Details of a Researcher - Suzuki, Norihiro

Papers - Suzuki, Norihiro

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Trends of Antiplatelet Therapy for the Management of Moyamoya Disease in Japan: Results of a Nationwide Survey

Oki K., Katsumata M., Izawa Y., Takahashi S., Suzuki N., Houkin K.

Journal of Stroke and Cerebrovascular Diseases (Journal of Stroke and Cerebrovascular Diseases) 27 ( 12 ) 3605 - 3612 2018.12

ISSN 10523057

© 2018 National Stroke Association Background: The efficacy and safety of antiplatelet drugs in the treatment of moyamoya disease remain unclear. This study reports results of a nationwide survey conducted in 2016 on the trends of antiplatelet therapy for moyamoya disease in Japan. Methods: Data were obtained through questionnaires related to treatment policies regarding antiplatelet drugs from each specialized stroke management department of 765 hospitals in Japan. Data were also compared between experienced facilities (defined as facilities managing more than 10 cases per year) and those less experienced (not more than 10 cases per year) to determine experts' opinion. Results: Of the 389 departments in 375 hospitals that responded, 330 departments provided medical care for moyamoya disease. Regarding ischemic stroke, numerous departments considered the use of antiplatelet drugs “in principle” (218 departments). After surgery for ischemic moyamoya disease, the use of antiplatelet drugs for a certain period of time was the most popular opinion (74 departments). Regarding asymptomatic moyamoya disease, majority departments reported no use of APDs “in principle” (256 departments). The experienced facilities reported “no use of antiplatelet drugs” more frequently than those less experienced for treating asymptomatic moyamoya disease. In moyamoya disease, aspirin was the most commonly used antiplatelet drugs followed by cilostazol and clopidogrel. Conclusions: This survey revealed details of treatment policies, and the selection of antiplatelet drugs widely varied across facilities. Further prospective studies are necessary to improve the current unclear situation regarding the use of antiplatelet drugs for the management of moyamoya disease.

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Differences in Clinical Features in Patients with Acute Coronary Syndrome and Stroke: Japanese Multicenter Registry Results

Naito R., Miyauchi K., Nojiri S., Suzuki N., Daida H.

Internal medicine (Tokyo, Japan) (Internal medicine (Tokyo, Japan)) 57 ( 22 ) 3233 - 3240 2018.11

Objective Coronary artery and cerebrovascular disease are the main causes of non-communicable diseases. In particular, acute coronary syndrome (ACS) and ischemic stroke are the most serious conditions of coronary artery disease and cerebrovascular disease, respectively. Therefore, it is important to prevent these conditions by identifying populations at high risk of these diseases. We sought to investigate the differences in the clinical features of patients with these atherothrombotic diseases in nationwide Japanese multicenter registries. Gender differences were also examined. Methods The dataset of the two nationwide multicenter registries for ACS [Prevention of AtherothrombotiC Incidents Following Ischemic Coronary (PACIFIC)] and ischemic stroke [Effective Vascular Event REduction after STroke (EVEREST)] was analyzed. Clinical features were examined and compared using datasets from the two registries. Results A total of 6,878 patients (PACIFIC: n=3,426, EVEREST: n=3,452) were evaluated. The patients' background characteristics were significantly different between the two populations. Patients with ACS tended to be younger, had a higher body mass index, had a greater prevalence of diabetes mellitus and dyslipidemia, were current smokers, and more often had a prior history of ischemia heart disease than patients with a stroke. Hypertension was more prevalent in patients with stroke than in those with ACS. The differences in patients' background characteristics between ACS and stroke in men were similar to those in the whole sample. However, the prevalence of hypertension in women was similar between the ACS and stroke groups, in contrast to the results from the whole sample. Conclusion Patients' background characteristics were significantly different between those with ACS and stroke. Gender differences were also observed.

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Enhanced susceptibility to cortical spreading depression in two types of Na<sup>+</sup>,K<sup>+</sup>-ATPase α2 subunit-deficient mice as a model of familial hemiplegic migraine 2

Unekawa M., Ikeda K., Tomita Y., Kawakami K., Suzuki N.

