Faculty Profiles - MORIHARA Ryuuta

Papers - MORIHARA Ryuuta

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The potential mechanism maintaining transactive response DNA binding protein 43 kDa in the mouse stroke model. International journal

Yuting Bian, Yusuke Fukui, Ricardo Satoshi Ota-Elliott, Xinran Hu, Hongming Sun, Zhihong Bian, Yun Zhai, Haibo Yu, Xiao Hu, Hangping An, Hongzhi Liu, Ryuta Morihara, Hiroyuki Ishiura, Toru Yamashita

Neuroscience research 2025.1

Language：English Publishing type：Research paper (scientific journal)

The disruption of transactive response DNA binding protein 43 kDa (TDP-43) shuttling leads to the depletion of nuclear localization and the cytoplasmic accumulation of TDP-43. We aimed to evaluate the mechanism underlying the behavior of TDP-43 in ischemic stroke. Adult male C57BL/6 J mice were subjected to 30 or 60 min of transient middle cerebral artery occlusion (tMCAO), and examined at 1, 6, and 24 h post reperfusion. Immunostaining was used to evaluate the expression of TDP-43, G3BP1, HDAC6, and RAD23B. The total and cytoplasmic number of TDP-43-positive cells increased compared with sham operation group and peaked at 6 h post reperfusion after tMCAO. The elevated expression of G3BP1 protein peaked at 6 h after reperfusion and decreased at 24 h after reperfusion in ischemic mice brains. We also observed an increase of expression level of HDAC6 and the number of RAD23B-positive cells increased after tMCAO. RAD23B was colocalized with TDP-43 24 h after tMCAO. We proposed that the formation of stress granules might be involved in the mislocalization of TDP-43, based on an evaluation of G3BP1 and HDAC6. Subsequently, RAD23B, may also contribute to the downstream degradation of mislocalized TDP-43 in mice tMCAO model.

DOI： 10.1016/j.neures.2025.01.006

レカネマブ治療に伴うAPOE遺伝子型検査の実際

森原隆太, 小坂田陽介, 池上憲, 平祐貴, 石田将大, 樹下明典, 柚木太淳, 武本麻美, 野村恵美, 河野智仁, 松岡千加, 山下徹, 加藤芙美乃, 深野智華, 平沢晃, 石浦浩之

Dementia Japan 38 ( 4 ) 681 - 681 2024.10

髄液中抗MOG抗体を指標にIVIGによる維持療法を行った再発性MOGADの一例

池上憲, 佐々木諒, 石田将大, 樹下明典, 平祐貴, 小坂田陽介, 武本麻美, 森原隆太, 柚木太淳, 山下徹, 石浦浩之

神経免疫学 29 ( 1 ) 262 - 262 2024.10

ATXN2遺伝子のCAGリピートをホモ接合性に有し同胞と臨床病型が異なりパーキンソニズムと痙性を呈した症例

小坂田陽介, 松岡千加, 中田有美, 佐々木諒, 中野由美子, 柚木太淳, 武本麻美, 森原隆太, 山下徹, 石浦浩之

臨床神経学 64 ( 10 ) 755 - 755 2024.10

当院における2家系のSCAR8の検討

柚木太淳, 松岡千加, 小坂田陽介, 中野由美子, 武本麻美, 森原隆太, 山下徹, 石浦浩之

臨床神経学 64 ( 10 ) 751 - 751 2024.10

Suppression of PTBP1 in hippocampal astrocytes promotes neurogenesis and ameliorates recognition memory in mice with cerebral ischemia. Reviewed International journal

Yusuke Fukui, Ryuta Morihara, Xinran Hu, Yumiko Nakano, Taijun Yunoki, Mami Takemoto, Koji Abe, Toru Yamashita

Scientific reports 14 ( 1 ) 20521 - 20521 2024.9

Language：English Publishing type：Research paper (scientific journal)

The therapeutic potential of suppressing polypyrimidine tract-binding protein 1 (Ptbp1) messenger RNA by viral transduction in a post-stroke dementia mouse model has not yet been examined. In this study, 3 days after cerebral ischemia, we injected a viral vector cocktail containing adeno-associated virus (AAV)-pGFAP-mCherry and AAV-pGFAP-CasRx (control vector) or a cocktail of AAV-pGFAP-mCherry and AAV-pGFAP-CasRx-SgRNA-(Ptbp1) (1:5, 1.0 × 1011 viral genomes) into post-stroke mice via the tail vein. We observed new mCherry/NeuN double-positive neuron-like cells in the hippocampus 56 days after cerebral ischemia. A portion of mCherry/GFAP double-positive astrocyte-like glia could have been converted into new mCherry/NeuN double-positive neuron-like cells with morphological changes. The new neuronal cells integrated into the dentate gyrus and recognition memory was significantly ameliorated. These results demonstrated that the in vivo conversion of hippocampal astrocyte-like glia into functional new neurons by the suppression of Ptbp1 might be a therapeutic strategy for post-stroke dementia.

DOI： 10.1038/s41598-024-71212-w

Protective effect of scallop-derived plasmalogen against vascular dysfunction, via the pSTAT3/PIM1/NFATc1 axis, in a novel mouse model of Alzheimer's disease with cerebral hypoperfusion. Reviewed International journal

Yun Zhai, Ryuta Morihara, Tian Feng, Xinran Hu, Yusuke Fukui, Zhihong Bian, Yuting Bian, Haibo Yu, Hongming Sun, Mami Takemoto, Yumiko Nakano, Taijun Yunoki, Ying Tang, Hiroyuki Ishiura, Toru Yamashita

Brain research 1828 148790 - 148790 2024.4

Language：English Publishing type：Research paper (scientific journal)

A strong relationship between Alzheimer's disease (AD) and vascular dysfunction has been the focus of increasing attention in aging societies. In the present study, we examined the long-term effect of scallop-derived plasmalogen (sPlas) on vascular remodeling-related proteins in the brain of an AD with cerebral hypoperfusion (HP) mouse model. We demonstrated, for the first time, that cerebral HP activated the axis of the receptor for advanced glycation endproducts (RAGE)/phosphorylated signal transducer and activator of transcription 3 (pSTAT3)/provirus integration site for Moloney murine leukemia virus 1 (PIM1)/nuclear factor of activated T cells 1 (NFATc1), accounting for such cerebral vascular remodeling. Moreover, we also found that cerebral HP accelerated pSTAT3-mediated astrogliosis and activation of the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome, probably leading to cognitive decline. On the other hand, sPlas treatment attenuated the activation of the pSTAT3/PIM1/NFATc1 axis independent of RAGE and significantly suppressed NLRP3 inflammasome activation, demonstrating the beneficial effect on AD.

