TN-05-4
Targeting Tauopathies for Tau Therapeutic Translation
University of California, San Francisco, USA
○Adam L. Boxer
Frontotemporal Lobar Degeneration (FTLD) is a group of neurodegenerative diseases characterized in most cases by accumulation of pathogenic tau tau) or TDP-43 protein (FTLD-TDP) in specific brain regions. Clinically, FTLD is associated with a variety of syndromes, including frontotemporal dementia (FTD), primary progressive aphasia, FTD with amyotrophic lateral sclerosis or the parkinsonian syndromes corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) . There are no effective treatments for FTLD, but new therapies targeting the underlying molecules that cause FTLD are rapidly entering clinical trials. Some of these therapies target tau protein and might also be useful for treating Alzheimer’s disease (AD). FTLD has important advantages over AD for clinical development, including a stronger link between clinical syndrome and tau pathology, stronger genetic links to tau and more rapid progression with fewer confounding variables in clinical trials. Of the FTLD-tau syndromes, PSP has advanced the farthest in therapeutic development. Recent, large, randomized controlled trials were negative in PSP, but developed novel methods and biomarkers that are being incorporated into new studies. Another multicenter biomarker study, the 4 Repeat Tauopathy Neuroimaging Initiative (4RTNI) is developing novel biomarkers for PSP and related disorders, including tau-specific PET ligands. Mutations in MAPT, GRN or C9ORF72 are the most frequent causes of familial FTLD, and may allow for pre-symptomatic interventions prevent disease. New North American (ARTFL and LEFFTDS) and EU (GENFI) clinical research networks have begun to prepare for future FTLD clinical trials.
《Curriculum Vitae》
Adam L. Boxer, MD, PhD is an Associate Professor of Neurology at the University of California, San Francisco (UCSF) where he directs the Neurosciences Clinical Research Unit. He also directs the Alzheimer’ s Disease and Frontotemporal Lobar Degeneration (FTLD) Clinical Trials Program at the UCSF Memory and Aging Center. Dr. Boxer’s research is focused on developing new treatments and biomarkers for neurodegenerative diseases, particularly those involving tau and TDP-43. He is the Principal Investigator of the Advancing Research and Treatment for FTLD (ARTFL;
https: //www.rarediseasesnetwork.org/cms/ARTFL ) Clinical Research Consortium, a collaborative project funded by the National Institutes of Health to create a 15 center North American research network to support the development of new therapies for FTLD including PSP and CBD. He also leads the Four Repeat Tauopathy Neuroimaging Initiative (4RTNI), a multicenter, longitudinal biomarker study focused on PSP and CBD. He was the PI for two recently-completed, multicenter, randomized, placebo controlled clinical trials of memantine for FTLD and davunetide for PSP. He leads the FTLD Treatment Study Group (FTSG), an academic-industry collaborative group working to speed the development of new therapies for FTLD. He is a recipient of the 2013 Part the Cloud Award for Translational Research from the Alzheimer’s Association.
なおる神経内科 TN-05：Recent advance of clinical trials and treatment in progressive supranuclear palsy
5月19日（木） 8：00～10：00 第10会場(神戸国際会議場B1F・1F メインホール)
162
TN-06-2
Motor and non motor features of prodromal & early stage genetic forms of Parkinson disease
1National Neuroscience Institute, Singapore，
2Duke NUS Graduate Medical School, Singapore
○Eng-King Tan1,2
Numerous pathogenic genes and genetic loci have been linked with Parkinson’s disease (PD). Carriers of these gene mutations or susceptibility loci are at a higher risk of developing PD even if they remain asymptomatic. Current literature suggests that asymptomatic genetic PD carriers have neuroimaging features of dopaminergic dysfunction.
Some have reported clinical differences between symptomatic PD gene carriers and non gene carriers.
Among PD patients, those with certain gene defects may progress differentially from those without. PD patients also experience a wide range of nonmotor symptoms (NMS) throughout the disease course. Some studies suggest that the frequency of NMS is not different between genetic and sporadic form of PD while others suggest that neuropsychiatric symptoms are more common in the genetic form. With the advent of high throughput genetic screening and intensive clinical evaluation, identification of motor and non motor features of prodromal/presymptomatic or even early stage PD will help identify at risk subjects who may be potential candidates for neuroprotective trials. Early recognition of specific non motor features may facilitate early diagnosis and monitoring of both sporadic and genetic PD.
