研究者詳細 - 山下　徹

論文 - 山下　徹

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Frequency of FGF14 intronic GAA repeat expansion in patients with multiple system atrophy and undiagnosed ataxia in the Japanese population

Toshiyuki Kakumoto, Kenta Orimo, Takashi Matsukawa, Jun Mitsui, Tomohiko Ishihara, Osamu Onodera, Yuta Suzuki, Shinichi Morishita, Ayaka Chikada, Kenta Orimo, Takashi Matsukawa, Tatsushi Toda, Jun Mitsui, Hiroyufki Ishiura, Koji Abe, Toru Yamashita, Hidehiro Mizusawa, Yuji Takahashi, Masahisa Katsuno, Kazuhiro Hara, Osamu Onodera, Tomohiko Ishihara, Masayoshi Tada, Satoshi Kuwabara, Atsuhiko Sugiyama, Yoshitaka Yamanaka, Ryosuke Takahashi, Yusuke Sakato, Tomoyuki Ishimoto, Nobukatsu Sawamoto, Ritsuko Hanajima, Yasuhiro Watanabe, Hiroshi Takigawa, Tadashi Adachi, Hiroshi Takashima, Keiko Higashi, Junichi Kira, Ichiro Yabe, Masaaki Matsushima, Katsuhisa Ogata, Kinya Ishikawa, Yoichiro Nishida, Taro Ishiguro, Kokoro Ozaki, Tetsuya Nagata, Shoji Tsuji, Tatsushi Toda, Shoji Tsuji

European Journal of Human Genetics 2024年11月

Suppression of PTBP1 in hippocampal astrocytes promotes neurogenesis and ameliorates recognition memory in mice with cerebral ischemia. 査読国際誌

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

Scientific reports 14 ( 1 ) 20521 - 20521 2024年9月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

The Japan MSA registry: A multicenter cohort study of multiple system atrophy

Ayaka Chikada, Kenta Orimo, Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda, Hidehiro Mizusawa, Yuji Takahashi, Masahisa Katsuno, Kazuhiro Hara, Osamu Onodera, Tomohiko Ishihara, Masayoshi Tada, Satoshi Kuwabara, Atsuhiko Sugiyama, Yoshitaka Yamanaka, Ryosuke Takahashi, Nobukatsu Sawamoto, Yusuke Sakato, Tomoyuki Ishimoto, Ritsuko Hanajima, Yasuhiro Watanabe, Hiroshi Takigawa, Tadashi Adachi, Koji Abe, Toru Yamashita, Hiroshi Takashima, Keiko Higashi, Junichi Kira, Ichiro Yabe, Masaaki Matsushima, Katsuhisa Ogata, Kinya Ishikawa, Yoichiro Nishida, Taro Ishiguro, Kokoro Ozaki, Tetsuya Nagata, Shoji Tsuji

Neurology and Clinical Neuroscience 12 ( 5 ) 271 - 277 2024年9月

掲載種別：研究論文（学術雑誌）

Background: Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic failure and various motor symptoms. While MSA-C (cerebellar type) predominates in East Asia, MSA-P (parkinsonian type) predominates in Europe and North America. This nationwide patient registry aimed to (1) conduct a prospective natural history study of MSA in Japan, (2) facilitate patient recruitment for clinical trials, and (3) deposit bioresources and clinical information in a biobank. Methods: Thirteen institutions participated in this study. Clinical information was obtained by neurologists from the patients visiting the hospital every 12 months to assess the UMSARS Part 2 scores and by telephone interviews by nurses every 6 months to assess UMSARS Part 1 scores and to determine whether clinical events had occurred. Results: Demographic data from 329 MSA patients (216 MSA-C and 113 MSA-P) were analyzed. The mean age at symptom onset was 58.2 years (standard deviation, 8.9); the mean duration of symptoms at enrollment was 3.5 years (standard deviation, 2.2). The mean 12-month changes in the UMSARS Part 1 and Part 2 scores were 7.9 (standard deviation, 5.6) and 6.4 (standard deviation, 5.9), respectively. The patient registry proved useful in recruiting participants for clinical trials, including those with gene variants. Clinical information and biospecimens were deposited in a biobank. Discussion: The study highlighted the importance of telephone interviews in minimizing drop-out rates in natural history studies and demonstrated similar MSA progression rates across populations. The deposited bioresources are available to researchers upon request, aiming to contribute to future MSA researches.

