2019.10.19 - 2019.10.20

    Language:Japanese   Presentation type:Poster presentation  

    Venue:神戸  

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  • 抗酸化サプリメントの電子スピン共鳴スペクトロメトリーを用いた酸化ストレス軽減効果

    馮田、角田慶一郎、商敬偉、山下徹、阿部康二

    第1回日本脳サプリメント学会(名古屋)  2019 

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    Event date: 2019.10.19

    Language:English   Presentation type:Oral presentation (general)  

    Venue:名古屋  

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  • 虚血性脳卒中マウスモデルにおけるTocotrienol 製剤(Tocovid)前投与の抗酸化ストレス効果

    平佑貴、Yuting Bian、山下徹、馮田、武本麻美、菱川望、太田康之、阿部康二

    第1回日本脳サプリメント学会(名古屋)  2019 

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    Event date: 2019.10.19

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    Venue:名古屋  

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  • 自動発信電話サービスによるアルツハイマー病患者の不安軽減効果

    太田康之、菱川望、山下徹、佐藤恒太、武本麻美、表芳夫、川野公子、堂垂伸治、阿部康二

    第9回日本認知症予防学会学術集会(名古屋)  2019 

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    Event date: 2019.10.18 - 2019.10.20

    Language:Japanese   Presentation type:Poster presentation  

    Venue:名古屋  

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  • 実は見逃されている血管性認知症の危険因子?Heterozygous HTRA1 mutation c.496 C>T の1家系からの考察?

    山下徹、野崎洋明、涌谷陽介、田所功、野村恵美、高橋義秋、佐藤恒太、菱川望、武本麻美、商敬偉、太田康之、小野寺理、阿部康二

    第9回日本認知症予防学会学術集会(名古屋)  2019 

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    Event date: 2019.10.18 - 2019.10.20

    Language:Japanese   Presentation type:Poster presentation  

    Venue:名古屋  

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  • Diabetic painful truncal neuropathyの1例

    樹下明典、池上憲、角田慶一郎、表芳夫、佐藤恒太、菱川望、阿部康二

    第121回内科学会中国地方会(岡山)  2019 

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    Event date: 2019.10.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:岡山  

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  • Animal models of vascular cognitive impairment.

    Asia Pacific Stroke Conference 2019 (Manila, Philippine)  2019 

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    Event date: 2019.10.2 - 2019.10.4

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

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  • In vivo direct reprogramming of glial linage to mature neurons after cerebral ischemia.

    Asia Pacific Stroke Conference 2019 (Manila, Philippine)  2019 

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    Event date: 2019.10.2 - 2019.10.4

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  • 神経難病患者への自動発信電話サービスによる在宅療養支援

    太田康之、山下徹、菱川望、佐藤恒太、武本麻美、表芳夫、川野公子、堂垂伸治、阿部康二

    第17回日本臨床医療福祉学会(下関)  2019 

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    Event date: 2019.9.20 - 2019.9.21

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:下関