DOI： 10.1016/j.brainres.2024.148790

【指定難病 Up to Date】前頭側頭葉変性症

森原隆太, 石浦浩之

岡山医学会雑誌 136 ( 1 ) 17 - 21 2024.4

リウマチ性疾患の中枢神経症状と神経自己抗体

高橋幸利, 井口晃宏, 矢部友奈, 千葉悠平, 伊倉崇浩, 須田顕, 山口佳剛, 土屋遙香, 土田優美, 中馬越清隆, 寺田真, 横手顕, 武井藍, 森原隆太

リウマチ科 71 ( 4 ) 444 - 452 2024.4

Neuroprotective effect of, a flavonoid, sudachitin in mice stroke model. Reviewed International journal

Ricardo Satoshi Ota-Elliott, Yusuke Fukui, Yuting Bian, Zhihong Bian, Xinran Hu, Hongming Sun, Haibo Yu, Ryuta Morihara, Hiroyuki Ishiura, Toru Yamashita

Brain research 1827 148745 - 148745 2024.3

Language：English Publishing type：Research paper (scientific journal)

A flavonoid, sudachitin, has been reported to show some beneficial health effects, including as an anti-inflammatory in LPS-stimulated macrophages, as well as improving glucose and lipid metabolism in mice fed a high-fat diet. In this study, we investigated the neuroprotective effect of sudachitin in the transient middle cerebral artery occlusion (tMCAO) mouse model. After daily pre-treatment of vehicle or sudachitin (5 or 50 mg/kg) for 14 days, mice (n = 76) were subjected to a sham operation or tMCAO for 45 min, and on the following days, they were treated daily with vehicle or sudachitin. The administration of sudachitin significantly reduced (p < 0.05) cerebral infarct volume and attenuated apoptosis, 5 days after tMCAO. Neurological impairment improved, the expression of an oxidative stress marker, 4-HNE, decreased, and the Sirt1/PGC-1α pathway was activated 5 days after tMCAO in the sudachitin-treated group. This is the first report to demonstrate the neuroprotective effect of sudachitin in cerebral ischemia/reperfusion injury mice model, probably by activating the Sirt1/PGC-1α axis. Sudachitin may be a promising supplement or therapeutic agent for reducing injury caused by ischemic strokes.

DOI： 10.1016/j.brainres.2023.148745

脳血栓回収療法後の認知機能の転帰の検討 Reviewed

森原隆太, 小坂田陽介, 角田慶一郎, 久我純弘, 阿部康二, 大西英之, 石浦浩之, 山下徹

日本脳血管・認知症学会総会プログラム・抄録集 14th 2024

A Novel Peptidome Technology for the Diagnosis of Mild Cognitive Impairment and Alzheimer's Disease by Selected Reaction Monitoring. Reviewed International journal

Yusuke Fukui, Koh Tadokoro, Minaki Hamada, Kyoichi Asada, Lyang-Ja Lee, Hidehisa Tachiki, Ryuta Morihara, Koji Abe, Toru Yamashita

Journal of Alzheimer's disease : JAD 100 ( 1 ) 219 - 228 2024

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: With the aging of populations worldwide, Alzheimer's disease (AD) has become a concern due to its high prevalence and the continued lack of established treatments. Early diagnosis is required as a preventive intervention to modify the disease's progression. In our previous study, we performed peptidomic analysis of serum samples obtained from AD patients and age-matched healthy subjects to seek peptide biomarker candidates for AD by using BLOTCHIP-MS analysis, and identified four peptides as AD biomarker candidates. OBJECTIVE: The objective was to validate the serum biomarker peptides to distinguish mild cognitive impairment (MCI) and AD in comparison to cognitively healthy controls using a new peptidome technology, the Dementia Risk Test. METHODS: We enrolled 195 subjects with normal cognitive function (NC; n = 70), MCI (n = 55), and AD (n = 70), The concentrations of cognitive impairment marker peptides (Fibrinogen α chain (FAC), Fibrinogen β chain (FBC), Plasma protease C1 inhibitor (PPC1I), α2-HS-glycoprotein (AHSG)) were quantified by using a selected reaction monitoring assay based on liquid chromatography-MS/MS. RESULTS: The present study confirmed that three peptides, FAC, FBC, and PPC1I, were significantly upregulated during the onset of AD. This three-peptide set was both highly sensitive in determining AD (sensitivity: 85.7%, specificity: 95.7%, AUC: 0.900) and useful in distinguishing MCI (sensitivity: 61.8%, specificity: 98.6%, AUC: 0.824) from NC. CONCLUSIONS: In this validation study, we confirmed the high diagnostic potential of the three peptides identified in our previous study as candidate serum biomarkers for AD. The Dementia Risk Test may be a powerful tool for detecting AD-related pathological changes.

DOI： 10.3233/JAD-230915

A Unique Case of Sarcoid-associated Myelopathy Accompanied by Lung Cancer. Reviewed

Koh Tadokoro, Yumi Nakada, Ryo Sasaki, Yumiko Nakano, Taijun Yunoki, Kotaro Shin, Masataka Taoka, Kiichiro Ninomiya, Emi Nomura, Mami Takemoto, Ryuta Morihara, Toru Yamashita

Internal medicine (Tokyo, Japan) 62 ( 23 ) 3531 - 3535 2023.12

Language：English Publishing type：Research paper (scientific journal)

The differential diagnosis of myelopathy in patients with malignancies may be challenging, as a spinal biopsy is not always applicable. A 66-year-old woman who had shown transient double vision and nausea developed spasticity and impaired deep sensation in both feet. Magnetic resonance imaging showed abnormal gadolinium enhancement of the brainstem, spinal meninges, and nerve root. Cerebrospinal fluid (CSF) revealed mild pleocytosis and elevated protein and decreased glucose levels, although CSF cytology was normal. Lung carcinoma was simultaneously detected, and noncaseating granuloma was detected from the hilar and axillary lymph nodes, so she was diagnosed with sarcoid-associated myelopathy. Her symptoms were kept stable by intravenous methylprednisolone, oral prednisolone, and methotrexate. This is the first case of sarcoid-associated myelopathy accompanied by lung cancer, suggesting the importance of clinical course, repetitive CSF cytology, and a biopsy of the lymph nodes to distinguish sarcoid-associated myelopathy from meningeal metastasis in patients with malignancies.

DOI： 10.2169/internalmedicine.0943-22

Exogenous amyloid-β oligomers exacerbate cognitive deficits and activated necroptosis in APP23 mice(タイトル和訳中) Reviewed

胡欣冉, 于海波, 山下徹, 森原隆太, 福井裕介, 石浦浩之

脳循環代謝 35 ( 1 ) 122 - 122 2023.11

外因性アミロイドβオリゴマーはAPP23マウスにおける認知障害を悪化させネクロトーシスを活性化させる(Exogenous amyloid-β oligomers exacerbate cognitive deficits and activated necroptosis in APP23 mice) Reviewed

胡欣冉, 于海波, 山下徹, 森原隆太, 福井裕介, 石浦浩之

脳循環代謝 35 ( 1 ) 122 - 122 2023.11

脳血栓回収療法がpost-stroke dementiaをひきおこすのか?

小坂田陽介, 森原隆太, 久我純弘, 阿部康二, 大西英之, 山下徹

神経科学研究所医誌 8 ( 1 ) 43 - 47 2023.11

Language：Japanese Publisher：(医社)英明会大西脳神経外科病院神経科学研究所

50歳以上のテント上急性期脳梗塞症例454例のうち31例を対象に、脳血栓回収療法がpost-stroke dementiaに与える影響について検討した。対象は内科治療群20例と血管内治療群11例に分け、脳梗塞発症後12ヵ月まで経過観察を行い認知機能を比較した。その結果、発症12ヵ月後の認知機能は、内科治療群でMMSEおよびMoCAで有意な改善を認めたが、血管内治療群は認知機能は改善せず、特にMoCAで差があった。以上より、脳血栓回収療法による血管壁への機械的侵襲や虚血再灌流障害はpost stroke dementiaのリスク因子となる可能性がある。

Protective Effects of Rivaroxaban on White Matter Integrity and Remyelination in a Mouse Model of Alzheimer's Disease Combined with Cerebral Hypoperfusion. Reviewed International journal

Zhihong Bian, Xinran Hu, Xia Liu, Haibo Yu, Yuting Bian, Hongming Sun, Yusuke Fukui, Ryuta Morihara, Hiroyuki Ishiura, Toru Yamashita

Journal of Alzheimer's disease : JAD 96 ( 2 ) 609 - 622 2023.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Alzheimer's disease (AD) is characterized by cognitive dysfunction and memory loss that is accompanied by pathological changes to white matter. Some clinical and animal research revealed that AD combined with chronic cerebral hypoperfusion (CCH) exacerbates AD progression by inducing blood-brain barrier dysfunction and fibrinogen deposition. Rivaroxaban, an anticoagulant, has been shown to reduce the rates of dementia in atrial fibrillation patients, but its effects on white matter and the underlying mechanisms are unclear. OBJECTIVE: The main purpose of this study was to explore the therapeutic effect of rivaroxaban on the white matter of AD+CCH mice. METHODS: In this study, the therapeutic effects of rivaroxaban on white matter in a mouse AD+CCH model were investigated to explore the potential mechanisms involving fibrinogen deposition, inflammation, and oxidative stress on remyelination in white matter. RESULTS: The results indicate that rivaroxaban significantly attenuated fibrinogen deposition, fibrinogen-related microglia activation, oxidative stress, and enhanced demyelination in AD+CCH mice, leading to improved white matter integrity, reduced axonal damage, and restored myelin loss. CONCLUSIONS: These findings suggest that long-term administration of rivaroxaban might reduce the risk of dementia.