DOI： 10.1111/ncn3.12809

CHCHD2 P14L, found in amyotrophic lateral sclerosis, exhibits cytoplasmic mislocalization and alters Ca2+ homeostasis. 査読国際誌

Aya Ikeda, Hongrui Meng, Daisuke Taniguchi, Muneyo Mio, Manabu Funayama, Kenya Nishioka, Mari Yoshida, Yuanzhe Li, Hiroyo Yoshino, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Yohei Okubo, Takashi Sakurai, Taku Amo, Ikuko Aiba, Yufuko Saito, Yuko Saito, Shigeo Murayama, Naoki Atsuta, Ryoichi Nakamura, Genki Tohnai, Yuishin Izumi, Mitsuya Morita, Asako Tamura, Osamu Kano, Masaya Oda, Satoshi Kuwabara, Toru Yamashita, Jun Sone, Ryuji Kaji, Gen Sobue, Yuzuru Imai, Nobutaka Hattori

PNAS nexus 3 ( 8 ) pgae319 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

CHCHD2 and CHCHD10, linked to Parkinson's disease and amyotrophic lateral sclerosis-frontotemporal dementia (ALS), respectively, are mitochondrial intermembrane proteins that form a heterodimer. This study aimed to investigate the impact of the CHCHD2 P14L variant, implicated in ALS, on mitochondrial function and its subsequent effects on cellular homeostasis. The missense variant of CHCHD2, P14L, found in a cohort of patients with ALS, mislocalized CHCHD2 to the cytoplasm, leaving CHCHD10 in the mitochondria. Drosophila lacking the CHCHD2 ortholog exhibited mitochondrial degeneration. In contrast, human CHCHD2 P14L, but not wild-type human CHCHD2, failed to suppress this degeneration, suggesting that P14L is a pathogenic variant. The mitochondrial Ca2+ buffering capacity was reduced in Drosophila neurons expressing human CHCHD2 P14L. The altered Ca2+-buffering phenotype was also observed in cultured human neuroblastoma SH-SY5Y cells expressing CHCHD2 P14L. In these cells, transient elevation of cytoplasmic Ca2+ facilitated the activation of calpain and caspase-3, accompanied by the processing and insolubilization of TDP-43. These observations suggest that CHCHD2 P14L causes abnormal Ca2+ dynamics and TDP-43 aggregation, reflecting the pathophysiology of ALS.

DOI： 10.1093/pnasnexus/pgae319

Linking LRP12 CGG repeat expansion to inherited peripheral neuropathy. 査読国際誌

Takahiro Hobara, Masahiro Ando, Yujiro Higuchi, Jun-Hui Yuan, Akiko Yoshimura, Fumikazu Kojima, Yutaka Noguchi, Jun Takei, Yu Hiramatsu, Satoshi Nozuma, Tomonori Nakamura, Tadashi Adachi, Keiko Toyooka, Toru Yamashita, Yusuke Sakiyama, Akihiro Hashiguchi, Eiji Matsuura, Yuji Okamoto, Hiroshi Takashima

Journal of neurology, neurosurgery, and psychiatry 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions. METHODS: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12, GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies. RESULTS: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12-oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases. CONCLUSION: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN.

DOI： 10.1136/jnnp-2024-333403

Anti-IgLON5 disease as a differential diagnosis of multiple system atrophy. 査読国際誌

Yoya Ono, Koh Tadokoro, Taijun Yunoki, Toru Yamashita, Daisuke Sato, Hiroyasu Sato, Shintaro Akamatsu, Heisuke Mizukami, Yasuyuki Ohta, Yoshihisa Yamano, Akio Kimura, Takayoshi Shimohata

