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3 Table of Contents Introduction 05 Information 07 Program Feb 21 (Fri) 08 Feb 22 (Sat) 10 Feb 23 (Sun) 12 Abstract Feb 21 (Fri) 15 Feb 22 (Sat) 59 Feb 23 (Sun) 79 Acknowledgements

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6 Takamatsu Parkinson Disease Foundation President Mitsutoshi Yamamoto, MD, PhD Director, Takamatsu Neurology Clinic President, Takamatsu Parkinson Disease Foundation Co-President Nobutaka Hattori, MD, PhD Professor of Neurology Department of Neurology Juntendo University International Advisory Board David J Burn Newcastle upon Tyne Werner Poewe Innsburck Olivier Rascol Toulous Heinz Reichmann Dresden Anthony Schapira London EK Tan Singapore Louis Tan Singapore Eduardo Tolosa Barcelona Genjiro Hirose Kanazawa Shigeki Kuzuhara Mie Eldad Melamed Tel-Aviv Yoshikuni Mizuno Tokyo Ruey-Meei Wu Taipei The local organizing committee Chair Mitsutoshi Yamamoto Co-Chair Nobutaka Hattori Member Kazuko Hasegawa Kenichi kashihara Seiji Kikuchi Jun-ichi Kira Sadako kuno Yasuyuki Okuma Norihiro Suzuki Ryousuke Takahashi Atsushi Takeda Hidehiro Mizusawa Miho Murata Hirohisa Watanabe Fumihito Yoshii Yoshio Tsuboi Operating committee Chair Hirohisa Watanabe Member Masaaki Hirayama Tadashi Ichikawa Katsuo Kimura Ryouichi Kurisaki Tetsuya Maeda Suguru Nishida Hidemoto Saiki Kazuto Yoshida - 6 -

7 Information Registration Information Registration: on-site only available Pre-registration is appreciated. No discount for pre-registration is available Registration Times: Registration Fee: Feb 21(Fri) 08:20-18:40 Feb 22(Sat) 08:30-17:30 Feb 23(Sun) 08:30-15:40 Until January31 Until February10 Onsite Medical student free free 3,000 Trainee/Co-medical 5,000 6,000 7,000 Neurologist 15,000 20,000 25,000 Non-professionals 20,000 25,000 30,000 Notice to Speaker and Chair (presentation material) Your presentation can be pre-checked and accepted in PC desk located in 6th floor on conference hall. Internet Service A wireless internet service is available. Official Language is English (Day1,2) Social event Reception: 18:30-20:30 free of charge on Feb. 21, 2014 Mykeila near congress venue 5 minutes walk Symposium dinner: 20:00-22:00 at Japanese restaurant Ryoutei Ni-cho Seats is still available ( 10,000JPY) Notice Recoding and Photos are strictly prohibited. The eating and drinking in the hall is prohibited. (Only the PET bottle can be brought in.) - 7 -

8 Day 1: Feb. 21 (Fri) Program Plenary Session : Atypical parkinsonism Chair M.Yamamoto & W.Poewe 08:20-08:30 Opening remarks & welcome speech M. Yamamoto 08:30-09:00 What is atypical parkinsonism? W.Poewe 09:00-09:30 The definition of PD E.Tolosa 09:30-10:00 Aging and parkinsonism H.Reichmann 10:00-10:30 Parkinsonism in CBS and PSP S.Murayama 10:30-11:00 coffee break Chair H.Watanabe & H.Reichmann 11:00-11:30 Parkinsonism in MSA T.Shimohata 11:30-12:00 Parkinsonism in AD D.J.Burn 12:00-12:30 Parkinsonism and dystonia R.Kaji -Molecular dissection of X-linked Dystonia-Parkinsonism 12:30-13:00 Parkinsonism in SCA T.Matsuura 13:00-13:30 Lunch Chair Ruey-Meei Wu & R.Bhidayasiri 13:30-14:00 FTD and parkinsonism Ruey-Meei Wu 14:00-14:30 Drug-induced parkinsonism E.Melamed 14:30-15:00 Vascular parkinsonism R.Bhidayasiri - 8 -

9 15:00-15:30 Idiopathic normal pressure hydorocephalus EK.Tan 15:30-16:00 Psychogenic Parkinsonism E.Tolosa 16:00-16:20 coffee break Chair H.Mizusawa 16:20-16:50 Re-classifying Parkinson`s disease by neuroimage S.Hirano Chair N.Hattori 共催セミナー : 日本メジフィジックス 16:50-17:30 DAT scan in parkinsonism W.Poewe Chair J.Kira 17:30-18:10 Treatment strategy for MSA and neurodegenerative parkinsonian syndromes O.Rascol 18:40- Reception free of charge Welcome speech by The Governor of kagawa prefecture Mr.K.Hamada - 9 -

10 Day 2 : Feb.22 (Sat) Program Education session : Hot topics Hot topics Chair R.Takahashi & R.Wu 共催セミナー : 協和発酵キリン (08:30-09:30) 08:30-09:00 Premotor symptoms in MSA H.Watanabe 09:00-09:30 Premotor symptoms in PD K.Takahashi 09:30-10:00 Genetics in MSA J.Mitsui 10:00-10:30 Biomarker in PD T.Tokuda 10:30-11:00 coffee break Emergency in PD Chair F.Yoshii & T.Toda 11:00-11:30 The phenomena and their management E. Melamed 11:30-12:00 Acute confusional state K.Kashihara 12:00-12:30 Management at general surgery L.Tan Chair D.Burn Luncheon seminar 共催 : 日本ベーリンガーインゲルハイム 12:30-13:30 Hyposmia and cholinergic deficiency in Parkinson Disease A.Takeda Video session Chair Y.Mizuno & W.Poere 13:30-15:30 Video session Part1:by travel awards Part2:by experts 15:30-16:00 coffee break