《Curriculum Vitae》
Dr EK Tan is a senior consultant neurologist and clinician scientist at the National Neuroscience Institute and a Professor at Duke-NUS graduate medical school. Dr Tan completed his Neurology training in Singapore and received further clinical fellowship training in Movement Disorders under the ministry of Health scholarship, and subsequently a research fellowship in Neurogenetics. He completed both fellowships at the Baylor College of Medicine, Texas, USA.
Dr Tan is the associate editor of European Journal of Neurology, Parkinsonism Related Disorders, Parkinson’s disease Journal, and Basal Ganglia journal, and the chief editor of Annals Academy of Medicine, Singapore. Dr Tan has served in various committees in the International Movement Disorders Society (MDS) and a founding member of the MDS Asian Oceanic Section. He is also member of American Neurological Association. He has been involved in numerous educational activities in the Asian Oceanic region.
Dr Tan’ s primary research interests are in clinical and functional genomics and experimental therapeutics in Parkinson’s disease and Movement Disorders.
TN-06-3
Nuclear neuroimaging: Potential diagnostic value of SPECT and PET
Department of Neurology, Kanto Central Hospital
○Satoshi Orimo
Although the diagnosis of Parkinson’s disease (PD) is still based on the clinical features and clear beneficial response to dopaminergic therapy,some examinations including nuclear neuroimagings have been used as the supportive diagnostic tools and they have an ancillary role in confirming the diagnosis.In this symposium,I’ll review the following nuclear neuroimagings for the diagnosis of PD and prodromal PD.
1) MIBG cardiac scintigraphy can assess pathophysiology of postganglionic presynaptic cardiac sympathetic nerve endings. Cardiac MIBG uptake is reduced in patients with PD, even in the early stage, but not in multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), vascular parkinsonism (VP), and essential tremor (ET). Therefore, MIBG cardiac scintigraphy is a sensitive diagnostic tool to differentiate PD from other related disorders. Reduced cardiac MIBG uptake can be a potential biomarker for the presence of Lewy bodies in the nervous system.
2) FP-CIT SPECT can assess pathophysiology of presynaptic nigrostriatal dopaminergic nerve endings. Striatal FP-CIT uptake is reduced in neurodegenerative parkinsonian syndromes such as PD, MSA, PSP, and CBD, even in pre-motor stage, but not in VP and ET.
Therefore, FP-CIT SPECT is a sensitive diagnostic tool to differentiate neurodegenerative parkinsonian syndromes from other non-neurodegenerative parkinsonian syndromes and ET, but it cannot differentiate PD from the other neurodegenerative parkinsonian syndromes. 3) Brain perfusion SPECT and FDG PET measure brain blood flow and brain glucose metabolism, respectively, and both tools can assess synaptic density or integrated synaptic activity of a certain brain region. Regional blood flow and brain glucose metabolism in PD show a reduction in parieto-occipital and frontal regions along with a relative increase in striatum, thalamus, pons, cerebellum, and primary motor cortex.
《Curriculum Vitae》
Dr. Orimo graduated from Faculty of Medicine, Shinshu University and obtained his Ph.D. at Tokyo Medical and Dental University. He trained as to be a clinical neurologist at Tokyo Medical and Dental University Hospital and Kanto Teishin Hospital. Now he is a director of the Department of Neurology, Kanto Central Hospital and a visiting research fellow of Tokyo Metropolitan Institute of Medical Science. He has been working at several hospitals as a neurologist and also has been researching on the pathophysiology of Parkinson’s disease and dementia with Lewy bodies. He received Ueda Memorial Heart Trust award in 1999, Narabayashi award in 2007, Medical Research award of Tokyo Medical Association in 2008, and Alumni Association of Shinshu University award in 2009 for his research works. Daily he makes an effort on examining patients with both a mind of “Akahige doctor” and the eyes of a scientist.