Parkinsonism & related disorders 124 106992 - 106992 2024年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Anti-immunoglobulin-like cell adhesion molecule 5 (IgLON5) disease is a rare autoimmune encephalitis that can mimic progressive supranuclear palsy or corticobasal syndrome. Moreover, anti-IgLON5 disease can present with symptoms characteristic of multiple system atrophy (MSA), such as cerebellar ataxia and autonomic dysfunction. However, the clinical features of anti-IgLON5 disease resembling MSA have not been well established. METHODS: We enrolled 35 patients with suspected MSA for whom anti-IgLON5 antibody tests were requested. We evaluated immunoglobulin G (IgG) against IgLON5 using cell-based assays. We also summarized the clinical characteristics of patients who were positive for anti-IgLON5 antibodies. RESULTS: We identified serum and cerebrospinal fluid anti-IgLON5 antibodies in three patients. These patients had many clinical features characteristic of MSA, including parkinsonism, cerebellar ataxia, severe orthostatic hypotension, acute respiratory failure, sleep parasomnia, vocal cord paralysis, and pyramidal tract signs. Clinical features atypical for MSA were myorhythmia, horizontal eye movement restriction, fasciculations, and painful muscle cramps. CONCLUSION: Anti-IgLON5 disease may be an important differential diagnosis of MSA. A comprehensive physical examination, including assessments of eye movement, lower motor neuron signs, and atypical involuntary movements, is important to avoid misdiagnosis.

DOI： 10.1016/j.parkreldis.2024.106992

Donor Muse Cell Treatment Without HLA-Matching Tests and Immunosuppressant Treatment. 査読国際誌

Shinya Minatoguchi, Yasuyuki Fujita, Kuniyasu Niizuma, Teiji Tominaga, Toru Yamashita, Koji Abe, Mari Dezawa

Stem cells translational medicine 13 ( 6 ) 532 - 545 2024年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

The strength of stem cell therapy is the regeneration of tissues by synergistic pleiotropic effects. Among many stem cell types, mesenchymal stem cells (MSCs) that are comprised of heterogenous population are widely used for clinical applications with the expectation of pleiotropic bystander effects. Muse cells are pluripotent-like/macrophage-like stem cells distributed in the bone marrow, peripheral blood, and organ connective tissues as cells positive for the pluripotent surface marker stage-specific-embryonic antigen -3. Muse cells comprise ~1% to several percent of MSCs. While Muse cells and MSCs share several characteristics, such as mesenchymal surface marker expression and their bystander effects, Muse cells exhibit unique characteristics not observed in MSCs. These unique characteristics of Muse cells include selective homing to damaged tissue after intravenous injection rather than being trapped in the lung like MSCs, replacement of a wide range of damaged/apoptotic cells by differentiation through phagocytosis, and long-lasting immunotolerance for donor cell use. In this review, we focus on the basic properties of Muse cells clarified through preclinical studies and clinical trials conducted by intravenous injection of donor-Muse cells without HLA-matching tests or immunosuppressant treatment. MSCs are considered to differentiate into osteogenic, chondrogenic, and adipogenic cells, whereas the range of their differentiation has long been debated. Muse cells may provide clues to the wide-ranging differentiation potential of MSCs that are observed with low frequency. Furthermore, the utilization of Muse cells may provide a novel strategy for clinical treatment.

DOI： 10.1093/stcltm/szae018

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. 査読国際誌

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年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

Neuroprotective effect of, a flavonoid, sudachitin in mice stroke model. 査読国際誌

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年3月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

Update on Antioxidant Therapy with Edaravone: Expanding Applications in Neurodegenerative Diseases. 査読国際誌

Toru Yamashita, Koji Abe

International journal of molecular sciences 25 ( 5 ) 2024年3月

担当区分：筆頭著者記述言語：英語掲載種別：研究論文（学術雑誌）

The brain is susceptible to oxidative stress, which is associated with various neurological diseases. Edaravone (MCI-186, 3-methyl-1 pheny-2-pyrazolin-5-one), a free radical scavenger, has promising effects by quenching hydroxyl radicals (∙OH) and inhibiting both ∙OH-dependent and ∙OH-independent lipid peroxidation. Edaravone was initially developed in Japan as a neuroprotective agent for acute cerebral infarction and was later applied clinically to treat amyotrophic lateral sclerosis (ALS), a neurodegenerative disease. There is accumulating evidence for the therapeutic effects of edaravone in a wide range of diseases related to oxidative stress, including ischemic stroke, ALS, Alzheimer's disease, and placental ischemia. These neuroprotective effects have expanded the potential applications of edaravone. Data from experimental animal models support its safety for long-term use, implying broader applications in various neurodegenerative diseases. In this review, we explain the unique characteristics of edaravone, summarize recent findings for specific diseases, and discuss its prospects for future therapeutic applications.