11 How to Academic works Chair G.Hirose & O.Rascol 16:00-16:30 How to write English paper H.Otsubo 16:30-17:00 How dose editor treat submitted paper? D.J.Burn / EK.Tan 17:00-17:30 How to make an effective presentation H.Otsubo 17:30 Closing remarks N.Hattori

12 Japanese Session Day 3 : Feb.23 (Sun) Program Advances in PD Chair S.Kuzuhara & K.Nakajima 08:30-09:00 PD dementia update H.Mori 09:00-09:30 PD depression : update H.Nagayama 09:30-10:00 Why do PD patients fall? Y.Okuma 10:00-10:30 coffee break Chair H.Tachibana & S.Orimo 10:30-11:00 Rehabilitation in PD from walking to speech : the state of the art T.Ichikawa 11:00-11:30 Excersie and cognition in PD and AD R.Kurisaki Chair Y.Tuboi 共催セミナー : ノバルティスファーマ 11:30-12:00 Pathogenesis in PD : update T.Hatano Chair K.Yoshida Luncheon seminar 共催 : グラクソ スミスクライン 12:00-12:40 Pathogenesis of dyskinesia M.Tomiyama Chair G.Hirose 共催セミナー : 日本メドトロニック 12:40-13:10 DBS in PD : update H.Saiki Chair K.Hasegawa 共催セミナー : 大塚製薬 13:10-13:40 Dopamine withdrawal syndrome Y.Shimo Chair Y.Okuma 共催セミナー : 大日本住友製薬 13:40-14:10 How can we do individual treatment in PD? M.Murata

13 Chair T.Maeda 14:10-14:40 Guideline in the practice M.Hirayama 14:40-15:40 Video session K.Hasegawa & Y.Okuma 15:40 Closing remarks H.Watanabe M.Yamamoto

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15 International Parkinson s Disease Symposium in Takamatsu 2014 February 21 Abstract

16 Feb.21 08:30-09:00 What is Atypical Parkinsonism? Werner Poewe Dept of Neurology, Innsbruck Medical University The term Atypical Parkinsonism is being used to describe a heterogeneousgroup of neurodegenerative conditions, where the clinical motor syndrome of parkinsonism is associated with additional clinical features not typically seen in classical idiopathic Parkinson s Disease (PD). The textbook listings of the atypical parkinsonian disorders usually include the Multiple System Atrophy (MSA) and Dementia with Lewy Bodies (DLB) which like PD are associated with synuclein pathology, as well as Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), where tau-positive neuronal inclusions are the pathological hallmark. The clinical qualifyer of atypical features, however, maybe imperfect for several reasons: first, some atypical features used to distinguish these conditions from PD may also occur in post-mortem confirmed PD including early severe dementia, autonomic dysfunction, dystonia and poor Levodopa response (Hughes et al., Brain, 2002). Second, some patients suffering from one of these types of atypical parkinsonism may not show any of the defining atypical features. This is best exemplified by the parkinsonian variants of MSA or PSP which can be associated with a sustained meaningful response to Levodopa. In addition, PSP-P patients may show classical rest tremor and a rather benign course of disease progression with absence of early falls and supranuclear gaze palsy,mimicking the clinical signature of PD. Likewise, MSA-P patients may present with asymmetric or even unilateral parkinsonism without significant autonomic dysfunction. These typical-pd-look-alike presentations are the prime source of diagnostic difficulty in atypical parkinsonism. Finally, DLB in particular does not have any features which in themselves are at all atypical for PD. In fact, everything listed in the

17 clinical diagnostic criteria is also a classical symptom in PD dementia, such that the only clinical anchor of DLB is the timing of dementia diagnosis relative to the diagnosis of parkinsonism (i.e. the one-year-rule ). Nevertheless, classifying certain features, drug-responses and modes of progression as atypical for PD is highly useful for alerting clinicians to consider or reconsider initial diagnostic classifications and to plan diagnostic work-up. Misclassifications of patients with degenerative parkinsonian disorders will, however, continue to occur particularly in early disease stages - until there are sensitive and specific biomarkers enabling secure discrimination between these conditions

18 Feb.21 09:00-09:30 The definition of Parkinson Disease Eduardo Tolosa, MD Parkinson disease definition: An insidious unilateral onset of bradykinesia, rigidity and rest tremor between ages of 30 and 85 years. Mild male preponderance,no more than one affected first degree relative. Spread to involve other side within 3 years, but disability remains asymmetrical throughout. Good sustained response to l-dopa with eventual emergence of psychomotor fluctuations and dyskinesias. Increasing gait, balance and speech problems after 5 years disease Death on average 14 years after diagnosis (may be over 30 years in young-onset cases). Whether presence of Lewy bodies in the central nervous system or the presence of certain non motor symptoms are part of the definition of Parkinson disease is a matter of debate which I will discuss in my presentation

