Updated on 2022/09/15

写真a

 
Nakano Yumiko
 
Organization
Okayama University Hospital Assistant Professor
Position
Assistant Professor
Other name(s)
Nakano Yumiko
External link

Research Interests

  • stroke

Research Areas

  • Life Science / Neurology  / stroke

Education

  • The University of Tokushima   医学部   医学科

    2004.4 - 2010.3

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    Country: Japan

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Research History

  • Okayama university hospital   Department of neurology   Assistant Professor   M.D., Ph.D.

    2021.4

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    Country:Japan

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Professional Memberships

  • The Japanese society of internal medicine

    2012.10

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  • Japanese society of neurology

    2012.10

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Papers

  • Clinical and Pathological Benefits of Scallop-Derived Plasmalogen in a Novel Mouse Model of Alzheimer's Disease with Chronic Cerebral Hypoperfusion. International journal

    Tian Feng, Xinran Hu, Yusuke Fukui, Zhihong Bian, Yuting Bian, Hongming Sun, Mami Takemoto, Taijun Yunoki, Yumiko Nakano, Ryuta Morihara, Koji Abe, Toru Yamashita

    Journal of Alzheimer's disease : JAD   2022.3

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    BACKGROUND: The oral ingestion of scallop-derived plasmalogen (sPlas) significantly improved cognitive function in Alzheimer's disease (AD) patients. OBJECTIVE: However, the effects and mechanisms of sPlas on AD with chronic cerebral hypoperfusion (CCH), a class of mixed dementia contributing to 20-30% among the dementia society, were still elusive. METHODS: In the present study, we applied a novel mouse model of AD with CCH to investigate the potential effects of sPlas on AD with CCH. RESULTS: The present study demonstrated that sPlas significantly recovered cerebral blood flow, improved motor and cognitive deficits, reduced amyloid-β pathology, regulated neuroinflammation, ameliorated neural oxidative stress, and inhibited neuronal loss in AD with CCH mice at 12 M. CONCLUSION: These findings suggest that sPlas possesses clinical and pathological benefits for AD with CCH in the novel model mice. Furthermore, sPlas could have promising prevention and therapeutic effects on patients of AD with CCH.

    DOI: 10.3233/JAD-215246

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  • Protective Effect of Rivaroxaban Against Amyloid Pathology and Neuroinflammation Through Inhibiting PAR-1 and PAR-2 in Alzheimer's Disease Mice. International journal

    Zhihong Bian, Xia Liu, Tian Feng, Haibo Yu, Xiao Hu, Xinran Hu, Yuting Bian, Hongming Sun, Koh Tadokoro, Mami Takemoto, Taijun Yunoki, Yumiko Nakano, Yusuke Fukui, Ryuta Morihara, Koji Abe, Toru Yamashita

    Journal of Alzheimer's disease : JAD   86 ( 1 )   111 - 123   2022

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    BACKGROUND: Recent studies have revealed that atrial fibrillation (AF) patients have a high risk of developing cognitive impairment, vascular dementia, and Alzheimer's disease (AD). Some reports suggest that the application of oral anticoagulant with an appropriate dose may have a preventive effect on AD. However, which oral anticoagulant drug is more appropriate for preventing AD and the underlying mechanism(s) is still unknown. OBJECTIVE: The aim of the present study was to assess the treatment effect of rivaroxaban administration as well as investigate the roles of PAR-1 and PAR-2 in the AD + CAA mice model. METHODS: In the present study, we compared a traditional oral anticoagulant, warfarin, and a direct oral anticoagulant (DOAC), rivaroxaban, via long-term administration to an AD with cerebral amyloid angiopathy (CAA) mice model. RESULTS: Rivaroxaban treatment attenuated neuroinflammation, blood-brain barrier dysfunction, memory deficits, and amyloid-β deposition through PAR-1/PAR-2 inhibition in the AD + CAA mice model compared with warfarin and no-treatment groups. CONCLUSION: The present study demonstrates that rivaroxaban can attenuate AD progress and can be a potential choice to prevent AD.

    DOI: 10.3233/JAD-215318

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

    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.

    DOI: 10.1111/ncn3.12414

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

    DOI: 10.1016/j.jns.2020.116906

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  • Familial dropped head syndrome with extremity muscle weakness Reviewed

    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.

    DOI: 10.1111/ncn3.12382

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

    DOI: 10.1016/j.jstrokecerebrovasdis.2020.104743

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  • Diabetic painful truncal neuropathy with hypohidrosis and facial palsy Reviewed

    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.