DOI： 10.3233/JAD-230413

視線計測計を用いた認知機能検査の有用性 Reviewed

田所功, 福井裕介, 野村恵美, 中野由美子, 柚木太淳, 武本麻美, 森原隆太, 阿部康二, 山下徹

日本老年医学会雑誌 60 ( 4 ) 476 - 477 2023.10

Injection of exogenous amyloid-β oligomers aggravated cognitive deficits, and activated necroptosis, in APP23 transgenic mice. International journal

Haibo Yu, Ryuta Morihara, Ricardo Ota-Elliott, Zhihong Bian, Yuting Bian, Xinran Hu, Hongming Sun, Yusuke Fukui, Koji Abe, Hiroyuki Ishiura, Toru Yamashita

Brain research 1821 148565 - 148565 2023.9

Language：English Publishing type：Research paper (scientific journal)

Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by the loss of synapses and neurons in the brain, and the accumulation of amyloid plaques. Aβ oligomers (AβO) play a critical role in the pathogenesis of AD. Although there is increasing evidence to support the involvement of necroptosis in the pathogenesis of AD, the exact mechanism remains elusive. In the present study, we explored the effect of exogenous AβO injection on cell necroptosis and cognitive deficits in APP23 transgenic mice. We found that intrahippocampal injection of AβO accelerated the development of AD pathology and caused cognitive impairment in APP23 mice. Specifically, AβO injection significantly accelerated the accumulation of AβO and increased the expression level of phosphorylated-tau, and also induced necroptosis. Behavioral tests showed that AβO injection was associated with cognitive impairment. Furthermore, necroptosis induced by AβO injection occurred predominantly in microglia of the AD brain. We speculate that AβO increased necroptosis by activating microglia, resulting in cognitive deficits. Our results may aid in an understanding of the role played by AβO in AD from an alternative perspective and provide new ideas and evidence for necroptosis as a potential intervention and therapeutic target for AD.

DOI： 10.1016/j.brainres.2023.148565

抗AQP4抗体陽性のNMOsd患者の髄液におけるIL-6測定の有用性の検討

柚木太淳, 中田有美, 松岡千加, 田所功, 佐々木諒, 中野由美子, 武本麻実, 森原隆太, 山下徹, 石浦浩之

臨床神経学 63 ( Suppl. ) S298 - S298 2023.9

脊髄性筋萎縮症患者7名に対するリスジプラムの治療効果 Reviewed

山下徹, 柚木太淳, 中田有美, 松岡千加, 佐々木涼, 田所功, 中野由美子, 武本麻美, 森原隆太, 石浦浩之

臨床神経学 63 ( Suppl. ) S215 - S215 2023.9

MRgFUS Vim ThalamotomyにおけるBrain Mapping Applicationの有効性 Reviewed

小坂田陽介, 平林秀裕, 森原隆太, 山下徹, 阿部康二, 久我純弘, 大西英之

臨床神経学 63 ( Suppl. ) S244 - S244 2023.9

Foix-Chavany-Marie症候群を呈した持続性部分てんかんの一例 Reviewed

佐々木諒, 柚木太淳, 中田有美, 松岡千加, 田所功, 中野由美子, 武本麻美, 森原隆太, 山下徹, 石浦浩之

臨床神経学 63 ( 9 ) 620 - 620 2023.9

エフガルチギモドへのスイッチを行った抗アセチルコリン受容体抗体・抗横紋筋抗体陽性の全身型重症筋無力症の一例 Reviewed

中野由美子, 佐々木諒, 中田有美, 松岡千加, 小坂田陽介, 田所功, 野村恵美, 柚木太淳, 武本麻美, 森原隆太, 山下徹, 石浦浩之

臨床神経学 63 ( 9 ) 621 - 621 2023.9

神経疾患患者における遠隔診療のニーズ調査 Reviewed

佐々木諒, 田所功, 福井裕介, 中野由美子, 柚木太淳, 武本麻美, 森原隆太, 山下徹

臨床神経学 63 ( Suppl. ) S261 - S261 2023.9

Foix-Chavany-Marie症候群を呈した持続性部分てんかんの一例 Reviewed

佐々木諒, 柚木太淳, 中田有美, 松岡千加, 田所功, 中野由美子, 武本麻美, 森原隆太, 山下徹, 石浦浩之

臨床神経学 63 ( 9 ) 620 - 620 2023.9

脊髄性筋萎縮症患者7名に対するリスジプラムの治療効果 Reviewed

山下徹, 柚木太淳, 中田有美, 松岡千加, 佐々木涼, 田所功, 中野由美子, 武本麻美, 森原隆太, 石浦浩之

臨床神経学 63 ( Suppl. ) S215 - S215 2023.9

エフガルチギモドへのスイッチを行った抗アセチルコリン受容体抗体・抗横紋筋抗体陽性の全身型重症筋無力症の一例 Reviewed

中野由美子, 佐々木諒, 中田有美, 松岡千加, 小坂田陽介, 田所功, 野村恵美, 柚木太淳, 武本麻美, 森原隆太, 山下徹, 石浦浩之

臨床神経学 63 ( 9 ) 621 - 621 2023.9

MRgFUS Vim ThalamotomyにおけるBrain Mapping Applicationの有効性 Reviewed

小坂田陽介, 平林秀裕, 森原隆太, 山下徹, 阿部康二, 久我純弘, 大西英之

臨床神経学 63 ( Suppl. ) S244 - S244 2023.9

抗AQP4抗体陽性のNMOsd患者の髄液におけるIL-6測定の有用性の検討 Reviewed

柚木太淳, 中田有美, 松岡千加, 田所功, 佐々木諒, 中野由美子, 武本麻実, 森原隆太, 山下徹, 石浦浩之

臨床神経学 63 ( Suppl. ) S298 - S298 2023.9

神経疾患患者における遠隔診療のニーズ調査 Reviewed

佐々木諒, 田所功, 福井裕介, 中野由美子, 柚木太淳, 武本麻美, 森原隆太, 山下徹

臨床神経学 63 ( Suppl. ) S261 - S261 2023.9

MRガイド下集束超音波療法による淡蒼球内節凝固術にて片側ジスキネジア改善を認めたパーキンソン病の一例

小坂田陽介, 平林秀裕, 久我純弘, 森原隆太, 山下徹, 阿部康二, 大西英之

臨床神経学 63 ( 6 ) 392 - 392 2023.6

ADSSL1遺伝子変異を認め心不全を発症したが早期介入にて改善しえたネマリンミオパチーの一例 Reviewed

柚木太淳, 中野由美子, 野村恵美, 中田有美, 佐々木諒, 田所功, 武本麻美, 森原隆太, 山下徹, 斎藤良彦, 西野一三

臨床神経学 63 ( 5 ) 322 - 322 2023.5

両側声帯麻痺から診断に至ったdouble seronegative myasthenia gravisの一例 Reviewed

中野由美子, 柚木太淳, 浦口健介, 中田有美, 佐々木諒, 田所功, 森原隆太, 山下徹

臨床神経学 63 ( 5 ) 322 - 322 2023.5

Neuroprotective effects of carnosine in a mice stroke model concerning oxidative stress and inflammatory response. Reviewed International journal