19 Bioskech Prof. Eduardo Tolosa MD, February 2014 FRCP Eduardo Tolosa obtained his MD degree from the University of Barcelona and received his neurological training at the University of Minnesota Hospital in Minneapolis. He is Professor of Neurology at the University of Barcelona and Director of the Parkinson Disease Research Program at the University of Barcelona Hospital. He is a founding member and past president of the Movement Disorder Society. He is also past president of the European Neurological Society. Prof. Tolosa was certified as a neurologist by the American Board of Neurology and Psychiatry and is currently a Fellow of the American Academy of Neurology, the American Neurological Association and the Royal College of Physicians. He is the recipient of the American Academy of Neurology 2014 Movement Disorders Research Award. Professor Tolosa s research interests are in movement disorders and particularly in issues related to experimental therapeutics, etiology and pathophysiology of various Parkinson syndromes. In the area of experimental therapeutics, he was involved in pioneering studies defining mechanisms underlying levodopa-related motor fluctuations, and his team has been among the first in Europe to evaluate the efficacy of novel surgical strategies for Parkinson s disease, such as subthalamic nucleus stimulation, subcutaneous dopamine agonist infusions and intraduodenal infusions of levodopa. Other areas of current research include assessment of non-motor symptoms in asymptomatic carriers of Parkinson-associated genetic mutations and the role of neuroimaging in early detection of Parkinson disease

20 Feb.21 09:30-10:00 Aging and Parkinson s disease Heinz Reichmann, MD, PhD, FRCP, FAAN Director of Department of Neurology, Technische Universitaet Dresden, Fetscherstrasse 74, D Dresden Heinz.Reichmann@mailbox.tu-dresden.de The most important risk factor for the development of Parkinson s disease (PS) is aging. With increasing age, more and more individuals develop a Parkinson syndrome. Thus, the question arises whether PS is an abnormal aging process of the brain. Until now, most neuroscientists claim that the cellular mechanisms which are responsible for ageing of midbrain dopaminergic neurons, are not related to those which cause dopamine neuron degeneration in Parkinson s disease (PD). In contrast, other studies in non-human primates suggest that ageing induces a pre-parkinsonian state and that the degeneration of dopaminergic neurons in PD patients is only an accelerated form of ageing; they imply that all of us would suffer from PD if we only lived long enough. There is also increasing evidence that there are more than 30 gene constellations which put an individuum at risk of developing PD. Several mechanisms of accelerated cell death have been described so far, in particular RNA oxidation is more frequently observed in vulnerable neurons at an early-stage of age-related neurodegenerative disease. In contrast to normal ageing, PD patients show more alpha-synuclein accumulation in the basal ganglia and in other regions of the central and enteric nervous system. Interestingly, alpha-synuclein accumulation is infrequently seen in normal ageing brain. Some people assume that in PD patients there may be insufficient compensatory mechanisms in vulnerable brain regions, which discriminates patients with the full picture of PD from those with only Parkinsonian features such as slow gait. Clinically, there are several interesting features which might help to distinguish normal ageing from PD. The rate of progression of white matter hyperintensities is slower in the MRI of normal old individuals compared to those with PD. Whilst the annual decrease in striatal dopamine receptor binding is approximately 0.5% in normal old

21 people, it is much higher (5%) in patients with PD. Life expectancy of PD patients is only mildly reduced compared to an age-related control group. Clinically, it is rather intriguing that the decline in olfaction is faster in PD than in normal ageing. This observation correlates well with the abundance of alpha-synuclein in the olfactory bulb of normal people and patients with PD. There is a strong correlation between hyposmia or anosmia and the development of PD. There is also a significant difference, when non-motor symptoms which occur in most PD patients, are compared to age-matched controls. Non-motor symptoms are very common both in the healthy elderly and in PD patients. A significantly higher prevalence of non-motor symptoms (sexual function, perceptual problems/hallucinations, fatigue and mood changes) is observed in PD patients. Since PD is a movement disorder and physical mobility is reduced in the elderly, it is also of interest that PD patients present with step length asymmetry and increased co-activation of agonists and antagonists when walking or performing arm motor skills. This might also indicate that patients with PD lack compensatory mechanisms in their motor and pre-motor cortex which are still available to age-matched controls. A large body of literature covers neuropsychological differences between normal old people and PD patients. For example, PD patients are less able to learn new tasks. Impairments of word identification, of the number of words used and other speech abnormalities are well documented. Decision-making and executive functions (Wisconsin card sorting test) are major problems in PD patients. It is rather interesting that the theory of mind is highly impaired in PD patients which might also contribute to their social isolation in late stages of the disease. Although both controls and PD patients prefer familiar tasks to new ones, PD patients do so even more. There is also good evidence that PD has a major impact on error processing. In conclusion, these selected examples confirm that there is a major and significant difference between normal aging and PD

22 Heinz Reichmann, MD, PhD, FRCP, FAAN biosketch Heinz Reichmann MD PhD graduated from the University of Freiburg, Germany in He spent the following four years as a research fellow at the Institute for Biochemistry, University of Konstanz, Germany and the Institute of Neurology, Columbia University, USA. This was paid for by honorary grants for excellency to Dr. Reichmann. He returned to Germany where he held a number of positions at the University of Würzburg, becoming Professor of Neurology in In 1996, he was appointed Chairmann of the Department of Neurology at the University of Dresden, where he is now also Dean of the Medical Faculty. Heinz Reichmann is a member of numerous scientific societies including the German Neurological Society, the European Neurological Society, the American Academy of Neurology, the Royal Society of Medicine and the Movement Disorder Society. In addition, Dr Reichmann serves on the editorial boards for a number of prestigious neurology journals. His major research interests are energy metabolism, neuroprotection, premotor symptoms in Parkinson s disease, etiopathogenesis and treatment in PD. He serves on many Neurological Boards and was President of the German Parkinson Society and the German Muscle Society. In 2009 Professor Reichmann started his 2-year term as President of the German Neurological Society. He is Past-President of the European Neurological Society and has helped to initiate the new European Academy of Neurology, starting from

