301
-シン ポジ ウム
S-16-2
Hyperexcitability and ALS: Past, present and future
The University of New South Wales, Australia
○Cindy Shin-yi Lin
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons. A combination of upper/lower motor neuron dysfunction comprises the clinical ALS phenotype that was first observed by Charcot. However, the site of ALS onset and the pathophysiological mechanisms underlying the development of degeneration remain to be elucidated. Measurements of nerve excitability by threshold tracking have been developed over 30yrs to provide complementary information to conventional nerve conduction studies, these techniques have been introduced to investigate ALS. Wide-spread fasciculations are prominent clinical features, they frequently arise from the motor nerve terminals, and the hyperexcitability of motor axons appears to constitute the pathophysiology of ALS. Neurophysiologic investigations of both upper/lower motor neurons have demonstrated increased excitability.
Axonal excitability studies enable investigation of longitudinal changes in axonal dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS. In addition, the assessment of cortical excitability via Transcranial Magnetic Stimulation (TMS) has contributed to enhancing our understanding of ALS pathophysiology. TMS enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. TMS excitability studies have established motor cortical/corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms and preceding the clinical onset of familial ALS. Cortical excitability studies facilitate an earlier diagnosis of ALS. Findings from peripheral/cortical excitability studies have yielded novel insights into disease mechanisms, pathophysiology and treatment strategies of ALS.This presentation aims to provide an overview of how past, current excitability techniques are employed in ALS and the future of excitability parameters as useful biomarkers.
《Curriculum Vitae》
Cindy Shin-Yi Lin is the Associate Professor of Neurophysiology at the Department of Physiology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney Australia. She has published a total of >100 manuscripts and 3 book chapters in the highest-impact international multidisciplinary journals incorporating the fields of Clinical Neurology, Oncology and Endocrinology yielding an H-index of 30. A/Prof Lin’s main research interest is clinical translation using axonal excitability. A/Prof Lin has qualifications in Biomedical Engineering, Masters of Engineering Science (Biomedical Engineering) and PhD in Neurophysiology. She was awarded a prestigious NHMRC CJ Martin Fellowship, spending two years at the Sobell Department at the Institute of Neurology, Queen Square, University College London. She has established cross-discipline collaborations within Australia at Prince of Wales Hospital. Her international collaborations include Chiba University Hospital, Japan, the National Hospital for Neurology and Neurosurgery, University College London, UK, and National Taiwan University Hospital, Taipei Medical University (TMU) and Wang Fang Hospital, Taiwan and focus on clinical research in patients with various neurological disorders. She has a strong interest in neuroscience education, lecturing in Muscle and Motor Control, Fundamentals of Neuroscience and Neuromuscular rehabilitation courses and she is also the honorary A/Prof for TMU.
S-16-3
Sodium channelopathy in disuse neuromyopathy
Department of Neurology, Tokushima Univeristy
○Hiroyuki Nodera
Disuse neuromuscular atrophy is an important clinical issue because of its poor prognosis. To approach its pathomechanism, we characterized the excitability changes in peripheral motor axons caused by hindlimb unloading in mice, which is a model of disuse neuromuscular atrophy. The amplitudes of the motor responses of the unloading group were approximately half of the control amplitudes. Multiple axonal excitability analysis showed that the unloading group had a smaller strength-duration time constant (SDTC) and late subexcitability (recovery cycle) than the controls. Three weeks after releasing from HLU, the SDTC became comparable to the control range. Using a modeling study, the observed differences in the waveforms could be explained by reduced persistent sodium currents along with parameters related to current leakage. Axonal sodium current might be a novel therapeutic target for disuse neuromuscular atrophy.
《Curriculum Vitae》
2012 - present
Tokushima University: Senior Assistant professor, Director, EMG lab 2010 - 2012
Beth Israel Deaconess Medical Center/Harvard Medical School:
Staff physician, assistant professor 2009 - 2010
Weill Cornell Medical College: Peripheral Neuropathy Fellow 2002 - 2009
Tokushima University: Instructor, Director, Electromyography Lab 2000 - 2002
University of Rochester Medical Center: EMG/Neuromuscular fellow 1997 - 2000
Indiana University Medical Center: Neurology resident 1996 - 1997
Ball Memorial Hospital: Transitional resident 1993 - 1995
Kitano Hospital: Neurology resident 1993Kyoto University Hospital: Neurology resident
シンポジウム S-16：Pathomechanisms and therapeutic intervention of abnormal excitability in the upper and lower motor neuron systems
5月20日（金） 13：15～14：55 第15会場(神戸国際会議場5F Room 502 )
シン ポジ ウム
S-16-2
Hyperexcitability and ALS: Past, present and future
The University of New South Wales, Australia
○Cindy Shin-yi Lin
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the motor neurons. A combination of upper/lower motor neuron dysfunction comprises the clinical ALS phenotype that was first observed by Charcot. However, the site of ALS onset and the pathophysiological mechanisms underlying the development of degeneration remain to be elucidated. Measurements of nerve excitability by threshold tracking have been developed over 30yrs to provide complementary information to conventional nerve conduction studies, these techniques have been introduced to investigate ALS. Wide-spread fasciculations are prominent clinical features, they frequently arise from the motor nerve terminals, and the hyperexcitability of motor axons appears to constitute the pathophysiology of ALS. Neurophysiologic investigations of both upper/lower motor neurons have demonstrated increased excitability.