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

Journal of the neurological sciences 447 120608 - 120608 2023.4

Language：English Publishing type：Research paper (scientific journal)

Carnosine (β-alanyl-L-histidine) is a natural dipeptide with multiple neuroprotective properties. Previous studies have advertised that carnosine scavenges free radicals and displays anti-inflammatory activity. However, the underlying mechanism and the efficacies of its pleiotropic effect on prevention remained obscure. In this study, we aimed to investigate the anti-oxidative, anti-inflammative, and anti-pyroptotic effects of carnosine in the transient middle cerebral artery occlusion (tMCAO) mouse model. After a daily pre-treatment of saline or carnosine (1000 mg / kg / day) for 14 days, mice (n = 24) were subjected to tMCAO for 60 min and continuously treated with saline or carnosine for additional 1 and 5 days after reperfusion. The administration of carnosine significantly decreased infarct volume 5 days after the tMCAO (*p < 0.05) and effectively suppressed the expression of 4-HNE, 8-OHdG, Nitrotyrosine 5 days, and RAGE 5 days after tMCAO. Moreover, the expression of IL-1β was also significantly suppressed 5 days after tMCAO. Our present findings demonstrated that carnosine effectively relieves oxidative stress caused by ischemic stroke and significantly attenuates neuroinflammatory responses related to IL-1β, suggesting that carnosine can be a promising therapeutic strategy for ischemic stroke.

DOI： 10.1016/j.jns.2023.120608

Actual Telemedicine Needs of Japanese Patients with Neurological Disorders in the COVID-19 Pandemic. Reviewed

Ryo Sasaki, Taijun Yunoki, Yumiko Nakano, Yusuke Fukui, Mami Takemoto, Ryuta Morihara, Koji Abe, Toru Yamashita

Internal medicine (Tokyo, Japan) 62 ( 3 ) 365 - 371 2023.2

Language：English Publishing type：Research paper (scientific journal)

Objective During the coronavirus disease 2019 (COVID-19) pandemic, many social activities have moved online using applications for digital devices (e.g. computers, smartphones). We investigated the needs of telemedicine and trends in medical status and social care situations of Japanese patients with neurological disorders in order to estimate their affinity for an online telemedicine application. Methods We designed an original questionnaire for the present study that asked participants what problems they had with hospital visits, how the COVID-19 pandemic had affected their lives, and whether or not they would like to receive telemedicine. Patients The present study included volunteer caregivers, participants with Parkinson's disease (PD), epilepsy, stroke, dementia, immune-mediated neurological disease (IMMD), spinocerebellar degeneration (SCD), amyotrophic lateral sclerosis (ALS), headache, myopathy, and other neurological diseases from Okayama University Hospital. Results A total of 29.6% of patients wanted to use telemedicine. Patients with headaches (60.0%) and epilepsy (38.1%) were more likely to want to use telemedicine than patients with PD (17.8%) or stroke (19.0%). Almost 90% of patients had access to a digital device, and there was no association between favoring telemedicine, ownership of a digital device, hospital visiting time, or waiting time at the hospital, although age was associated with motivation to telemedicine use (52.6 vs. 62.2 years old, p <0.001*). Conclusion We can contribute to the management of the COVID-19 pandemic and the medical economy by promoting telemedicine, especially for young patients with headaches or epilepsy.

DOI： 10.2169/internalmedicine.9702-22

A young female case of asymptomatic immune-mediated necrotizing myopathy: a potential diagnostic option of antibody testing for rhabdomyolysis. Reviewed International journal

Ryo Sasaki, Taijun Yunoki, Yumiko Nakano, Yusuke Fukui, Mami Takemoto, Ryuta Morihara, Eri Katsuyama, Ichizo Nishino, Toru Yamashita

Neuromuscular disorders : NMD 33 ( 2 ) 183 - 186 2023.2

Language：English

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) is a neuromuscular disorder that presents muscle weakness in proximal extremities and/or the trunk with an elevation of creatine kinase (CK). Young and asymptomatic anti-HMGCR IMNM patients are very rare and a treatment regimen has not been established. The present case, a 17-year-old woman without any muscular symptoms, only showed hyperCKemia that was detected by chance. After close examinations, including a muscle biopsy and antibody search, she was diagnosed as anti-HMGCR IMNM, and initial treatment with methotrexate and continuous intravenous immunoglobulin seemed to be effective. The present case is the unusually young asymptomatic case of anti-HMGCR IMNM. The diagnosis was successfully made, leading to the early introduction of a treatment. Given the course of this case, we believe that the preceding antibody testing is one of the diagnostic option for rhabdomyolysis.

DOI： 10.1016/j.nmd.2022.12.012

脳低灌流アルツハイマー病マウスにおけるホタテ由来プラズマローゲンの脳血管保護効果 Reviewed

福井裕介, ZHAI Yun, FENG Tian, 森原隆太, 石浦浩之, 山下徹

日本脳サプリメント学会(Web) 5th 2023

エフガルチギモドへのスイッチを行った抗アセチルコリン受容体抗体・抗横紋筋抗体陽性の全身型重症筋無力症の一例

中野由美子, 佐々木諒, 中田有美, 松岡千加, 小坂田陽介, 田所功, 野村恵美, 柚木太淳, 武本麻美, 森原隆太, 山下徹, 石浦浩之

臨床神経学(Web) 63 ( 9 ) 2023

Exogenous amyloid-β oligomers exacerbate cognitive deficits and activated necroptosis in APP23 mice Reviewed

胡欣冉, 于海波, 山下徹, 森原隆太, 福井裕介, 石浦浩之

脳循環代謝(Web) 35 ( 1 ) 2023

Human Cord Blood-Endothelial Progenitor Cells Alleviate Intimal Hyperplasia of Arterial Damage in a Rat Stroke Model. Reviewed International journal

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

Cell transplantation 32 9636897231193069 - 9636897231193069 2023

Language：English Publishing type：Research paper (scientific journal)

Human cord blood-endothelial progenitor cells (hCB-EPCs) isolated from the human umbilical cord can be used to repair damaged arteries. In this study, we used an animal model with pathological changes that mimics artery wall damage caused by stent retrievers in humans. We injected hCB-EPCs to investigate their effect on endothelial hyperplasia and dysfunction during intimal repair. Four groups were established based on the length of reperfusion (3 and 28 days), as well as the presence or absence of hCB-EPC therapy. Damage to the internal carotid artery was evaluated by hematoxylin-eosin and immunohistochemical staining. Stroke volume was not significantly different between non-EPC and EPC groups although EPC treatment alleviated intimal hyperplasia 28 days after intimal damage. Vascular endothelial growth factor (VEGF) and eNOS expression were significantly higher in the EPC-treated group than in the non-EPC group 3 days after intimal damage. In addition, MMP9 and 4HNE expression in the EPC-treated group was significantly lower than in the non-EPC group. Ultimately, this study found that venous transplantation of hCB-EPCs could inhibit neointimal hyperplasia, alleviate endothelial dysfunction, suppress intimal inflammation, and reduce oxidative stress during healing of intimal damage.