Cephalalgia (Cephalalgia) 38 ( 9 ) 1515 - 1524 2018.08

ISSN 03331024

© International Headache Society 2017. Background: Patients with familial hemiplegic migraine type 2 (FHM2) have a mutated ATP1A2 gene (encoding Na+,K+-ATPase α2 subunit) and show prolonged migraine aura. Cortical spreading depression (CSD), which involves mass depolarization of neurons and astrocytes that propagates slowly through the gray matter, is profoundly related to aura. Methods: In two types of Atp1a2-defective heterozygous mice, Atp1a2tm1Kwk (C-KO) and Atp1a2tm2Kwk (N-KO), the sensitivity and responsiveness to CSD were examined under urethane anesthesia. Results: In both cases, heterozygotes exhibited a low threshold for induction of CSD, faster propagation rate, slower recovery from DC deflection, and profound suppression of the electroencephalogram, compared to wild-type mice. A high dose of KCl elicited repeated CSDs for a longer period, with a tendency for a greater frequency of CSD occurrence in heterozygotes. The difference of every endpoint was slightly greater in N-KO than C-KO. Change of regional cerebral blood flow in response to CSD showed no significant difference. Conclusion: Heterozygotes of Atp1a2-defective mice simulating FHM2 demonstrated high susceptibility to CSD rather than cortical vasoreactivity, and these effects may differ depending upon the knockout strategy for the gene disruption. These results suggest that patients with FHM2 may exhibit high susceptibility to CSD, resulting in migraine.

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Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial

Misawa S., Kuwabara S., Sato Y., Yamaguchi N., Nagashima K., Katayama K., Sekiguchi Y., Iwai Y., Amino H., Suichi T., Yokota T., Nishida Y., Kanouchi T., Kohara N., Kawamoto M., Ishii J., Kuwahara M., Suzuki H., Hirata K., Kokubun N., Masuda R., Kaneko J., Yabe I., Sasaki H., Kaida K., Takazaki H., Suzuki N., Suzuki S., Nodera H., Matsui N., Tsuji S., Koike H., Yamasaki R., Kusunoki S., Misawa S., Kuwabara S., Sato Y., Yamaguchi N., Nagashima K., Katayama K., Sekiguchi Y., Iwai Y., Amino H., Suichi T., Yokota T., Nishida Y., Kanouchi T., Kohara N., Kawamoto M., Ishii J., Kuwahara M., Suzuki H., Hirata K., Kokubun N., Masuda R., Kaneko J., Yabe I., Sasaki H., Kaida K., Takazaki H., Suzuki N., Suzuki S., Nodera H., Matsui N., Tsuji S., Koike H., Yamasaki R., Kusunoki S., Nagashima T., Shimizu T., Hirotani M., Kadoya M., Nakahara J., Shimizu J., Tanaka M., Sobue G., Katsuno M., Yamaguchi H., Ogata H.

The Lancet Neurology (The Lancet Neurology) 17 ( 6 ) 519 - 529 2018.06

ISSN 14744422

© 2018 Elsevier Ltd Background: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. Methods: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3–5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. Findings: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42–78; n=14) in the eculizumab group, and 45% (20–73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. Interpretation: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. Funding: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

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Neuroprotective Role of Astroglia in Parkinson Disease by Reducing Oxidative Stress Through Dopamine-Induced Activation of Pentose-Phosphate Pathway

Mashima K., Takahashi S., Minami K., Izawa Y., Abe T., Tsukada N., Hishiki T., Suematsu M., Kajimura M., Suzuki N.

ASN Neuro (ASN Neuro) 10 2018.05

© The Author(s) 2018. Oxidative stress plays an important role in the onset and progression of Parkinson disease. Although released dopamine at the synaptic terminal is mostly reabsorbed by dopaminergic neurons, some dopamine is presumably taken up by astroglia. This study examined the dopamine-induced astroglial protective function through the activation of the pentose-phosphate pathway (PPP) to reduce reactive oxygen species (ROS). In vitro experiments were performed using striatal neurons and cortical or striatal astroglia prepared from Sprague-Dawley rats or C57BL/6 mice. The rates of glucose phosphorylation in astroglia were evaluated using the [ 14 C]deoxyglucose method. PPP activity was measured using [1- 14 C]glucose and [6- 14 C]glucose after acute (60 min) or chronic (15 hr) exposure to dopamine. ROS production was measured using 2′,7′-dichlorodihydrofluorescein diacetate. The involvement of the Kelch-like ECH-associated protein 1 (Keap1) or nuclear factor-erythroid-2-related factor 2 (Nrf2) system was evaluated using Nrf2 gene knockout mice, immunohistochemistry, and quantitative reverse transcription polymerase chain reaction analysis for heme oxygenase-1. Acute exposure to dopamine elicited increases in astroglial glucose consumption with lactate release. PPP activity in astroglia was robustly enhanced independently of Na + -dependent monoamine transporters. In contrast, chronic exposure to dopamine induced moderate increases in PPP activity via the Keap1/Nrf2 system. ROS production from dopamine increased gradually over 12 hr. Dopamine induced neuronal cell damage that was prevented by coculturing with astroglia but not with Nrf2-deficient astroglia. Dopamine-enhanced astroglial PPP activity in both acute and chronic manners may possibly reduce neuronal oxidative stress.