Axonal excitability studies enable investigation of longitudinal changes in axonal dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS. In addition, the assessment of cortical excitability via Transcranial Magnetic Stimulation (TMS) has contributed to enhancing our understanding of ALS pathophysiology. TMS enables non-invasive assessment of the functional integrity of the motor cortex and its corticomotoneuronal projections. TMS excitability studies have established motor cortical/corticospinal dysfunction in ALS, with cortical hyperexcitability being an early feature in sporadic forms and preceding the clinical onset of familial ALS. Cortical excitability studies facilitate an earlier diagnosis of ALS. Findings from peripheral/cortical excitability studies have yielded novel insights into disease mechanisms, pathophysiology and treatment strategies of ALS.This presentation aims to provide an overview of how past, current excitability techniques are employed in ALS and the future of excitability parameters as useful biomarkers.
《Curriculum Vitae》
Cindy Shin-Yi Lin is the Associate Professor of Neurophysiology at the Department of Physiology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney Australia. She has published a total of >100 manuscripts and 3 book chapters in the highest-impact international multidisciplinary journals incorporating the fields of Clinical Neurology, Oncology and Endocrinology yielding an H-index of 30. A/Prof Lin’s main research interest is clinical translation using axonal excitability. A/Prof Lin has qualifications in Biomedical Engineering, Masters of Engineering Science (Biomedical Engineering) and PhD in Neurophysiology. She was awarded a prestigious NHMRC CJ Martin Fellowship, spending two years at the Sobell Department at the Institute of Neurology, Queen Square, University College London. She has established cross-discipline collaborations within Australia at Prince of Wales Hospital. Her international collaborations include Chiba University Hospital, Japan, the National Hospital for Neurology and Neurosurgery, University College London, UK, and National Taiwan University Hospital, Taipei Medical University (TMU) and Wang Fang Hospital, Taiwan and focus on clinical research in patients with various neurological disorders. She has a strong interest in neuroscience education, lecturing in Muscle and Motor Control, Fundamentals of Neuroscience and Neuromuscular rehabilitation courses and she is also the honorary A/Prof for TMU.
S-16-3
Sodium channelopathy in disuse neuromyopathy
Department of Neurology, Tokushima Univeristy
○Hiroyuki Nodera
Disuse neuromuscular atrophy is an important clinical issue because of its poor prognosis. To approach its pathomechanism, we characterized the excitability changes in peripheral motor axons caused by hindlimb unloading in mice, which is a model of disuse neuromuscular atrophy. The amplitudes of the motor responses of the unloading group were approximately half of the control amplitudes. Multiple axonal excitability analysis showed that the unloading group had a smaller strength-duration time constant (SDTC) and late subexcitability (recovery cycle) than the controls. Three weeks after releasing from HLU, the SDTC became comparable to the control range. Using a modeling study, the observed differences in the waveforms could be explained by reduced persistent sodium currents along with parameters related to current leakage. Axonal sodium current might be a novel therapeutic target for disuse neuromuscular atrophy.
《Curriculum Vitae》
2012 - present
Tokushima University: Senior Assistant professor, Director, EMG lab 2010 - 2012
Beth Israel Deaconess Medical Center/Harvard Medical School:
Staff physician, assistant professor 2009 - 2010
Weill Cornell Medical College: Peripheral Neuropathy Fellow 2002 - 2009
Tokushima University: Instructor, Director, Electromyography Lab 2000 - 2002
University of Rochester Medical Center: EMG/Neuromuscular fellow 1997 - 2000
Indiana University Medical Center: Neurology resident 1996 - 1997
Ball Memorial Hospital: Transitional resident 1993 - 1995
Kitano Hospital: Neurology resident 1993Kyoto University Hospital: Neurology resident
シンポジウム S-16：Pathomechanisms and therapeutic intervention of abnormal excitability in the upper and lower motor neuron systems
5月20日（金） 13：15～14：55 第15会場(神戸国際会議場5F Room 502 )
302 -シン
ポジ ウム
S-16-4
Peripheral nerve excitability
abnormality in spinocerebellar ataxia type 6
1Department of Neurology, Institute of Biomedical
Sciences, Tokushima University Graduate School，2Research Institute for Radiation Biology and Medicine, Hiroshima University
○Yusuke Osaki1，Hiroyuki Nodera1， Yuishin Izumi1，Ryosuke Oki1，
Ryosuke Miyamoto1，Toshitaka Kawarai1， Hideshi Kawakami2，Ryuji Kaji1
[Objective] Spinocerebellar ataxia type 6 (SCA6) is hereditary spinocerebellar degeneration caused by expansion of triplet repeats in CACNA1A encoding α1A subunit of P/Q type voltage-gated Ca2+
channel Cav2.1. Cav2.1 was present not only at cerebellar Purkinje cells but also at peripheral nerve terminals. This study was made to evaluate pathophysiological dysfunction of peripheral nerves in SCA6. [Methods]
Fifteen patients with genetically confirmed SCA6 underwent nerve excitability testing with QtracS software (Digitimer, UK). Excitability properties of median motor axons were compared with those in 22 age-matched healthy control subjects. Then, sensory axonal properties in 13 patients were compared with 15 controls. In addition, two male normal mice underwent motor nerve excitability testing before and after intraperitoneal injection of ω-agatoxin-ⅣA which is a selective P type Ca2+channel blocker. [Results] All SCA6 patients had similar motor nerve excitability changing, including decreased electrical threshold with long subthreshold depolarizing currents (TEd90-100ms, p ＜ 0.006) and increased S2 accommodation (p ＜ 0.003) in threshold electrotonus, which indicated increased slow activating voltage gated K+currents. In the recovery cycle, relative refractory period was prolonged (p ＜ 0.03) and subexcitability was increased (p ＜ 0.02).