    DOI: 10.1111/ncn3.12370

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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 ALZHEIMERS DISEASE   73 ( 1 )   209 - 215   2020

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    Language:English   Publishing type:Research paper (scientific journal)   Publisher:IOS PRESS  

    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 ((parallel to parallel to)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.

    DOI: 10.3233/JAD-190669

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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.

    DOI: 10.3233/JAD-191016

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

    DOI: 10.1016/j.brainres.2019.146379

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

    DOI: 10.1016/j.neuroscience.2019.07.050

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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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    DOI: 10.1111/ncn3.12317

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

    DOI: 10.1038/s41598-019-47482-0

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

    DOI: 10.1016/j.neures.2018.06.002

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

    DOI: 10.1002/jnr.24368

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

    DOI: 10.3233/JAD-190369

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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. 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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  • In Vivo Direct Reprogramming of Glial Linage to Mature Neurons in Post-stroke Brain Reviewed

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

    CEREBROVASCULAR DISEASES   48   110 - 110   2019

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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   68 ( 4 )   1667 - 1675   2019

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    © 2019 - IOS Press and the authors. All rights reserved. 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 novelADmodel (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 TNF-dependent AHSG in a novel AD plus HP mice model.

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  • Neuroprotective effects of SMTP-44D in mice stroke model in relation to neurovascular unit and trophic coupling. 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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  • 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   27 ( 11 )   3084 - 3094   2018.11

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    © 2018 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 60 minutes 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 24 hours 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 24 hours 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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  • Chronic cerebral hypoperfusion accelerates Alzheimer's disease pathology with the change of mitochondrial fission and fusion proteins expression in a novel mouse model. 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. 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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  • Detecting spinal spinal pyramidal tract of amyotrophic lateral sclerosis patients with diffusion tensor tractography

    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 (Delta FRS-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 Delta FRS-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. (C) 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

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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   27 ( 8 )   2096 - 2105   2018.8

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    © 2018 National Stroke Association 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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  • 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   27 ( 8 )   2166 - 2174   2018.8

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    © 2018 National Stroke Association 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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  • 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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  • Two cases of late onset familial amyloid polyneuropathy with a Glu61Lys transthyretin variant. 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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  • 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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    © 2018 Elsevier B.V. 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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  • 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 (Korea)   14 ( 1 )   29 - 34   2018.1

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    © 2018 Korean Neurological Association. 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 Reviewed

    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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  • 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   57 ( 10 )   1455 - 1458   2018

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    © 2018 The Japanese Society of Internal Medicine. 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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  • 大脳白質病変を伴うアルツハイマー病患者における抗認知症薬の臨床的効果

    福井 裕介, 菱川 望, 佐藤 恒太, 中野 由美子, 森原 隆太, 武本 麻美, 商 敬偉, 太田 康之, 山下 徹, 阿部 康二

    Anti-aging Science   9 ( 2 )   110 - 110   2017.12

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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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  • Behavioral and affective features of amyotrophic lateral sclerosis patients Reviewed

    Yasuyuki Ohta, Kota Sato, Mami Takemoto, Yoshiaki Takahashi, Ryuta Morihara, Yumiko Nakano, Keiichiro Tsunoda, Emi Nomura, Nozomi Hishikawa, Toni 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. 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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  • 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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  • 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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  • 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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  • 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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  • 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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  • Neuroprotective Effects of a Novel Antioxidant Mixture Twendee X in Mouse Stroke Model Reviewed

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

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   26 ( 6 )   1191 - 1196   2017.6

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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 N-epsilon-(carboxymethyl) lysine (one of advanced glycation end products), as well as inflammatory markers such as ionized calcium binding adapter molecule-1, tumor necrosis factor-alpha, and monocyte chemotactic protein-1. Conclusions: In the present study, the neuroprotective effects of Twendee X were shown on transient middle cerebral artery occlusion mice via antioxidative and anti-inflammatory pathways, providing a potential of Twendee X as one preventive and therapeutic treatment. (C) 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

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

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

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   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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  • 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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  • Emergency caesarean section saved both an anti-musk antibody-positive myasthenia gravis mother with pregnancy-induced hypertension and her premature baby

    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   56 ( 24 )   3361 - 3364   2017

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    © 2017 The Japanese Society of Internal Medicine. 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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  • Temporal Profiles of Stress Protein Inductions after Focal Transient Ischemia in Mice Brain Reviewed

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

    JOURNAL OF STROKE & CEREBROVASCULAR DISEASES   25 ( 10 )   2344 - 2351   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-1 alpha (HIF-1 alpha), 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-1 alpha, 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-1 alpha 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-1 alpha, 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. (C) 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

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  • Effects of Pretreatment with Warfarin or Rivaroxaban on Neurovascular Unit Dissociation after Tissue Plasminogen Activator Thrombolysis in Ischemic Rat Brain. 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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  • 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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  • 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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  • 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. 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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  • 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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  • 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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  • 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   48 ( 3 )   757 - 763   2015.10

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    © 2015 - IOS Press and the authors. All rights reserved. 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.