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Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: Relevance to migraine pathophysiology

Kayama Y., Shibata M., Takizawa T., Ibata K., Shimizu T., Ebine T., Toriumi H., Yuzaki M., Suzuki N.

Cephalalgia (Cephalalgia) 38 ( 5 ) 833 - 845 2018.04

ISSN 03331024

© 2017, © International Headache Society 2017. Background: Recent genome-wide association studies have identified transient receptor potential M8 (TRPM8) as a migraine susceptibility gene. TRPM8 is a nonselective cation channel that mediates cool perception. However, its precise role in migraine pathophysiology is elusive. Transient receptor potential V1 (TRPV1) is a nonselective cation channel activated by noxious heat. Both TRPM8 and TRPV1 are expressed in trigeminal ganglion (TG) neurons. Methods: We investigated the functional roles of TRPM8 and TRPV1 in a meningeal inflammation-based migraine model by measuring the effects of facial TRPM8 activation on thermal allodynia and assessing receptor coexpression changes in TG neurons. We performed retrograde tracer labeling to identify TG neurons innervating the face and dura. Results: We found that pharmacological TRPM8 activation reversed the meningeal inflammation-induced lowering of the facial heat pain threshold, an effect abolished by genetic ablation of TRPM8. No significant changes in the heat pain threshold were seen in sham-operated animals. Meningeal inflammation caused dynamic alterations in TRPM8/TRPV1 coexpression patterns in TG neurons, and colocalization was most pronounced when the ameliorating effect of TRPM8 activation on thermal allodynia was maximal. Our tracer assay disclosed the presence of dura-innervating TG neurons sending collaterals to the face. Approximately half of them were TRPV1-positive. We also demonstrated functional inhibition of TRPV1 by TRPM8 in a cell-based assay using c-Jun N-terminal kinase phosphorylation as a surrogate marker. Conclusions: Our findings provide a plausible mechanism to explain how facial TRPM8 activation can relieve migraine by suppressing TRPV1 activity. Facial TRPM8 appears to be a promising therapeutic target for migraine.

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Diameter of fluorescent microspheres determines their distribution throughout the cortical watershed area in mice

Tsukada N., Katsumata M., Oki K., Minami K., Abe T., Takahashi S., Itoh Y., Suzuki N.

Brain Research (Brain Research) 1679 109 - 115 2018.01

ISSN 00068993

© 2017 Elsevier B.V. A hemodynamic mechanism has long been assumed to play an important role in watershed infarction. In recent years, however, clinical evidence has indicated that an embolic mechanism is involved. The mechanism by which emboli are trapped preferentially in watershed areas remains unclear. In the present study, we developed a mouse embolus model using fluorescent microspheres with different diameters and evaluated the role of the microspheres’ diameters in the generation of a watershed-patterned distribution. We injected fluorescent microspheres of four different diameters (i.e., 13, 24, 40, and 69 μm) into the internal carotid artery of C57BL/6 mice either (1) without ligation of the common carotid artery (normal perfusion pressure model: NPPM) or (2) with ligation of the common carotid artery (low perfusion pressure model: LPPM). Left common carotid artery ligation induced reductions in local cerebral blood flow in both the periphery and the core area of the left middle cerebral artery. A greater reduction in the border-zone area between the left anterior cerebral artery and the middle cerebral artery was also noted. After 24 h, the brains were removed and the distribution of the microspheres in the brain was evaluated using a fluorescence microscope. The 24-μm microspheres were distributed in the watershed area more frequently than the other microsphere sizes (P <.05, ANOVA followed by Tukey's test). Meanwhile, the distribution rates were similar between the NPPM and LPPM models for all microsphere sizes. This study suggested that the distribution pattern of the microspheres was only affected by the microspheres’ diameters.

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Advantages of Staged Angioplasty in a Patient with Internal Carotid Artery Pseudo-Occlusion Besides Prevention of Cerebral Hyperperfusion Syndrome

Takahashi S., Akiyama T., Nakahara J., Yoshizaki T., Suzuki N., Yoshida K.