DOI： 10.3390/ijms25052945

A Novel Peptidome Technology for the Diagnosis of Mild Cognitive Impairment and Alzheimer's Disease by Selected Reaction Monitoring. 査読国際誌

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年

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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. 査読

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年12月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

First evidence of tick-borne encephalitis (TBE) outside of Hokkaido Island in Japan. 査読国際誌

Masayuki Ohira, Kentaro Yoshii, Yasuhiro Aso, Hideto Nakajima, Toru Yamashita, Ikuko Takahashi-Iwata, Norihisa Maeda, Katsuro Shindo, Toshihiko Suenaga, Tohru Matsuura, Kazuma Sugie, Tadanori Hamano, Akira Arai, Rikiya Furutani, Yasuhiro Suzuki, Chikako Kaneko, Yasuhiro Kobayashi, Eduardo Campos-Alberto, Lisa R Harper, Juanita Edwards, Cody Bender, Andreas Pilz, Shuhei Ito, Frederick J Angulo, Wilhelm Erber, Harish Madhava, Jennifer Moïsi, Luis Jodar, Hidehiro Mizusawa, Masaki Takao

Emerging microbes & infections 12 ( 2 ) 2278898 - 2278898 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

Tick-borne encephalitis (TBE) is an infection of the central nervous system caused by the tick-borne encephalitis virus (TBEV). TBE is endemic in parts of Europe and Asia. TBEV is transmitted to humans primarily by Ixodes ticks. There have been 5 TBE cases identified in Japan, all on the northern island of Hokkaido. Rodents with TBEV antibodies and Ixodes ticks have been identified throughout Japan, indicating that TBEV infection might be undiagnosed in Japan. Residual serum and cerebrospinal fluid (CSF) collected in 2010-2021 from 520 patients ≥1 year-of-age previously hospitalized with encephalitis or meningitis of unknown etiology at 15 hospitals (including 13 hospitals outside of Hokkaido) were screened by ELISA for TBEV IgG and IgM antibodies; TBEV infection was confirmed by the gold standard neutralization test. Residual serum was available from 331 (63.6%) patients and CSF from 430 (82.6%) patients; both serum and CSF were available from 189 (36.3%). Two patients were TBE cases: a female aged 61 years hospitalized for 104 days in Oita (2000 km south of Hokkaido) and a male aged 24 years hospitalized for 11 days in Tokyo (1200 km south of Hokkaido). Retrospective testing also identified a previous TBEV infection in a female aged 45 years hospitalized for 12 days in Okayama (1700 km south of Hokkaido). TBEV infection should be considered as a potential cause of encephalitis or meningitis in Japan. TBE cases are likely undiagnosed in Japan, including outside of Hokkaido, due to limited clinical awareness and lack of availability of TBE diagnostic tests.

DOI： 10.1080/22221751.2023.2278898

Characteristics of the muscle involvement along the disease progression in a large cohort of oculopharyngodistal myopathy compared to oculopharyngeal muscular dystrophy 査読

Nobuyuki Eura, Satoru Noguchi, Masashi Ogasawara, Theerawat Kumutpongpanich, Shinichiro Hayashi, Ichizo Nishino, Takahiko Mukaino, Mori Yoshimura Madoka, Makiko Nagai, Masayuki Ochi, Makoto Shibata, Kazutaka Shiomi, Satoshi Yamashita, Toru Yamashita