DOI： 10.1177/09636897231193069

Safety and Clinical Effects of a Muse Cell-Based Product in Patients With Amyotrophic Lateral Sclerosis: Results of a Phase 2 Clinical Trial. Reviewed International journal

Toru Yamashita, Yumiko Nakano, Ryo Sasaki, Koh Tadokoro, Yoshio Omote, Taijun Yunoki, Yuko Kawahara, Namiko Matsumoto, Yuki Taira, Chika Matsuoka, Ryuta Morihara, Koji Abe

Cell transplantation 32 9636897231214370 - 9636897231214370 2023

Language：English Publishing type：Research paper (scientific journal)

Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of motor neurons. Multilineage-differentiating stress-enduring (Muse) cells are unique endogenous stem cells that show therapeutic effects on motor function in ALS mouse models. We conducted a single-center open phase II clinical trial to evaluate the safety and clinical effects of repeated intravenous injections of an allogenic Muse cell-based product, CL2020, in patients with ALS. Five patients with ALS received CL2020 intravenously once a month for a total of six doses. The primary endpoints were safety and tolerability, and the secondary endpoint was the rate of change in the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. In addition, serum tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), sphingosine-1-phosphate (S1P), cerebrospinal fluid chitotriosidase-1 (CHIT-1), and neurofilament light chain (NfL) levels were evaluated. The CL2020 treatment was highly tolerated without serious side effects. The ALSFRS-R score change trended upward at 12 months post-CL2020 treatment compared with that at 3 months pre-administration, but the difference was not statistically significant. Among five patients diagnosed with ALS, three exhibited a decrease in the rate of ALSFRS-R score change, one demonstrated an increase, and another showed no change. In addition, the patients' serum IL-6 and TNF-α levels and cerebrospinal fluid CHIT-1 and NfL levels increased for up to 6 months post-treatment; however, their serum S1P levels continuously decreased over 12 months. These findings indicate a favorable safety profile of CL2020 therapy. In the near future, a double-blind study of a larger number of ALS patients should be conducted to confirm the efficacy of ALS treatment with CL2020.

DOI： 10.1177/09636897231214370

Tocovid Attenuated Oxidative Stress and Cognitive Decline by Inhibiting Amyloid-β-Induced NOX2 Activation in Alzheimer's Disease Mice. International journal

Zhihong Bian, Haibo Yu, 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 2022.12

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: NADPH oxidase 2 (NOX2) is an important source of reactive oxygen species (ROS). Activated NOX2 may contribute to Alzheimer's disease (AD). Our previous studies showed that a novel vitamin E mixture, Tocovid, had potential neuroprotective effects in a stroke mice model and an AD cell model. OBJECTIVE: The aim of this study was two-fold: to assess whether long-term Tocovid treatment can regulate NOX2, and the therapeutic effects of long-term administration of Tocovid to an AD mice model. METHODS: Therapeutic effects of long-term administration of Tocovid (200 mg/kg /day) on an Aβ-overexpressed transgenic AD mice model (APP23, n = 8) was investigated. The therapeutic effect of Tocovid in 16-month-old mice compared with the no-treatment APP23 group (n = 9) was assessed. RESULTS: Tocovid treatment strongly improved motor and memory deficits of APP23 mice by attenuating NOX2 expression, oxidative stress, neuroinflammation, neurovascular unit dysfunction, synaptic alteration, and Aβ deposition after 16 months. CONCLUSION: These findings suggest that NOX2 is a potential target in AD pathology. Long-term administration of Tocovid may be a promising candidate for AD treatment.

DOI： 10.3233/JAD-220761

Novel <scp> ABCD1 </scp> mutation detected in a symptomatic female carrier of adrenoleukodystrophy

Yumiko Nakano, Yuki Taira, Ryo Sasaki, Koh Tadokoro, Taijun Yunoki, Emi Nomura, Yusuke Fukui, Mami Takemoto, Ryuta Morihara, Nobuyuki Shimozawa, Toru Yamashita

Neurology and Clinical Neuroscience 2022.10

Protective and anti-oxidative effects of curcumin and resveratrol on Aβ-oligomer-induced damage in the SH-SY5Y cell line. International journal

Haibo Yu, Toru Yamashita, Xiao Hu, Zhihong Bian, Xinrang Hu, Tian Feng, Koh Tadokoro, Ryuta Morihara, Koji Abe

Journal of the neurological sciences 441 120356 - 120356 2022.10

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

Alzheimer's disease (AD) is a degenerative disorder characterized by the loss of synapses and neurons in the brain, and results in the accumulation of amyloid-based neurotic plaques. Amyloid-β oligomers (AβO) are widely accepted as the main neurotoxin that induces oxidative stress and neuronal loss in AD. In this study, an oxidative stress model of the neuroblastoma SH-SY5Y cell line exposed to AβO was established to simulate an AD cell model. Exposure to AβO significantly reduced the viability of cultured SH-SY5Y cells (p < 0.05) and significantly increased intracellular reactive oxygen species (ROS) (p < 0.01). AβO exposure also induced oxidative stress in SH-SY5Y cells. Furthermore, AβO significantly increased the level of hyperphosphorylation of tau at sites T181 and T205 in SH-SY5Y cells (p < 0.01). Using edaravone, a free radical scavenger with neuroprotective properties, as the control, the possible protective and anti-oxidative effects of curcumin (40 μM) and resveratrol (20 μM) were evaluated. The results suggest that curcumin and resveratrol decreased ROS generation, attenuated oxidative stress, inhibited tau hyperphosphorylation, and protected SH-SY5Y cells from AβO damage. Both curcumin and resveratrol are promising supplements or medicine as therapeutic agents for the treatment of AD.

DOI： 10.1016/j.jns.2022.120356

視線計測計Gazefinderを用いた認知症診断の可能性

田所功, 福井裕介, 野村恵美, 涌谷陽介, 高尾芳樹, 東靖人, 小坂田陽介, 松本菜見子, 佐々木諒, 武本麻美, 菱川望, 森原隆太, 阿部康二, 山下徹

臨床神経学 62 ( Suppl. ) S323 - S323 2022.10

AβオリゴマーによるSH-SY5Y細胞傷害に対するクルクミンとレスベラトロールの保護効果(Protective effects of curcumin and resveratrol on Aβ-oligomer-induced damage in the SH-SY5Y cell)

于海波, 山下徹, 胡梟, 卞之宏, 胡欣冉, 馮田, 田所功, 森原隆太, 阿部康二

脳循環代謝 34 ( 1 ) 159 - 159 2022.10

脳低灌流を伴うアルツハイマー病モデルマウスにおけるプラズマローゲンの有効性(Efficiency of Plasmalogen in a Mouse Model of Alzheimer's Disease with Cerebral Hypoperfusion)

Zhai Yun, Feng Tian, 胡欣冉, 福井裕介, 卞之宏, Bian Yuting, 孫洪銘, 武本麻美, 柚木太淳, 中野由美子, 森原隆太, 阿部康二, 山下徹

脳循環代謝 34 ( 1 ) 160 - 160 2022.10

パーキンソン病におけるMRgFUSによる片側視床または淡蒼球破壊術の治療成績検討

小坂田陽介, 平林秀裕, 森原隆太, 山下徹, 阿部康二, 久我純弘, 大西英之

臨床神経学 62 ( Suppl. ) S206 - S206 2022.10

RivaroxabanはADマウスのPAR-1/PAR-2阻害によりアミロイド病態と神経炎症を抑制する(Rivaroxaban attenuated amyloid pathology and neuroinflammation by inhibiting PAR-1/PAR-2 in AD mice)

Bian Zhihong, Liu Xia, Yu Haibo, Hu Xinran, Bian Yuting, Sun Hongming, 田所功, 武本麻美, 柚木太淳, 中野由美子, 福井裕介, 森原隆太, 阿部康二, 山下徹