World Neurosurgery (World Neurosurgery) 109 409 - 412 2018.01

ISSN 18788750

© 2017 Elsevier Inc. Background Staged angioplasty for carotid artery stenosis has been reported to be effective in preventing postoperative cerebral hyperperfusion syndrome (CHS) in patients with severe carotid stenosis; thus, it is also recommended for patients with internal carotid artery (ICA) pseudo-occlusion, the treatment strategy for which is controversial. Case Description This study reports the case of an Asian man in his 50s who had motor aphasia and right-side weakness caused by pseudo-occlusion of the left ICA. After medical treatment, he underwent a staged angioplasty. After the first stage of percutaneous transluminal angioplasty, anterograde blood flow to the left ICA increased but the distal ICA remained partially collapsed. Initially, the second stage of carotid artery stenting (CAS) was planned for 2 weeks after the first stage; however, hemorrhagic infarction was observed the day before the CAS, and it was postponed by 2 weeks, after adjustment of antiplatelet therapy. At the time of the CAS, the diameter of the initially collapsed left distal ICA was remodeled and it was fully dilated; thus, we used a balloon-type embolic protection device and conducted CAS successfully without apparent embolic complications. The postoperative course was uneventful. The patient did not develop CHS. Conclusions Besides preventing CHS, staged angioplasty has advantages when used for treating patients with ICA pseudo-occlusions in that the extent of dilation of the distal ICA after percutaneous transluminal angioplasty can be confirmed and the development of a possible hemorrhagic infarction can be assessed before stent placement.

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Clinical analysis of opticospinal multiple sclerosis (OSMS) presentation detecting anti-myelin oligodendrocyte glycoprotein (MOG) antibody

Kitagawa S., Osada T., Kaneko K., Takahashi T., Suzuki N., Nakahara J.

Clinical Neurology (Clinical Neurology) 58 ( 12 ) 737 - 744 2018

ISSN 0009918X

© 2018 Clinical Neurolog. All rights reserved. We report an 18 year-old-male, who had been aware of decreased visual acuity for 6 months, newly presented with paresis and sensory disturbance in his right leg. On admission, his critical flicker frequency was reduced bilaterally, and his spinal cord MRI revealed T 2 -hyperintense lesions in cervical and thoracic cord with occasional contrast enhancements, but none of them were longitudinally extensive. There was no evidence of T 2 -hyperintense in his brain MRI. Anti-aquapolin-4 (AQP4) antibody was negative but the patient was positive for oligoclonal bands in his cerebrospinal fluid. The patient was tentatively diagnosed as opticospinal multiple sclerosis (OSMS). However, he later tuned out to be positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibody. The 2017 revised McDonald criteria don't take anti-MOG antibody into account in detail as to how clinicians should deal with patients fulfilling the MS criteria when they were also positive for anti-MOG antibody, because of its difficult problem of independence. So, we need to accumulate knowledge about these cases.

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The first report of a japanese case of seipinopathy with a BSCL2 N88S mutation

Minami K., Takahashi S., Nihei Y., Oki K., Suzuki S., Ito D., Takashima H., Suzuki N.

Internal Medicine (Internal Medicine) 57 ( 4 ) 613 - 615 2018

ISSN 09182918

© 2018 The Japanese Society of Internal Medicine. Seipinopathy is an autosomal dominant neurodegenerative disease caused by mutations of the Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) gene. We report the first Japanese case of seipinopathy with a heterozygous mutation of p.N88S in the BSCL2 gene. The patient showed bilateral hyperreflexia of the biceps, triceps, brachioradialis, and knee, as well as the pes cavus and distal dominant weakness and atrophy of both arms and legs, suggesting the involvement of both upper and lower motor neurons. Mutations of the BSCL2 gene have been known to cause motor neuron degeneration through endoplasmic reticulum stress. Seipinopathy should be considered in patients with symptoms mimicking amyotrophic lateral sclerosis.

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Spatiotemporal changes in cerebral blood flow induced by transcranial photostimulation to cortical neurons or astrocytes in the transgenic mice expressing channelrhodopsin-2

Hatakeyama, N., Masamoto, K., Unekawa, M., Takuwa, H., Kanno, I., Matsui, K., Tanaka, K. F., Tomita, Y., Suzuki, N.

JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM 37 367 - 368 2017.04