なおる神経内科 TN-06：Improvement in the management of Parkinson’s disease:
Present status and prospect of ultra-early diagnosis
5月19日（木） 15：15～17：15 第10会場(神戸国際会議場B1F・1F メインホール)
なお る神 経内 科
TN-06-2
Motor and non motor features of prodromal & early stage genetic forms of Parkinson disease
1National Neuroscience Institute, Singapore，
2Duke NUS Graduate Medical School, Singapore
○Eng-King Tan1,2
Numerous pathogenic genes and genetic loci have been linked with Parkinson’s disease (PD). Carriers of these gene mutations or susceptibility loci are at a higher risk of developing PD even if they remain asymptomatic. Current literature suggests that asymptomatic genetic PD carriers have neuroimaging features of dopaminergic dysfunction.
Some have reported clinical differences between symptomatic PD gene carriers and non gene carriers.
Among PD patients, those with certain gene defects may progress differentially from those without. PD patients also experience a wide range of nonmotor symptoms (NMS) throughout the disease course. Some studies suggest that the frequency of NMS is not different between genetic and sporadic form of PD while others suggest that neuropsychiatric symptoms are more common in the genetic form. With the advent of high throughput genetic screening and intensive clinical evaluation, identification of motor and non motor features of prodromal/presymptomatic or even early stage PD will help identify at risk subjects who may be potential candidates for neuroprotective trials. Early recognition of specific non motor features may facilitate early diagnosis and monitoring of both sporadic and genetic PD.
《Curriculum Vitae》
Dr EK Tan is a senior consultant neurologist and clinician scientist at the National Neuroscience Institute and a Professor at Duke-NUS graduate medical school. Dr Tan completed his Neurology training in Singapore and received further clinical fellowship training in Movement Disorders under the ministry of Health scholarship, and subsequently a research fellowship in Neurogenetics. He completed both fellowships at the Baylor College of Medicine, Texas, USA.
Dr Tan is the associate editor of European Journal of Neurology, Parkinsonism Related Disorders, Parkinson’s disease Journal, and Basal Ganglia journal, and the chief editor of Annals Academy of Medicine, Singapore. Dr Tan has served in various committees in the International Movement Disorders Society (MDS) and a founding member of the MDS Asian Oceanic Section. He is also member of American Neurological Association. He has been involved in numerous educational activities in the Asian Oceanic region.
Dr Tan’ s primary research interests are in clinical and functional genomics and experimental therapeutics in Parkinson’s disease and Movement Disorders.
TN-06-3
Nuclear neuroimaging: Potential diagnostic value of SPECT and PET
Department of Neurology, Kanto Central Hospital
○Satoshi Orimo
Although the diagnosis of Parkinson’s disease (PD) is still based on the clinical features and clear beneficial response to dopaminergic therapy,some examinations including nuclear neuroimagings have been used as the supportive diagnostic tools and they have an ancillary role in confirming the diagnosis.In this symposium,I’ll review the following nuclear neuroimagings for the diagnosis of PD and prodromal PD.
1) MIBG cardiac scintigraphy can assess pathophysiology of postganglionic presynaptic cardiac sympathetic nerve endings. Cardiac MIBG uptake is reduced in patients with PD, even in the early stage, but not in multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), vascular parkinsonism (VP), and essential tremor (ET). Therefore, MIBG cardiac scintigraphy is a sensitive diagnostic tool to differentiate PD from other related disorders. Reduced cardiac MIBG uptake can be a potential biomarker for the presence of Lewy bodies in the nervous system.
2) FP-CIT SPECT can assess pathophysiology of presynaptic nigrostriatal dopaminergic nerve endings. Striatal FP-CIT uptake is reduced in neurodegenerative parkinsonian syndromes such as PD, MSA, PSP, and CBD, even in pre-motor stage, but not in VP and ET.
Therefore, FP-CIT SPECT is a sensitive diagnostic tool to differentiate neurodegenerative parkinsonian syndromes from other non-neurodegenerative parkinsonian syndromes and ET, but it cannot differentiate PD from the other neurodegenerative parkinsonian syndromes. 3) Brain perfusion SPECT and FDG PET measure brain blood flow and brain glucose metabolism, respectively, and both tools can assess synaptic density or integrated synaptic activity of a certain brain region. Regional blood flow and brain glucose metabolism in PD show a reduction in parieto-occipital and frontal regions along with a relative increase in striatum, thalamus, pons, cerebellum, and primary motor cortex.