    DOI: 10.3233/JAD-150518

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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   47 ( 2 )   487 - 493   2015.7

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    © 2015 - IOS Press and the authors. All rights reserved. The clinical benefits of memantine, depending on the baseline cognitive and affective conditions in realworld 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 improvedBPSDsymptoms 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.

    DOI: 10.3233/JAD-150094

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

    DOI: 10.1016/j.jstrokecerebrovasdis.2015.03.037

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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   46 ( 3 )   687 - 693   2015.6

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    © 2015-IOS Press and the authors. All rights reserved. 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.

    DOI: 10.3233/JAD-150175

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  • Estimation of the Presence of Small Dense Lipoprotein Cholesterol in Acute Ischemic Stroke. Reviewed International journal

    Yasuhiro Manabe, Ryuta Morihara, Kosuke Matsuzono, Yumiko Nakano, Yoshiaki Takahashi, Hisashi Narai, Nobuhiko Omori, Koji Abe

    Neurology international   7 ( 1 )   5973 - 5973   2015.3

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    Small dense low-density lipoprotein (sdLDL) is an established risk factor in ischemic heart disease. However, its clinical significance in acute ischemic stroke (AIS) is uncertain. This study evaluates the prognostic value of the presence of sdLDL in patients with AIS by determining whether it contributes to clinical outcome or not. We studied 530 consecutive patients admitted within the first 48 hours after onset of ischemic stroke and 50 corresponding controls. Serum lipid parameters were measured on admission by standard laboratory methods. The percentage of AIS patients with sdLDL was significantly higher than the one of matched controls with sdLDL. Concerning comparisons between AIS patients with or without sdLDL, the percentages of males and patients with histories of smoking, hypertension, and cardiovascular disease were significantly higher in AIS patients with sdLDL. Concerning the grade of severity, modified Rankin Scale (mRS) on discharge was significantly higher in AIS patients with sdLDL. On logistic regression analysis, age (OR=2.29, P<0.001), male gender (OR=0.49, P<0.01), history of atrial fibrillation (OR=3.46, P<0.001), and the presence of sdLDL (OR=1.59, P<0.05) were significantly associated with poor prognosis (mRS on discharge >3). Our study showed that the presence of sdLDL might be independently associated with a poor prognosis after AIS.

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

    DOI: 10.3233/JAD-150308

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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.

    DOI: 10.3233/JAD-143084

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

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

    Japanese Journal of Medicine   54 ( 14 )   1717 - 1723   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).<br> 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.<br> 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.<br> 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.<br>

    DOI: 10.2169/internalmedicine.54.4747

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    Other Link: http://search.jamas.or.jp/link/ui/2016310060

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  • 神経疾患治療ストラテジー : 既存の治療・新規治療・今後の治療と考え方

    祖父江, 元( Role: Contributor ,  抗酸化療法)

    中山書店  2017.9  ( ISBN:9784521745435

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    Total pages:xi, 451p   Language:Japanese

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  • メディカルスタッフのための臨床医学

    吉澤, 篤人, 矢崎, 義雄( Role: Contributor ,  認知症)

    医薬ジャーナル社  2016.8  ( ISBN:9784753227914

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  • 大脳白質病変を考慮したアルツハイマー病の治療薬の選択

    福井 裕介, 菱川 望, 佐藤 恒太, 中野 由美子, 森原 隆太, 太田 康之, 山下 徹, 阿部 康二

    日本老年医学会雑誌   54 ( 4 )   625 - 625   2017.10

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  • タッチパネル式コンピュータを活用した脳梗塞既往患者の認知機能と画像所見の関連の検討

    出口 健太郎, 河野 祥一郎, 柚木 太淳, 松薗 構佑, 中野 由美子, 角田 慶一郎, 河原 由子, 幡中 典子, 武本 麻美, 太田 康之, 菱川 望, 山下 徹, 阿部 康二

    脳循環代謝   26 ( 1 )   168 - 168   2014.11

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  • Central and Peripheral Nervous System (2021academic year) Prophase  - 6月14日(月)・3限