Strength-duration time constant and resting I/V slope in current-response curve showed no significant differences. Sensory nerve excitaility abnormality was similar to motor nerve, however, S2 accommodation increment was not significant. Two mice injected with ω-agatoxin-ⅣA also showed decreased TEd90-100 and increased S2 accommodation. [Conclusions] Peripheral nerves in SCA6 patients reveal increased slow K+currents. It might be due to dysfunction associated with voltage-gated Ca2+channel.
《Curriculum Vitae》
Bachelor of science in medicine
Tokushima university, Tokushima, Japan March, 2007
Currently attending the master’s course in neurology at Tokushima graduate school
シンポジウム S-16：Pathomechanisms and therapeutic intervention of abnormal excitability in the upper and lower motor neuron systems
5月20日（金） 13：15～14：55 第15会場(神戸国際会議場5F Room 502 )
303
-シン ポジ ウム
座長：
望月秀樹(大阪大学大学院医学系研究科 神経内科学) 髙橋良輔(京都大学医学部附属病院 神経内科)
≪ねらい≫
神経研究の重要性はいうまでもないが，神経難病を含め神 経疾患の一部は大きな社会問題にもなっている．将来構想 委員会では，神経学会の重要性を内外に広く提示し，学会が 各省庁との連携を模索している．今回は，各省庁の各省庁か ら，神経内科学に関連するキーパーソンの方にお出でいただ き，各省庁の神経科学研究に期待することや，それに関わる 政策，研究費などの将来的なご意見などについて伺う．最後 には，将来構想員会委員と討論会を行う．
S-17-1
神経内科の将来構想
大阪大学病院 神経内科学
○望月秀樹
神経・筋疾患のスペクトラムは極めて広く，国内の患者数 約460万人の認知症や同約300万人に上る脳血管障害をはじ め，超高齢化社会を迎えた今，加齢とともに頻度の増加する 神経疾患の患者数は軒並み急激に上昇しており，治療法や予 防法開発の必要性がより一層高まっている．また，本邦では 行政的に稀少疾患という意味を含めて原因不明で治療法の ない疾患を「難病」と呼ぶことが多いが，神経疾患にはこの 定義に該当するものが数多く含まれる．
日本神経学会では，「国際社会の先駆けとなる健康長寿社 会の実現」という国家目標が提示された今，日本神経学会理 事や将来構想委員会が中心となりこれらの神経疾患・筋疾患 を俯瞰して，その克服への道筋を検討し，「神経疾患克服に 向けた研究推進の提言」としてまとめた．本講演では，この 提言を中心に紹介・解説し，将来構想委員会の活動について も紹介する．
《略歴》1985年 順天堂大学医学部 卒業
1990年 順天堂大学医学部 脳神経内科 助手 1996年 米国，NIH, NINDS留学 (visiting associate) 2000年 順天堂老人性疾患病態・治療研究センター 講師 2005年 順天堂大学越谷病院 脳神経内科 助教授 2009年 北里大学医学部神経内科学 教授
2010年 北里大学医学部寄附講座神経再生医療学 講座責任者 2011年 大阪大学大学院医学系研究科神経内科学 教授 2012年 大阪大学医学部附属病院 遺伝子診療部 部長 兼任
＜学会活動＞
日本神経学会(理事)，日本神経治療学会（理事），日本遺伝子治療学会 (評議員)
日本パーキンソン病・運動障害疾患学会（Executive committee）
＜専門医＞
日本神経学会認定専門医，日本内科学会認定医，日本人類遺伝学会 臨床遺伝専門医，日本認知症学会専門医
＜賞罰＞2004年 順天堂大学同窓会学術奨励賞
2007年 1st Asia & Oceania PD-MDS Congress, Best Research Award
2008年 日本神経学会 楢林賞 2009年 順天堂医師会賞