《Curriculum Vitae》
Dr. Orimo graduated from Faculty of Medicine, Shinshu University and obtained his Ph.D. at Tokyo Medical and Dental University. He trained as to be a clinical neurologist at Tokyo Medical and Dental University Hospital and Kanto Teishin Hospital. Now he is a director of the Department of Neurology, Kanto Central Hospital and a visiting research fellow of Tokyo Metropolitan Institute of Medical Science. He has been working at several hospitals as a neurologist and also has been researching on the pathophysiology of Parkinson’s disease and dementia with Lewy bodies. He received Ueda Memorial Heart Trust award in 1999, Narabayashi award in 2007, Medical Research award of Tokyo Medical Association in 2008, and Alumni Association of Shinshu University award in 2009 for his research works. Daily he makes an effort on examining patients with both a mind of “Akahige doctor” and the eyes of a scientist.
なおる神経内科 TN-06：Improvement in the management of Parkinson’s disease:
Present status and prospect of ultra-early diagnosis
5月19日（木） 15：15～17：15 第10会場(神戸国際会議場B1F・1F メインホール)
164 -なお
る神 経内 科
TN-06-4
Novel neuroimaging approaches for exploring cerebral functional and anatomical connectivity
1Brain and Mind Research Center, Nagoya
University，2Department of Neurology, Nagoya University Graduate School of Medicine，3Department of Radiology, Nagoya University Graduate School of Medicine
○Epifanio Bagarinao1，Hirohisa Watanabe1,2， Shinji Naganawa1,3，Gen Sobue1,2
Recent neuroimaging advances have provided the needed tools to better understand the anatomical as well as the functional changes that occur in the brain with Parkinson’s disease (PD). One such technique is resting state functional magnetic resonance imaging (rsfMRI), which measures the spontaneous activity of the brain when an individual is not performing an explicit task. Using low-frequency fluctuations of the blood-oxygen-level dependent signal, rsfMRI can be used to identify several resting state networks representing clusters of distinct brain regions that exhibit synchronous fluctuations at rest. Methods such as seed-based connectivity analysis, independent component analysis, and network analysis, among others, have been used to analyze rsfMRI data to investigate functional connections between different brain regions and the corresponding changes in these connections in the diseased brain. Another important technique is diffusion tensor imaging (DTI), which measures the diffusion of molecules, mainly water, in biological tissues. By imaging the limited diffusion of water within white matter tracts, DTI can be used to examine anatomical connections between different parts of the brain as well as reveal white matter structural abnormalities. The combination of rsfMRI and DTI could provide new and valuable insights into the dynamic connectivity changes occurring in PD and could be useful to monitor disease progression, improve clinical diagnosis, monitor response to levodopa treatment, and promptly detect relevant brain changes in patients at risk of developing PD.
《Curriculum Vitae》
Epifanio Bagarinao is currently a project associate professor of the Brain and Mind Research Center, Nagoya University in Japan. Prior to joining the center, he was a research associate at the Systems Neuroscience and Pain Lab in the Division of Pain Medicine, Stanford University School of Medicine, where he worked on the development of a real-time fMRI system and its application to pain management.
He was also actively involved in the analysis of neuroimaging datasets from different pain-related studies including the use of machine learning algorithms to detect chronic pelvic pain and analysis of resting state functional MRI to characterize neuropathic pain. Previously, he worked at the National Institute of Advanced Industrial Science and Technology in Japan and did research on topics related to real-time functional MRI, advance medical applications of grid technology, pattern classification using support vector machines, and the use of nonlinear dynamics theoretic approach to time series analysis. Dr. Bagarinao obtained his Bachelor of Science in Applied Physics and Master of Science in Physics from the University of the Philippines in the Philippines and his Doctor of Science in Biophysical Engineering from Osaka University in Japan.