Journal of Neurology 270 ( 12 ) 5988 - 5998 2023年12月

掲載種別：研究論文（学術雑誌）

Background and objectives: Oculopharyngodistal myopathy (OPDM) is an autosomal dominant myopathy clinically characterized by distal muscle weakness. Even though the identification of four causative genes, LRP12, GIPC1, NOTCH2NLC and RILPL1, it is unclear whether the myopathy progressed similarly among OPDM subtypes. We aimed to establish diagnostic clues in muscle imaging of OPDM in comparison with clinicopathologically similar oculopharyngeal muscular dystrophy (OPMD). Methods: Axial muscle CT and/or T1-weighted MRI data from 54 genetically confirmed patients with OPDM (OPDM_LRP12; n = 43, OPDM_GIPC1; n = 6, OPDM_NOTCH2NLC; n = 5) and 57 with OPMD were evaluated. We scored the degree of fat infiltration in each muscle by modified Mercuri score and performed hierarchical clustering analyses to classify the patients and infer the pattern of involvement on progression. Results: All OPDM subtypes showed a similar pattern of distribution in the affected muscles; soleus and medial gastrocnemius involved in the early stage, followed by tibialis anterior and extensor digitorum longus. For differentiating OPDM and OPMD, severely affected gluteus medius/minimus and adductor magnus was indicative of OPMD. Discussion: We identified a diagnostic muscle involvement pattern in OPDM reflecting its natural history. The results of this study will help in the appropriate intervention based on the diagnosis of OPDM, including its stage.

DOI： 10.1007/s00415-023-11906-9

Edaravone Confers Neuroprotective, Anti-inflammatory, and Antioxidant Effects on the Fetal Brain of a Placental-ischemia Mouse Model. 査読国際誌

Marwa Atallah, Toru Yamashita, Xiao Hu, Xinran Hu, Koji Abe

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 18 ( 4 ) 640 - 656 2023年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Reduced uterine perfusion pressure (RUPP) is a well-established model which mimics many clinical features of preeclampsia (PE). Edaravone is a free radical scavenger with neuroprotective, antioxidant and anti-inflammatory effects against different models of cerebral ischemia. Therefore, we aimed to elucidate the different potential mechanisms through which PE affects fetal brain development using our previously established RUPP-placental ischemia mouse model. In addition, we investigated the neuroprotective effect of edaravone against the RUPP-induced fetal brain development alterations. On gestation day (GD) 13, pregnant mice were divided into four groups; sham (SV), edaravone (SE), RUPP (RV), and RUPP+edaravone (RE). SV and SE groups underwent sham surgeries, however, RV and RE groups were subjected to RUPP surgery via bilateral uterine ligation. Edaravone (3mg/kg) was injected via tail i.v. injection from GD 14-18. The fetal brains from different groups were collected on GD 18 and subjected to further investigations. The results showed that RUPP altered the structure of fetal brain cortex, induced neurodegeneration, increased the expression of the investigated pro-inflammatory markers; TNF-α, IL-6, IL-1β, and MMP-9. RUPP resulted in microglial and astrocyte activation in the fetal brains, in addition to upregulation of Hif-1α and iNOS. Edaravone conferred a neuroprotective effect via alleviating the inflammatory response, restoring the neuronal structure and decreasing oxidative stress in the developing fetal brain. In conclusion, RUPP-placental ischemia mouse model could be a useful tool to further understand the underlying mechanisms of PE-induced child neuronal alterations. Edaravone could be a potential adjuvant therapy during PE to protect the developing fetal brain. The current study investigated the effects of a placenta-induced ischemia mouse model using reduced uterine perfusion pressure (RUPP) surgery on the fetal brain development and the potential neuroprotective effects of the drug edaravone. The study found that the RUPP model caused neurodegeneration and a pro-inflammatory response in the developing fetal brain, as well as hypoxia and oxidative stress. However, maternal injection of edaravone showed a strong ability to protect against these detrimental effects and target multiple pathways associated with neuronal damage. The current study suggests that the RUPP model could be useful for further study of the impact of preeclampsia on fetal brain development and that edaravone may have potential as a therapy for protecting against this damage.

DOI： 10.1007/s11481-023-10095-6

Protective Effects of Rivaroxaban on White Matter Integrity and Remyelination in a Mouse Model of Alzheimer's Disease Combined with Cerebral Hypoperfusion. 査読国際誌

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年10月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

Genetic factors affecting survival in Japanese patients with sporadic amyotrophic lateral sclerosis: a genome-wide association study and verification in iPSC-derived motor neurons from patients. 査読国際誌