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24 Feb.21 10:00-10:30 Atypical Parkinsonism: CBD and PSP Shigeo Murayama M.D. Ph.D. Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) are categorized into atypical Parkinsonism. Pathological diagnosis of typical cases with these two disorders are relatively easy, based on the presence of either tuft- shaped astrocytes or astrocytic plaques. However, atypical cases may require immunoblot of tau or mutation analysis of tau gene. Both of these molecular pathological studies are now included for new pathological diagnostic criteria of CBD/ PSP. Clinical aspects has also been causing confusion and clinical and pathological mismatch is frequent. Typical clinical presentation of PSP is now called Richardson syndrome (RS) and that of CBD, corticobasal syndrome (CBS). Less than 50% of clinical CBS proved to be pathological CBD. Subtypes of PSP included RS, CBS, pure akinesia (PA), cerebellar type (CE), progressive non- fluent aphasia (PNLA), frontotemporal dementia behavioral variant (FTD-bv) and senile dementia (SD). Subtypes of CBD also included all of the above, except for PA and CE. There is no definite differential diagnostic criteria for CBD and PSP at this point. PSP/ CBD brain banks are established in Mayo Clinic Jacksonville in collaboration with Cure PSP by Professor Dennis Dickson and accumulated more than 1,000 cases of PSP and 300 cases of CBD. These bioresources are useful for biochemical and molecular studies. However, they have very few correlations with biomarkers and neuro- images. We Japanese have susceptible subtypes of tau gene for PSP and racial background could be important in this field. In order to conquer these problems, we are going to start accumulating biomarker samples of clinically suspected CBD/ PSP cases in collaboration with Japanese Society of Neurology (JALPAC). In addition, with the leadership of National Institute of Radiation Research (NIRR), we are also going to run histopathological studies of Tau- PET together with MRI and amyloid PET studies

25 Biosketch Dr.Sigeo Murayama,MD,PhD Graduate from the Faculty of Medicine, the University of Tokyo (UT) Ph.D. of UT: Immunocytochemical and ultrastructural studies of Pick s disease Medical Board, State of North Carolina (UNC, Professor Kinuko Suzuki) Chairman, Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology (TMGHIG) Director, Brain Bank for Aging Research, TMGHIG PI, Japanese Brain Bank Network for Neuroscience Research Chairman, Department of Neurology and Bio- resource Center, TMGHIG

26 Feb.21 11:00-11:30 Multiple system atrophy: Prognosis, sleep disturbance, and sudden death Takayoshi Shimohata, Masatoyo Nishizawa Department of Neurology, Brain Research Institute, Niigata University Multiple system atrophy (MSA) is an adult-onset neurodegenerative disorder characterized by diverse clinical symptoms including cerebellar ataxia, Parkinsonism, and autonomic dysfunction. In this session, we would like to discuss the mean survival time and prognostic factors, clinical features of the sleep disturbance, and mechanisms of sudden death in MSA. 1. Mean survival time and prognostic factors in MSA Several studies, including prospective studies, have revealed that the mean survival time in MSA is 7 10 years. However, some patients survive for more than 15 years, suggesting the existence of a benign subgroup. Autonomic dysfunction and respirator therapy might be prognostic factors. 2. Clinical features of sleep disturbance in MSA MSA patients develop various types of sleep disturbance including sleep deprivation, REM sleep behavior disorder (RBD), and restless legs syndrome (RLS). They also develop sleep-disordered breathing (SDB) caused by upper airway obstructions not only at the vocal cords but also at the soft palate, the base of the tongue, the arytenoid, and the epiglottis. These sleep disturbances cause excessive daytime sleepiness. 3. Mechanisms of sudden death in MSA Tracheostomy and non-invasive positive pressure ventilation (NPPV) do not always prevent sudden death in patients with MSA. We judged that there are multiple mechanisms of sudden death, including choking during sleep, central respiratory disturbance, upper airway obstruction associated with NPPV, and cardiac autonomic

27 disturbance. To prevent sudden death, early detection of food stagnation within the esophagus, respirator therapy, and discontinuation of NPPV in patients with floppy epiglottis might be beneficial

28 Biosketch Takayoshi Shimohata, M.D., Ph.D., FAAN Address (Work) Department of Neurology, Brain Research Institute, Niigata University Asahi-machi-dori Niigata, Niigata , Japan Phone: Fax: EDUCATION and PROFESIONAL TRAINING 1992 M.D. Niigata University, Medical School, Niigata, Japan Japanese Medical License Registration (No ) Medical intern in Department of Internal Medicine and Department of Neurology, Niigata University Medical Hospital, Japan 1993 Medical intern in Department of Internal Medicine, Shimotsuga Hospital, Tochigi, Japan 1994 Resident in Department of Neurology, Niigata University Medical Hospital, Japan Resident, Department of Neurology, Shinrakuen Hospital, Nigata, Japan 1995 Resident, Department of Neurology, Akita Red Cross Hospital, Akita, Japan Ph.D. course (Dr. of Medical Science) Niigata University, Medical School, Japan 1998 AAN member 2002 Research Associate, Department of Neurology, Brain Research Institute, Niigata University, Japan Visiting Assistant Professor, Department of Neurosurgery, Stanford University, USA 2007-present Associate Professor, Department of Neurology, Brain Research Institute, Niigata University, Japan MEMBERSHIPS American Academy of Neurology (Fellow) American Stroke Association Movement Disorder Society Society for Neuroscience Japanese Society of Neurology Japan Neuroscience Society