脳循環代謝 34 ( 1 ) 158 - 158 2022.10

視線計測計を用いた認知機能障害の早期スクリーニング

福井裕介, 田所功, 野村恵美, 涌谷陽介, 高尾芳樹, 東靖人, 中野由美子, 柚木太淳, 武本麻美, 森原隆太, 阿部康二, 山下徹

脳循環代謝 34 ( 1 ) 150 - 150 2022.10

脳梗塞モデルマウスにおけるカルノシンの抗酸化作用と抗炎症作用(Anti-oxidative and the anti-inflammatory response of carnosine in a mice stroke model)

胡欣冉, 阿部康二, 福井裕介, 中野由美子, 柚木太淳, 武本麻美, 森原隆太, 山下徹

脳循環代謝 34 ( 1 ) 153 - 153 2022.10

慢性進行性の頭頂葉性運動失調症を認めた家族性及び孤発性の7症例

森原隆太, 山下徹, 池内健, 北口正孝, 阿部康二

脳循環代謝 34 ( 1 ) 151 - 151 2022.10

髄液検体から診断に至った再発性の抗MOG抗体関連疾患の2症例

中野由美子, 佐々木諒, 中田有美, 田所功, 柚木太淳, 野村恵美, 武本麻美, 森原隆太, 山下徹

臨床神経学 62 ( 10 ) 824 - 824 2022.10

腺性自己免疫症候群3型に抗MOG抗体関連急性脊髄炎を合併した一例

柚木太淳, 中野由美子, 中田有美, 佐々木諒, 田所功, 武本麻美, 森原隆太, 山下徹

臨床神経学 62 ( 10 ) 824 - 824 2022.10

Japanese case of Charcot-Marie-Tooth disease type 2Z with severe retinitis pigmentosa

Emi Nomura, Koh Tadokoro, Ryo Sasaki, Yumi Nakata, Yumiko Nakano, Taijun Yunoki, Mami Takemoto, Ryuta Morihara, Masahiro Ando, Hiroshi Takashima, Toru Yamashita

NEUROLOGY AND CLINICAL NEUROSCIENCE 10 ( 5 ) 266 - 268 2022.9

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

Charcot-Marie-Tooth disease type 2Z (CMT2Z) shows highly variable clinical features. We report the first Japanese CMT2Z patient with a c.754C>T (p.R252W) substitution of the MORC2 gene, complicating severe retinitis pigmentosa. The MORC2 mutants were involved in a decrease in cell survival through induction of apoptosis. Thus, the MORC2 mutation might be involved in the degeneration of photoreceptors and the development of retinitis pigmentosa.

DOI： 10.1111/ncn3.12660

A case of successful renal transplantation of Charcot-Marie-Tooth disease associated with FSGS due to mutation of the INF2 gene

Chika Matsuoka, Yuki Taira, Ryo Sasaki, Namiko Matsumoto, Koh Tadokoro, Emi Nomura, Yuko Kawahara, Mami Takemoto, Ryuta Morihara, Akihiro Hashiguchi, Hiroshi Takashima, Hidemi Takeuchi, Motoo Araki, Koji Abe, Toru Yamashita

Neurology and Clinical Neuroscience 10 ( 5 ) 252 - 254 2022.9

Publishing type：Research paper (scientific journal)

Focal and segmental areas of glomerular sclerosis (FSGS) have various subcategories. Here, we report on a 35-year-old man who suffered from Charcot-Marie-Tooth disease (CMT) with FSGS carrying the INF2 mutation (c.206 T > C, p.L69P). The INF2 mutation might cause abnormal actin filaments of the podocytes and Schwann cells, leading to CMT associated with FSGS. He successfully underwent living donor kidney transplantation from a mother with a normal INF2 gene without any serious adverse events. Following genetic testing, the identification of the INF2 mutation allows a recipient to reduce the use of immunosuppressive drugs. Genetic testing may provide a treatment plan for kidney transplantation.

DOI： 10.1111/ncn3.12651

Efficacy and safety of spot heating and ultrasound irradiation on in vitro and in vivo thrombolysis models. International journal

Ryuta Morihara, Toru Yamashita, Yosuke Osakada, Tian Feng, Xinran Hu, Yusuke Fukui, Koh Tadokoro, Mami Takemoto, Koji Abe

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 42 ( 7 ) 1322 - 1334 2022.7

Language：English Publishing type：Research paper (scientific journal)

The feasibility of transcranial sonothrombolysis has been demonstrated, although little is known about the relationships between thermal or mechanical mechanisms and thrombolytic outcomes. Therefore, the present study aims to reveal the effect and safety of temperature and ultrasound through in vitro and in vivo thrombolysis models. Artificial clots in microtubes were heated in a water bath or sonicated by ultrasound irradiation, and then clots weight decrease with rising temperature and sonication time was confirmed. In the in vitro thrombotic occlusion model, based on spot heating, clot volume was reduced and clots moved to the distal side, followed by recanalization of the occlusion. In the in vivo study, the common carotid artery of rats was exposed to a spot heater or to sonication. No brain infarct or brain blood barrier disruption was shown, but endothelial junctional dysintegrity and an inflammatory response in the carotid artery were detected. The present spot heating and ultrasound irradiation models seem to be effective for disintegrating clots in vitro, but the safety of the in vivo model was not fully supported by the data. However, the data indicates that a shorter time exposure could be less invasive than a longer exposure.

DOI： 10.1177/0271678X221079127

A Japanese case of successful surgical resection of cerebral cavernous malformations with a CCM2 mutation

Emi Nomura, Yoshio Omote, Mami Takemoto, Nozomi Hishikawa, Yumiko Nakano, Taijun Yunoki, Ryuta Morihara, Tatsuya Sasaki, Hiroyuki Akagawa, Koji Abe, Toru Yamashita

NEUROLOGY AND CLINICAL NEUROSCIENCE 2022.6

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

Cerebral cavernous malformations (CCMs) are congenital abnormalities of cerebral vessels. Surgical resection is rarely considered for the control of epilepsy in a first seizure patient with vascular malformation. In contrast, lesions that produce repetitive or progressive symptoms should be considered for surgical resection as treatment. Herein, we report a Japanese patient with a CCM2 mutation, c.609G>A (p.K203K) substitution, who showed drug-resistant epilepsy and dramatic improvement after surgical resection.

DOI： 10.1111/ncn3.12649

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 86 ( 4 ) 1973 - 1982 2022.3

Language：English Publishing type：Research paper (scientific journal)

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

A case of a heterozygous ABCC6 mutation showing recurrent ischemic strokes and intracranial hemorrhages

Emi Nomura, Yuko Kawahara, Yoshio Omote, Yoshiaki Takahashi, Namiko Matsumoto, Ken Ikegami, Mami Takemoto, Nozomi Hishikawa, Yumiko Nakano, Taijun Yunoki, Ryuta Morihara, Masahiro Uemura, Koji Abe, Toru Yamashita

Neurology and Clinical Neuroscience 10 ( 2 ) 98 - 101 2022.3

Publishing type：Research paper (scientific journal)

Mutations in the ATP-binding cassette subfamily C member 6 (ABCC6) gene are responsible for pseudoxanthoma elasticum (PXE). PXE is a rare genetic metabolic disease with autosomal recessive inheritance that shows ectopic mineralization in skin, eyes, and blood vessels and causes cerebrovascular disease. There are few reports of intracranial hemorrhages in patients with the ABCC6 mutation. We report the first Japanese case with a heterozygous ABCC6 mutation displaying recurrent ischemic strokes and intracranial hemorrhages. We propose that the ABCC6 mutation may be one cause of neurovascular diseases with a family history.