なおる神経内科 TN-06：Improvement in the management of Parkinson’s disease:
Present status and prospect of ultra-early diagnosis
5月19日（木） 15：15～17：15 第10会場(神戸国際会議場B1F・1F メインホール)
165
-なお る神 経内 科
座長：
赤松直樹(国際医療福祉大学 福岡保健医療学部)
松本理器(京都大学大学院医学研究科 てんかん・運動 異常生理学講座)
≪ねらい≫
世界に先駆けて本邦は超高齢者社会になりつつある．か つてJ字型といわれた発病率は，超高齢化社会となりU字型 となった．原因となる脳血管障害，認知症が増加し，また従 来潜因性と考えられた中に自己免疫機序のてんかんが明ら かになりつつある．若年者のてんかんに比して，高齢者てん かんは，少量の抗てんかん薬でコントロール可能な群が存在 する一方，初発の発作がてんかん重積で治療に苦慮する症例 にも遭遇する．超高齢者社会として世界に発信できる，本邦 での高齢者てんかん診断と治療の最前線を，治るてんかんを 目指して，包括的に討議するシンポジウムを企画した．
共催：日本てんかん学会
TN-07-1
高齢者におけるてんかん診断上の留意 点：認知症との関連から
宇多野病院 神経内科
○木下真幸子
高齢者のてんかん発症率は高く，認知症はその重要な基礎疾患である．
A．高齢者のてんかん発作は，若年者と異なる特徴を持つ．けいれんを伴わないてんかん 発作の診断は一般に難しいが，特に高齢者では，単純部分発作を経ず突然に複雑部分発作を 生じる，明確な運動症状を欠く，症状が軽微かつ多彩である，発作後のもうろう状態が長い，
非けいれん性重積を示すことがある，などの特徴がある．患者本人は症状を十分に把握して いないことが多いため，てんかん発作に特徴的な症状を，家族や周囲の人から積極的に聴取 する．記憶の障害が主訴である場合，それが意識障害（意識減損）と関連している可能性に十 分注意する．
B．てんかん発作を誘発する要因が多数存在する．てんかん閾値を低下させる薬剤が多数 知られている．急性症候性発作の原因となる種々の病態のうち，特に治療可能なものを鑑別 する必要がある．自己免疫介在性の脳炎・脳症では，原疾患の症状とてんかん発作による症 状とが混在し，さらに精神症状が前景に立つ場合は管理が非常に困難である．
C．発作間欠期に進行性の認知機能障害を呈する症例がある．小児のてんかんではてんか ん性脳症の概念が確立している：すなわち，てんかん性活動自体が重篤な認知・行動の障害の 原因となり，治療によりてんかん性活動を抑えると，発作予後だけでなく発達予後も改善し うる．成人においても抗てんかん薬加療により，類似の認知機能改善を認める例があるが，
逆に薬剤の副作用により認知機能が悪化する場合もある．成人難治部分てんかんでは，発作 焦点の近傍，および焦点と強い機能連関を持つ領域には脳機能低下が存在することが知られ，
主に外科的治療（てんかん焦点切除術）による改善例がある．
D．てんかんの合併により認知症はさらに悪化しうる．ヒトの変異型アミロイド前駆体タ ンパク質を過剰発現するマウスでは，アミロイドベータ(Aβ)の蓄積によりてんかん発作が 誘発され，さらに海馬の神経回路で生じる抑制性の代償反応により学習や記憶が障害されう るとの報告がある．加えて，過剰なシナプス活動・グルタミン放出によるNMDA受容体刺激 は，Aβの分泌を促進する．ヒトにおいても，プレセニリン1遺伝子変異による常染色体優性 遺伝アルツハイマー病患者では，てんかん発作発症群における海馬CA1の神経脱落が，非発 症群と比較し有意に強いことが報告されている．
《略歴》【現職】独立行政法人国立病院機構宇多野病院神経内科医長
【学歴】1996年3月 京都大学医学部卒業
2005年3月 京都大学大学院医学研究科博士課程卒業
【略歴】1996年3月 京都大学医学部卒業
1996年5月 京都大学医学部附属病院神経内科研修医 1997年4月 大阪府済生会野江病院神経内科医師 1999年4月 関西電力病院内科医師
2001年4月 京都大学大学院医学研究科博士課程入学 2005年3月 京都大学大学院医学研究科博士課程卒業
2005年4月 京都大学大学院医学研究科臨床神経学（神経内科）医員 2007年4月 独立行政法人国立病院機構宇多野病院神経内科（発作科）医師 2011年4月 現職
【学会資格】
日本神経学会専門医・指導医，日本てんかん学会専門医・指導医，
日本臨床神経生理学会認定医（脳波分野）
【受賞】2003年 第27回 国際臨床神経生理学会 Fellowship Award受賞 2004年 第34回 日本臨床神経生理学会学術大会 優秀ポスター賞受賞 2005年 第26回 国際てんかん学会 Young Investigator Award受賞 2007年 第41回 日本てんかん学会Juhn and Mary Wada奨励賞受賞 2008年 日本てんかん学会Sponsored Award受賞