29 Japanese Society for Neurochemistry Japan Stroke Association HONORS & AWARDS 1999 Tsubaki Award for Research in Neurological diseases, Tsubaki foundation 2001 Naito Memorial Award for Research, Naito Foundation, presented at the 13 th Naito conferences on molecular biological approaches for intractable diseases (II) 2001 The 5 th Yujin Memorial Award, Yujin foundation 2002 Postdoctal fellowship of Japan Society of the Promotion of Science 2002 Erwin von Bälz Preis 2002, Boehringer Ingelheim 2003 Naito Memorial Award for Research, Naito Foundation, presented at the 15 th Naito conferences on molecular biological approaches for intractable diseases (III) 2009 Japanese Society of Neurological Therapeutics Award (Sleep medicine) 2010 Medical Award of The Japan Medical Association MAJOR RESEACH INTERESTS 1. Sleep disorders in neurodegenerative disorders (multiple system atrophy, Parkinson s disease) 2. Neuroprotection against cerebral ischemia

30 Feb.21 11:30-12:00 Parkinsonism in Alzheimer s Disease David J Burn (Newcastle upon Tyne, UK) The frequency of parkinsonism in Alzheimer s disease (AD) varies from 12-92%, according to reviews. This huge disparity reflects a number of factors. Many reports were written before the recognition of Dementia with Lewy Bodies (DLB) as a nosological entity. Previously, many patients with AD received typical neuroleptics to control neuropsychiatric symptoms and so drug induced parkinsonism is likely to have falsely elevated the prevalence, whilst it is only relatively recently that sodium valproate as a mood stabiliser has been acknowledged to cause drug-induced parkinsonism. Perhaps a more likely source of error is confusion over the interpretation of cortically mediated clinical signs such as apraxia and paratonic rigidity ( Gegenhalten ) as bradykinesia and extrapyramidal rigidity, respectively. Parkinsonism in AD may therefore be classified as following: 1. True parkinsonism in pathologically confirmed AD 2. False positive parkinsonism in AD (e.g. drugs, cortical signs) 3. Mixed pathology (i.e. Lewy bodies, vascular lesions) 4. AD phenocopies (e.g. Arg406Trp (R406W) missense mutations) In terms of genetic influences, presenilin 1 gene mutations, known to be causative for AD, are associated with marked heterogeneity in clinical phenotype, with parkinsonism well described as well as myoclonus, epileptic seizures, spastic paraparesis, and cerebellar ataxia being described. The Arg406Trp (R406W) missense mutation in the microtubule-associated protein-tau gene (MAPT) is a known cause of early-onset dementia. Various dementia phenotypes have been described, including an early-onset AD-like presentation and frontotemporal dementia with parkinsonism. Resting tremor is rarely encountered in the true parkinsonism of AD, with rigidity and bradykinesias most frequently reported. Gait disturbance is the next most common feature, although falls are less common than in DLB. The presence of extrapyramidal signs in AD is associated with a poor prognosis, including decreased survival, more

31 rapid rate of cognitive decline, higher rates of depression, and a greater likelihood of institutionalisation. The pathophysiological basis of parkinsonism in AD is unclear. Dopamine reuptake transporter imaging is regularly used clinically to differentiate AD from DLB, with reduced striatal tracer uptake noted in DLB but not in AD. Pathologically, nigral lesions vary from co-existing Lewy bodies (i.e. subtype 3 above), non-specific degenerative changes to no detectable lesions. Therapeutically, the main thing is to recognise that all that appears extrapyramidal is not necessarily so. Beware of false positives and drug-related effects in particular. Stopping offending medications or substituting with safer agents is important. L-dopa replacement has little or no benefit in managing the true parkinsonism of AD. David J Burn - Biopic David Burn is Professor of Movement Disorder Neurology at Newcastle University and Honorary Consultant Neurologist for Newcastle upon Tyne Hospitals NHS Foundation Trust. He is Director of the University s Institute for Ageing and Health, Director of Newcastle Biomedicine s Clinical Ageing Research Unit and a Senior NIHR Investigator. He qualified from Oxford University and Newcastle upon Tyne Medical School in His MD was in the functional imaging of parkinsonism. He runs the Movement Disorders service in Newcastle upon Tyne which provides a large regional service. He was a member of the International Movement Disorder Society Parkinson s Dementia Task Force (2004-6). He was Clinical Reviews Editor for the Movement Disorder Journal from January 2007 before taking on an Associate Editorial role in January Professor Burn was elected to the International Executive Committee of the International Parkinson and Movement Disorder Society in June 2009 and since June 2013 has been an Offier (Treasurer-Elect) of the Society. He has published over 200 articles on movement disorders in peer reviewed journals

32 Feb.21 12:00-12:30 Parkinsonism and dystonia -Molecular dissection of X-linked Dystonia-Parkinsonism Ryuji Kaji MD, PhD Department of Neurology, Tokushima University Graduate School of Medicine Lillian V. Lee MD Department of Health, Philippine Children's Medical Center Dystonia is defined as a syndrome of sustained muscle contraction frequently causing twisting, repetitive and patterned movements or abnormal postures. Much attention has been focused upon physiology of dystonia. Sensory trick is a maneuver which the patient uses for relieving symptoms by applying sensory input. Recent physiological studies indicate that dystonia is a disorder of matching proprioceptive sensory input with motor output. Its pathology has not been clarified, but has been hypothesized as localized in the motor loop including basal ganglia. DYT3 or X-linked dystonia-parkinsonism is a tragic disease affecting hundreds of Pilipino people. Its detailed pathology and the gene have recently been elucidated, providing a unique opportunity of relating dystonia to a specific pathology

