Faculty Profiles - TAKEMOTO Mami

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)

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

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

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

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

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

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

DOI： 10.2169/internalmedicine.6098-20

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

AIを用いたパーキンソン病患者の見た目年齢・感情の評価

田所功, 山下徹, 福井裕介, 武本麻美, 佐々木諒, 松本菜見子, 野村恵美, 森原隆太, 表芳夫, 阿部康二

パーキンソン病・運動障害疾患コングレスプログラム・抄録集 15回 81 - 81 2021.7

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

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

Scientific reports 11 ( 1 ) 12828 - 12828 2021.6

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

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

Neurological research 43 ( 6 ) 429 - 433 2021.6

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

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

DOI： 10.1080/01616412.2020.1866383

ALS患者における低酸素ストレスを可視化する

山下徹, 畠山哲宗, 佐藤恒太, 福井裕介, 菱川望, 武本麻美, 太田康之, 西山佳宏, 河井信行, 田宮隆, 阿部康二

日本抗加齢医学会総会プログラム・抄録集 21回 214 - 214 2021.6

化粧美容セラピーの認知・情動機能改善効果

田所功, 川野公子, 佐藤順子, 谷都美子, 表芳夫, 武本麻美, 森原隆太, 山下徹, 阿部康二

日本抗加齢医学会総会プログラム・抄録集 21回 211 - 211 2021.6

AIを用いたパーキンソン病の顔についての解析

田所功, 山下徹, 福井裕介, 武本麻美, 佐々木諒, 松本菜見子, 野村恵美, 表芳夫, 森原隆太, 阿部康二

日本抗加齢医学会総会プログラム・抄録集 21回 222 - 222 2021.6

AIによる新しい脳機能・認知症診断 AIなどの新たな技術を活用した認知症診療

田所功, 佐々木諒, 松本菜見子, 福井裕介, 表芳夫, 武本麻美, 森原隆太, 山下徹, 阿部康二

日本抗加齢医学会総会プログラム・抄録集 21回 155 - 155 2021.6

ALS患者における低酸素ストレスを可視化する

山下徹, 畠山哲宗, 佐藤恒太, 福井裕介, 菱川望, 武本麻美, 太田康之, 西山佳宏, 河井信行, 田宮隆, 阿部康二

日本抗加齢医学会総会プログラム・抄録集 21回 214 - 214 2021.6

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

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

Neuroscience research 166 55 - 61 2021.5

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

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

DOI： 10.1016/j.neures.2020.05.009

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

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

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

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

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

DOI： 10.1111/ncn3.12492

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

A new telestroke network system in northern area of Okayama prefecture

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

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

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

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

DOI： 10.1111/ncn3.12475

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

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

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

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

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

DOI： 10.2169/internalmedicine.5536-20

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

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

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

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

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

DOI： 10.1111/ncn3.12441