Ryoichi Nakamura, Genki Tohnai, Masahiro Nakatochi, Naoki Atsuta, Hirohisa Watanabe, Daisuke Ito, Masahisa Katsuno, Akihiro Hirakawa, Yuishin Izumi, Mitsuya Morita, Takehisa Hirayama, Osamu Kano, Kazuaki Kanai, Nobutaka Hattori, Akira Taniguchi, Naoki Suzuki, Masashi Aoki, Ikuko Iwata, Ichiro Yabe, Kazumoto Shibuya, Satoshi Kuwabara, Masaya Oda, Rina Hashimoto, Ikuko Aiba, Tomohiko Ishihara, Osamu Onodera, Toru Yamashita, Koji Abe, Kouichi Mizoguchi, Toshio Shimizu, Yoshio Ikeda, Takanori Yokota, Kazuko Hasegawa, Fumiaki Tanaka, Kenji Nakashima, Ryuji Kaji, Jun-Ichi Niwa, Manabu Doyu, Chikashi Terao, Shiro Ikegawa, Koki Fujimori, Shiho Nakamura, Fumiko Ozawa, Satoru Morimoto, Kazunari Onodera, Takuji Ito, Yohei Okada, Hideyuki Okano, Gen Sobue

Journal of neurology, neurosurgery, and psychiatry 94 ( 10 ) 816 - 824 2023年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Several genetic factors are associated with the pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) and its phenotypes, such as disease progression. Here, in this study, we aimed to identify the genes that affect the survival of patients with sporadic ALS. METHODS: We enrolled 1076 Japanese patients with sporadic ALS with imputed genotype data of 7 908 526 variants. We used Cox proportional hazards regression analysis with an additive model adjusted for sex, age at onset and the first two principal components calculated from genotyped data to conduct a genome-wide association study. We further analysed messenger RNA (mRNA) and phenotype expression in motor neurons derived from induced pluripotent stem cells (iPSC-MNs) of patients with ALS. RESULTS: Three novel loci were significantly associated with the survival of patients with sporadic ALS-FGF1 at 5q31.3 (rs11738209, HR=2.36 (95% CI, 1.77 to 3.15), p=4.85×10-9), THSD7A at 7p21.3 (rs2354952, 1.38 (95% CI, 1.24 to 1.55), p=1.61×10-8) and LRP1 at 12q13.3 (rs60565245, 2.18 (95% CI, 1.66 to 2.86), p=2.35×10-8). FGF1 and THSD7A variants were associated with decreased mRNA expression of each gene in iPSC-MNs and reduced in vitro survival of iPSC-MNs obtained from patients with ALS. The iPSC-MN in vitro survival was reduced when the expression of FGF1 and THSD7A was partially disrupted. The rs60565245 was not associated with LRP1 mRNA expression. CONCLUSIONS: We identified three loci associated with the survival of patients with sporadic ALS, decreased mRNA expression of FGF1 and THSD7A and the viability of iPSC-MNs from patients. The iPSC-MN model reflects the association between patient prognosis and genotype and can contribute to target screening and validation for therapeutic intervention.

DOI： 10.1136/jnnp-2022-330851

Neuroprotective effects of carnosine in a mice stroke model concerning oxidative stress and inflammatory response. 査読国際誌

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年4月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

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

A Case of Drug-Resistant Myoclonus Improved by Only Slight Adjustment to the Hemodialysis Setting. 査読国際誌

Ryo Sasaki, Chika Matsuoka, Toru Yamashita, Masaru Kinomura, Koji Abe

Cureus 15 ( 3 ) e36104 2023年3月

記述言語：英語

Myoclonus, a rare complication in patients with end-stage renal disease, is typically ameliorated through hemodialysis. The present case concerns an 84-year-old male with chronic renal failure undergoing hemodialysis, presenting involuntary movements in his limbs, which gradually worsened from the initiation of hemodialysis without constant elevation of serum blood urea nitrogen and electrolytes levels. Surface electromyography revealed characteristic findings consistent with myoclonus. He was diagnosed with subcortical-nonsegmental myoclonus related to hemodialysis, and the myoclonus was significantly alleviated after slightly increasing the post-dialysis target weight even though drug treatment was ineffective. This case suggests that drug-resistant myoclonus in patients with renal failure may be improved by adjusting hemodialysis settings, even in cases of atypical dialysis disequilibrium syndrome.

DOI： 10.7759/cureus.36104

A young female case of asymptomatic immune-mediated necrotizing myopathy: a potential diagnostic option of antibody testing for rhabdomyolysis. 査読国際誌

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年2月

担当区分：責任著者記述言語：英語

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

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