33 Curriculum Vitae Name Ryuji Kaji MD, PhD 59 y.o. M Birth Date Nov 2 nd, 1954 Current Position: Professor and Chairman, Department of Neurology, University of Tokushima Graduate School of Medicine, JAPAN Address: office: Department of Neurology, Tokushima University Hospital Kuramotocho 2-5-1, Tokushima City, Tokushima , JAPAN phone fax kajkyoto@mbox.kyoto-inet.or.jp Education: 1979 Graduated from Kyoto University School of Medicine (M.D.) Residency in Neurology and Medicine at Tokyo Metropolitan Geriatric Hospital PhD course in Medical Science (1985, PhD degree) Post-doctoral fellow in Department of Neurology, Hospital of the University of Pennsylvania Positions: Visiting Professor of Neurology at the Hospital of the University of Pennsylvania Assistant Professor of Neurology at the Louisiana State University Medical Center Assistant, Department of Neurology, Kyoto University School of Medicine Lecturer, Department of Neurology, Kyoto University Graduate School of Medicine Current Position

34 Academic Societies Japanese Society for Neurology, Executive Board Committee Member Japanese Society of Clinical Neurophysiology, Executive Board Committee Member Member-at-large, International Federation of Clinical Neurophysiology (IFCN) Executive Committee (2000~06) Trustee, World Federation of Neurology (2007~2013) A corresponding member, American Neurological Association A clinical associate member, American Academy of Neurology Movement Disorder Society (Member of Financial Committee) Selected Publications 1. Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H. Mutations of optineurin in amyotrophic lateral sclerosis. Nature;465: Sato K, Sumi-Ichinose C, Kaji R, et al. Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia. Proc Natl Acad Sci U S A 2008;105: Goto S, Yamada K, Shimazu H, Murase N, Matsuzaki K, Tamura T, Nagahiro S, Kuratsu J, Kaji R. Impact of bilateral pallidal stimulation on DYT1-generalized dystonia in Japanese patients. Mov Disord 2006;21(10): Makino S, Kaji R, Ando S, Tomizawa M, Yasuno K, Goto S, Matsumoto S, Tabuena MD, Maranon E, Dantes M, Lee LV, Ogasawara K, Tooyama I, Akatsu H, Nishimura M, Tamiya G. Reduced neuron-specific expression of the TAF1 gene is associated with X-linked dystonia-parkinsonism. Am J Hum Genet 2007;80(3): Goto S, Lee LV, Munoz EL, Tooyama I, Tamiya G, Makino S, Ando S, Dantes MB, Yamada K, Matsumoto S, Shimazu H, Kuratsu J, Hirano A, Kaji R. Functional anatomy of the basal ganglia in X-linked recessive dystonia-parkinsonism. Ann Neurol 2005;58(1): Nodera H, Bostock H, Kuwabara S, Sakamoto T, Asanuma K, Jia-Ying S, Ogawara K, Hattori N, Hirayama M, Sobue G, Kaji R. Nerve excitability properties in Charcot-Marie-Tooth disease type 1A. Brain 2004;127(Pt 1): Kaji R, Murase N, Urushihara R, Asanuma K. Sensory deficits in dystonia and

35 their significance. Adv Neurol 2004;94: Biosketch Dr. Ryuji Kaji is Professor and Chairman of Department of Neurology at Tokushima University, Graduate School of Medicine, Tokushima, Japan. He has been one of the Trustees of WFN since Dr. Kaji received neurology and neurophysiology training (EMG) at the University of Pennsylvania and completed a movement disorders training course at the Kyoto University Hospital. His research interests have been focused on the study of pathophysiology, molecular genetics, and functional neuroanatomy of dystonia, especially those of lubag dystonia. As an electromyographer, he also developed a keen interest in motor neuron disease, and recently published a paper on a new gene causing ALS (OPTN)

36 Feb.21 12:30-13:00 Parkinsonism in SCA Tohru.Matsuura Spinocerebellar ataxias (SCA) are a group of heterogenous neurodegenerative diseases that may affect the cerebellum and its connections. Although the clinical spectrum of SCA is mostly characterized by progressive cerebellar ataxia, phenotypic variability has often been reported. Moreover, a wide range of non-ataxia features can be observed during disease progression. Among non-ataxia features, several types of movement disorders may be found in SCA, and are not uncommon. Almost all types of movement disorders can be detected in patients with SCA, and may be related to basal ganglia involvement. Up to this moment, 36 subtypes of SCA are known. The most common related movement disorders with SCA subtype are: myoclonus in SCA2 and SCA14; dystonia in SCA2, SCA3 and SCA17; eyelid dystonia in SCA3; chorea in SCA3 and SCA17; akathisia in SCA3; action tremor SCA12 and SCA27; palatal tremor in SCA20. Thus, the observed movement disorder, when present in combination with cerebellar ataxia, could point to the underlying SCA. Conversely, some patients with SCA may present with complex and unusual movement disorders. At this symposium, I will review the clinical and genetic characteristics of parkinsonism in SCA2, SCA3, SCA12, SCA17, SCA21 and fragile X-associated tremor/ataxia syndrome (FXTAS)