DOI： 10.1111/ncn3.12575

Chronic Beneficial Effect of Makeup Therapy on Cognitive Function of Dementia and Facial Appearance Analyzed by Artificial Intelligence Software. International journal

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

Journal of Alzheimer's disease : JAD 85 ( 3 ) 1189 - 1194 2022

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

BACKGROUND: Makeup greatly impacts normal social lives but can also be a non-pharmacological form of therapy for dementia. OBJECTIVE: To evaluate the therapeutic effect of makeup therapy. METHODS: We carried out a prospective interventional study on female nursing home residents with dementia, focusing on the chronic therapeutic effect of makeup therapy. Thirty-four patients who received either only skin care (control group, n = 16) or skin care plus makeup therapy (makeup therapy group, n = 18) once every 2 weeks for 3 months were assessed. RESULTS: Three months of makeup therapy significantly improved the Mini-Mental State Examination (MMSE) score compared with control patients ( *p < 0.05). Artificial intelligence (AI) software revealed that the appearance of age decreased significantly in the makeup group compared with the control, especially among patients without depression ( *p < 0.05). Furthermore, a larger AI happiness score was significantly correlated with a greater improvement of ADL in the makeup therapy group (r = 0.43, *p < 0.05). CONCLUSION: Makeup therapy had a chronic beneficial effect on the cognitive function of female dementia patients, while the chronic effect of makeup therapy on facial appearance was successfully detected by the present AI software.

DOI： 10.3233/JAD-215385

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

Language：English Publishing type：Research paper (scientific journal)

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

Scallop-Derived Plasmalogen showed Neuroprotective and inflammation Effects in a Mouse Model of Ischemic Stroke

胡欣冉, 馮田, 福井裕介, 田所功, 中野由美子, 柚木太淳, 武本麻美, 森原隆太, 山下徹

日本脳サプリメント学会(Web) 4th 2022

Three cases of GFAP astrocytopathy, one with bilateral ovarian teratoma

Yosuke Osakada, Yoshio Omote, Yuki Taira, Chika Matsuoka, Ken Ikegami, Koh Tadokoro, Emi Nomura, Yuko Kawahara, Kota Sato, Yuka Terasawa, Nozomi Hishikawa, Ryuta Morihara, Mami Takemoto, Akio Kimura, Takayoshi Shimohata, Toru Yamashita, Koji Abe

Neurology and Clinical Neuroscience 10 ( 1 ) 30 - 34 2021.11

外傷と脳循環代謝 in vitro及びin vivo血栓モデルにおける温熱照射と超音波照射の有効性と安全性の検討

森原隆太, 馮田, 小坂田陽介, 山下徹, 胡欣冉, 福井祐介, 田所功, 武本麻美, 阿部康二

脳循環代謝 33 ( 1 ) 49 - 49 2021.11

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

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

Brain research 1767 147569 - 147569 2021.9

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.brainres.2021.147569

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

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

Brain research 1766 147516 - 147516 2021.9

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.brainres.2021.147516

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

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

NEUROLOGY AND CLINICAL NEUROSCIENCE 2021.9

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

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

DOI： 10.1111/ncn3.12541

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

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

Journal of the neurological sciences 427 117529 - 117529 2021.8

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

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

DOI： 10.1016/j.jns.2021.117529

A case of rheumatoid meningoencephalitis induced by pembrolizumab

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

NEUROLOGY AND CLINICAL NEUROSCIENCE 2021.8

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

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

DOI： 10.1111/ncn3.12540

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

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

Neuroscience 466 47 - 57 2021.7

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

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

DOI： 10.1016/j.neuroscience.2021.04.034

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

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

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

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

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

DOI： 10.1111/ncn3.12514

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.jstrokecerebrovasdis.2020.105583

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

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

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

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

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

DOI： 10.3233/JAD-210284

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

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

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

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

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

DOI： 10.3233/JAD-210327

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

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

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

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

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

DOI： 10.3233/JAD-201495

Neuroprotective and Therapeutic Effects of Tocovid and Twendee-X on Aβ Oligomer-Induced Damage in the SH-SY5Y Cell Line. International journal

Xiao Hu, Toru Yamashita, Haibo Yu, Zhihong Bian, Xinran Hu, Tian Feng, Koh Tadokoro, Ryuta Morihara, Koji Abe

Neuro-degenerative diseases 21 ( 5-6 ) 117 - 125 2021

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Alzheimer's disease (AD) is the most frequent cause of dementia among the elderly. The accumulation of amyloid beta (Aβ) and its downstream pathological events such as oxidative stress play central roles in AD. Recent studies revealed that Aβ oligomer (AβO)-induced strong neurotoxicity in SH-SY5Y cells via the induction of oxidative stress. OBJECTIVE: In the present study, we investigated the effect of two antioxidants, Tocovid and Twendee-X, on AβO-induced SH-SY5Y cell damage. METHODS: AβOs (2.5 μM) were applied to induce cellular damage in the SH-SY5Y cell line. Cell viability following AβO toxicity, Tau protein phosphorylation, cell morphology, and intracellular reactive oxygen species were assayed with or without different concentrations of Tocovid or Twendee-X. RESULTS: Tocovid (60 μg/mL) and Twendee-X (150 μg/mL) significantly recovered cell viability from AβO toxicity (**p < 0.01, vs. control), attenuated Tau protein phosphorylation (**p < 0.01, vs. AβOs), improved cell morphology (**p < 0.01, vs. AβOs), and suppressed intracellular ROS (**p < 0.01, vs. AβOs) in SH-SY5Y cells. CONCLUSION: These findings suggest the neuroprotective and therapeutic potential of Tocovid and Twendee-X for AD treatment.

DOI： 10.1159/000523983

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

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

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 29 ( 5 ) 104743 - 104743 2020.5

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

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

Two Cases of Very-Late-Onset Neuromyelitis Optica Spectrum Disorder (NMOSD) in Patients over the Age of 80 Reviewed International journal

Shunya Fujiwara, Yasuhiro Manabe, Ryuta Morihara, Taijun Yunoki, Syoichiro Kono, Hisashi Narai, Koji Abe

CASE REPORTS IN NEUROLOGY 12 ( 1 ) 13 - 17 2020.1

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

We report two cases of very-late-onset neuromyelitis optica spectrum disorder (NMOSD) in patients over the age of 80 with transverse myelopathy as the initial manifestation. In both cases, the patients presented with paraplegia and sensory, bladder, and rectal disturbances. Thoracic magnetic resonance imaging showed longitudinal high-intensity signals on a T2-weighted image. The patients received high-dose methylprednisolone. Their serum was positive for anti-AQP4 antibody (cell-based assay) during the clinical course. They were diagnosed with NMOSD and treated with immunoadsorption, plasmapheresis, and followed up with daily prednisolone. Very-late-onset NMOSD in patients over the age of 80 has only rarely been reported. The present cases suggest that NMOSD should be considered for elderly patients presenting with transverse myelitis. Early diagnosis and treatment are important.

DOI： 10.1159/000505231

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

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

Journal of Alzheimer's disease : JAD 73 ( 1 ) 209 - 215 2020.1

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 (||||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

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 2020.1

Language：English Publishing type：Research paper (scientific journal)

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

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1177/0271678X18810617

新規Sigma-1受容体刺激薬による急性期脳梗塞治療効果

佐々木諒, 森原隆太, 山下徹, 阿部康二

日本神経学会学術大会プログラム・抄録集 61st 2020

Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins. Reviewed International journal

Michael Fernandopulle, GuoZhen Wang, Jonathon Nixon-Abell, Seema Qamar, Varun Balaji, Ryuta Morihara, Peter H St George-Hyslop

Human molecular genetics 28 ( R2 ) R187-R196 2019.11

Language：English Publishing type：Research paper (scientific journal)

Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).