37 Tohru Matsuura, brief biosketch Instructor, Dept. of Neurology, Baylor College of Medicine, USA Assistant Prof., Dept. of Molecular & Human Genetics, Baylor College of Medicine, USA Associate Prof., Div. of Neurogenetics, Nagoya University Graduate School of Medicine, Japan Associate Prof., Dept. of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan 2013~ Professor, Div. of Neurology, Dept. of Medicine, Jichi Medical University, Japan

38 Feb.21 13:30-14:00 FTD and parkinsonism Ruey-Meei Wu Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan Frontotemporal dementia and parkinsonism (FTDP) is a major neurodegenerative syndrome, particularly for those with symptoms beginning before age 65. Sporadic or autosomal-dominant familial forms of FTDP have been associated with mutations in the microtubule-associated protein tau (MAPT) or progranulin (PGRN) linked to chromosome 17 (FTDP-17). Pathological mutations in MAPT cause the change of the ratio of tau isoforms and the ability of tau to bind with microtubules and to promote microtubules assembly. The brains of FTDP-17 patients are characterized by an atrophy of the frontotemporal cortex and basal ganglia and by a depigmentation of the substantia nigra. Histologically, it is characterized by cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau in neurons and glial cells the cortex, basal ganglia, brain stem and white matter (FTDP-17T). In contrast, patients with PGRN mutations have ubiquitin-positive cytoplasmic and intranuclear inclusions in neurons in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). The diagnostic criteria of FTDP are age at disease onset between the 3 rd and sixth decade, rapid disease progression, parkinsonism-plus syndrome, frontotemporal dementia, and behavioral disturbances. The motor symptoms include akinetic rigid parkinsonism without resting tremor and also dystonia, spasticity, supranuclear gaze palsy. Cognitive symptoms consist of impaired executive functions and non-fluent aphasia with a relative preservation of visuospatial orientation and common memory. Behavioural disturbance can be presented as impaired social conduct, hyperorality and hyperphagia, drug abuse, obsessive stereotyped behavior, apathy and psychosis. Several diseases are to be considered for differential diagnosis, including other types of FTD, Parkinson s disease with dementia, dementia with lewy bodies, Alzheimer s disease, Huntington s disease and prion disease. The therapy of FTDP-17 is only symptomatic and supportive. The response to levodopa is poor

39 WU, Ruey-Meei, MD, PhD Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan Dr. Ruey-Meei WU is Professor of National Taiwan University, Taipei, Taiwan, and Director of Centre of Parkinson s Disease and Movement Disorders at the department of Neurology, National Taiwan University Hospital (NTUH). She currently serves President of Parkinson Alliance of Taiwan ( ). Prof Wu is former Chair of the Neurology department at NTUH ( ) and funding president of Taiwan Movement Disorders Society ( ). She is organizer of 3rd Asian and Oceanian Parkinson s Disease and Movement Disorders Congress in Taipei in She served as Chair of Asian and Oceanian Section of The Movement Disorder Society from Dr Wu s research interests are clinical genetics, pharmacological therapy and non-motor symptoms of Parkinson s disease (PD). Her research group identified LRR2 G2385R and R1628P as risk factors for PD in Asian populations. She defined several susceptible genetic polymorphism and frequencies of autosomal dominant and recessive genes in early-onset or familial parkinsonism, for examples, LRRK2, parkin, DJ-1 and pink1 in Taiwanese ethnic Chinese population. Recently, she extends her research in the cognitive aspects in Parkinson and Dementia. Dr Wu has published more than 90 original articles in board reviewed international Journals. She currently serves as editorial board of Journal of Formosan Medical Association and Parkinsonism and Related Disorders. She is a corresponding member of American Neurological Association

40 Feb.21 14:00-14:30 Drug-induced parkinsonism Eldad Melamed, M.D. Neurology, Sackler School of Medicine Tel Aviv University, Tel-Aviv, Israel There are many etiologies causing signs and symptoms similar to those that occur in idiopathic Parkinson`s disease (ipd). In this context, drug-induced parkinsonism (DIP) is a common and important cause. There is a long list of chemical agents that can potentially generate pre- or postsynaptic, permanent or temporary DIP. These include molecules such as MPTP and the manganese-containing Ephedrone and dopamine receptor blocking neuroleptics (phenothiazines,butyrophenons and substituted benzamides), anticonvulsants (valproic acid), calcium channel blockers (flunarizine, cinnarizine), and antihypertensive dopamine depletors(reserpine, tetrabenazine). Of the above,neuroleptics most commonly cause DIP. Its emergence is directly related to duration, daily dosage,strength(affinity to the receptors),and probably also to yet undetermined genetic traits. Diagnosis of DIP and its differentiation from ipd are sometimes difficult.clinically, DIP is expected to be more symmetrical than ipd but in a certain percentage of patients, it can be asymmetrical. It is not generally manifested by axial motor problems such as postural instability,festinations and freezing of gait. There can be particular tremor types such as "rabbit" lip tremor. DIP may be commonly associated with akathysia (in early cases mainly) and in more chronic cases, with tardive dyskinesia.use of imaging techniques (eg F-18 levodopa PET or dopamine transporter SPECT) may be helpful in differentiating ipd from DIP. Asymmtrical loss of isotope tracer from putamen and caudate is more likely to occur in presynaptic ipd. By contrast, preservation of basal ganglia dopaminergic integrity is expected to occur in postsynaptic DIP. In most cases, DIP slowly (typically within weeks or months because of protracted washout) subsides and even totally disappears after discontinuation of the offending neuroleptic. However,in some, the clinical parkinsonian manifestations persist and even progress,suggesting unmasking and exacerbation of underlying subclinical ipd by the treatment. In a similar manner, in some patients with advanced ipd who develop severe psychosis, especially with delirium,psychomotor agitation and aggression, there is no