DOI： 10.1093/hmg/ddz162

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.jstrokecerebrovasdis.2019.104310

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

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

Neuroscience 416 126 - 136 2019.9

Language：English Publishing type：Research paper (scientific journal)

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

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

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

Scientific reports 9 ( 1 ) 10956 - 10956 2019.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

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

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.jstrokecerebrovasdis.2019.03.029

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

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

Neuroscience research 143 61 - 70 2019.6

Language：English Publishing type：Research paper (scientific journal)

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

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

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

Journal of Alzheimer's disease : JAD 71 ( 3 ) 1063 - 1069 2019.1

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

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.

DOI： 10.3233/JAD-190644

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

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

Journal of Alzheimer's disease : JAD 71 ( 1 ) 327 - 339 2019.1

Language：English Publishing type：Research paper (scientific journal)

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

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

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

Journal of Alzheimer's disease : JAD 68 ( 4 ) 1667 - 1675 2019.1

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3233/JAD-181218

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

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

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

Journal of neuroscience research 96 ( 12 ) 1887 - 1899 2018.12

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1002/jnr.24326

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

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

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 27 ( 11 ) 3084 - 3094 2018.11

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.jstrokecerebrovasdis.2018.06.039

Chronic cerebral hypoperfusion accelerates Alzheimer's disease pathology with the change of mitochondrial fission and fusion proteins expression in a novel mouse model. Reviewed International journal

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

Brain research 1696 63 - 70 2018.10

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.brainres.2018.06.003

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

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

Journal of neuroscience research 96 ( 10 ) 1707 - 1716 2018.10

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1002/jnr.24270

Neuroprotective Effects of Tocovid Pretreatment in a Mouse Stroke Model. Reviewed International journal

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

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 27 ( 8 ) 2166 - 2174 2018.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.jstrokecerebrovasdis.2018.03.014

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

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

Neuroscience research 133 58 - 63 2018.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.neures.2017.11.005

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

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

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 27 ( 8 ) 2096 - 2105 2018.8

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.jstrokecerebrovasdis.2018.03.012

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jns.2018.01.031

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

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

Journal of clinical neurology (Seoul, Korea) 14 ( 1 ) 29 - 34 2018.1

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.3988/jcn.2018.14.1.29

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC 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.

DOI： 10.2169/internalmedicine.8636-16

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 2017.11

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

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.

DOI： 10.1111/ncn3.12167

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1111/ggi.13007

緊急脳室ドレナージと全身抗生剤で救命しえた下垂体部膿瘍から脳室穿破を来した一例

高橋義秋, 山下徹, 森原隆太, 中野由美子, 商敬偉, 佐藤恒太, 武本麻美, 菱川望, 太田康之, 阿部康二

日本頭痛学会誌 44 ( 2 ) 386 - 386 2017.11

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

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

Journal of the neurological sciences 381 119 - 125 2017.10

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jns.2017.08.024

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1002/jnr.24047

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.2169/internalmedicine.8438-16

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1002/jnr.24013

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

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

NEUROLOGY AND CLINICAL NEUROSCIENCE 5 ( 5 ) 162 - 164 2017.7

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

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

DOI： 10.1111/ncn3.12139

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

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

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

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

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.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.02.001

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.jstrokecerebrovasdis.2017.01.003

Pregnancy and delivery after myelomeningocele repair, ventriculoperitoneal shunt implantation, and augmentation cystoplasty. Reviewed International journal

Masahiro Kameda, Etsuko Takahara, Motomu Kobayashi, Katsumi Sasaki, Ryuta Morihara, Isao Date

Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 33 ( 6 ) 1015 - 1017 2017.6

Language：English Publishing type：Research paper (scientific journal)

INTRODUCTION: Management of pregnancy and delivery of a patient with a history of myelomeningocele requires a multidisciplinary team approach. CASE REPORT: We report a case of pregnancy and delivery by a patient who had a history of myelomeningocele surgical repair, ventriculoperitoneal (VP) shunt, and bladder augmentation enterocystoplasty. Regarding types of delivery style, anesthesiologists recommended a Cesarean section under general anesthesia. However, urologists recommended a vaginal delivery because they were concerned that she would require a nephrostomy because of severe adhesion between her uterus and the neobladder if she had a Cesarean section. DISCUSSION: In a pregnant myelomeningocele patient with a VP shunt, neurosurgeons are expected to manage the VP shunt during pregnancy and delivery. The possible types of delivery style and the best options based on the neurological deficit should be discussed together with a medical team.

DOI： 10.1007/s00381-017-3364-7

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.neuroscience.2017.03.024

Factors related to continuous and discontinuous attendance at memory clinics. Reviewed International journal

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

European journal of neurology 24 ( 5 ) 673 - 679 2017.5

Language：English

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

DOI： 10.1111/ene.13268

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

Eur J Neurol 2017.5

Neuromyelitis Optica Spectrum Disorder Coinciding with Spinocerebellar Ataxia Type 31 Reviewed International journal

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

CASE REPORTS IN NEUROLOGY 9 ( 2 ) 127 - 130 2017.5

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

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

DOI： 10.1159/000475657

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jstrokecerebrovasdis.2016.04.002

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.1016/j.jns.2016.04.042

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

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

Recently, aging societies have been showing an increasingly strong relationship between Alzheimer's disease (AD) and chronic cerebral hypoperfusion (HP). In the present study, we created a new mouse model for AD with HP, and investigated its clinical and pathological characteristics. Alzheimer's disease transgenic mice (APP23) were subjected to bilateral common carotid arteries stenosis with ameroid constrictors for slowly progressive cerebral HP. In contrast to simple APP23 mice, cerebral HP exacerbated motor and cognitive dysfunctions with white matter lesions and meningo-parenchymal amyloid-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.

DOI： 10.3233/JAD-160345

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

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

A rapidly progressing aging society has raised attention to white matter lesions in Alzheimer's disease. In the present study, we applied an AD plus cerebral hypoperfusion (HP) mouse model and investigated the alternation of key protein molecules in the nodal, paranodal, and intermodal sites in the white matter as well as the efficacy of galantamine. Cerebral HP was induced in APP23 mice by bilateral common carotid arteries stenosis with ameroid constrictors. Compared with the wild type and simple APP23 mice, APP23 + HP mice showed a progressive loss of MAG and NF186 from 6 to 12 months, broken misdistribution of MBP, and extended relocation of 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.

DOI： 10.3233/JAD-160120

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

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

Translational stroke research 7 ( 2 ) 111 - 9 2016.4

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1007/s12975-016-0448-8

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.3233/JAD-151126

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

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

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

Language：English Publishing type：Research paper (scientific journal) Publisher：Blackwell Publishing Ltd

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

DOI： 10.1111/ene.12905

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

Eur J Neurol. 2016.1

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

Language：English Publishing type：Research paper (scientific journal)

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.

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

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

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

Language：English Publishing type：Research paper (scientific journal)

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

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

Language：English Publishing type：Research paper (scientific journal)

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.

DOI： 10.4081/ni.2015.5973

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

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

Journal of the neurological sciences 353 ( 1-2 ) 185 - 6 2015.1

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.1016/j.jns.2015.04.020

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

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

Journal of Alzheimer's disease : JAD 48 ( 1 ) 279 - 86 2015.1

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.3233/JAD-150416

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

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

Internal medicine (Tokyo, Japan) 54 ( 1 ) 79 - 82 2015.1

Language：English Publishing type：Research paper (scientific journal)

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

DOI： 10.2169/internalmedicine.54.3378

緩徐に進行し診断に苦慮した、EGFR遺伝子変異陽性でEGFR-TKIが奏効したびまん性細気管支肺胞上皮癌の1例

原田大二郎, 森原隆太, 亀井治人

肺癌 52 ( 5 ) 761 - 761 2012.10

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