41 therapeutic alternative but to administer classical neuroleptics. Such patients may rapidly deteriorate and even go into a parkinsonian crisis, due to the additional development of DIP.A management problem that frequently arises is the inability to stop the original antipsychotic drug treatment because of ongoing persistent psychosis.in such cases it is advisable to switch therapy to "atypical" neuroleptics such as clozapine or quetiapine that do not or only rarely cause DIP. Theoretically,the regular antiparkinsonian dopamine replacing therapy that is so effective in ipd, should not work in DIP because the striatal postsynaptic dopamine receptors are occupied by the high affinity neuroleptic agent. There is also concern that such treatment may cause worsening of the basic psychiatric illness.however, there is an increasing recent evidence indicating that administration of levodopa can be beneficial in ameliorating the motor signs and symptoms without exacerbation of the psychiatric status. As to primary prevention of DIP, it was believed that this can be achieved by coadministration of the neuroleptic agent with anticholinergic drugs or amantadine, but there is no available convincing evidence. The problem is likely to disappear with increasing use of atypical neuroleptics in the treatment of various psychiatric disorders

42 Professor Eldad Melamed, M.D- Brief C.V Professor and Chairman- Department of Neurology, Rabin Medical Center- Beilinson Campus, Petah Tiqva, Israel( ) Professor of Neurology- Sackler School of Medicine, Tel Aviv University, Tel Aviv Head-The Norma and Alan Aufzien Chair for Research in Parkinson s disease, Tel- Aviv University, Sackler School of Medicine( ) President- Israel Neurological Association ( ) Chairman - Advisory Board, Israel Parkinson s Disease Association ( ) Member- Scientific Advisory Board, Michael J. Fox Foundation for Research of Parkinson s Disease (2003) Founder- Brainstorm Cell Therapeutics Ltd. (2005) Elected -Honorary Member of the Movement Disorder Society (2007) Graduated with M.D. degree (1968)- Hebrew University and Hadassah Medical School, Jerusalem, Israel Residency in Neurology ( ), Department of Neurology, Hadassa University Hospital, Jerusalem Postdoctoral fellowship in Cerebral Blood Flow, National Hospital, Queen' s Square, London, England and Bispebjerg Hospital, Copenhagen, Denmark (1976) Postdoctoral Fellowship in Neurochemistry and Neuropharmacology, Massachusetts Institute of Technology, Cambridge- Boston, U.S.A ( ) Sebulsky - Royce Professor of Neurology, Hadassah Hospital and Hebrew University, Jerusalem (1983) Visiting Professor, Movement Disorders, King's College, London, England (1986) Visiting Professor, Mount Sinai School of Medicine, New- York, U.S.A (2002)

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44 Feb.21 14:30-15:00 Vascular parkinsonism Roongroj Bhidayasiri, MD, FRCP, FRCPI. Chulalongkorn Center of Excellence on Parkinson Disease & Related Disorders, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, 10330; and Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles 90095, USA Vascular parkinsonism (VP) is probably a heterogeneous clinical entity. Over the last 50 years, there has been continuous debate regarding the boundary of clinical syndromes that constitute this entity. In practice, the associations between parkinsonism and cerebrovascular disease (CVD) can occur in several settings. First, gait disorders of the lower body parkinsonism occur as a result of white matter lesions in the frontal lobes. Second, white matter lesions are frequently present in cases with typical clinical presentations of Parkinson s disease. Third, symptoms of parkinsonism occur in the presence of MR findings of VP. Fourth is the clinical presentation of hemiparkinsonism associated with contralateral basal ganglia lesions. While clinical associations seem to be common, CVD is confirmed at autopsy as a cause of parkinsonism in only 1-3% of cases posing the fact that cases of pure VP without evidence of Lewy body pathology is probably rare. Although structural imaging favored the presence of vascular involvement in more than one vascular territory as a supportive radiological feature of VP, the findings on functional imaging studies have been inconclusive. Due to marked clinical heterogeneity and a lack of consensus criteria, therapeutic approach seems to be individualized with observable levodopa responses only demonstrate in some. In this presentation, the focus will be on the current understanding of VP in clinical practice with a particular emphasis on gait and balance disorders

45 Abridge Biography: 2014 Roongroj Bhidayasiri, MD, FRCP, FRCPI. Director and Associate Professor of Neurology, Chulalongkorn Comprehensive Movement Disorders Center, Chulalongkorn University Hospital, Bangkok; Thailand Visiting Associate Professor of Neurology; Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, USA. Graduated in medicine at Chulalongkorn University in Received the membership of the Royal College of Physicians of London and Ireland in 1998 and certified by the American Board of Psychiatry and Neurology in Awarded the fellowship of the Royal College of Physicians of London in 2008 and the Royal College of Physicians of Ireland in Dr. Bhidayasiri s major interest is in movement disorders, particularly the clinical aspects and advanced therapeutics of Parkinson s disease and dystonia. Importantly, he leads a Parkinson s disease registry in Thailand in collaboration with the Thai Red Cross society, the Ministry of Public Health, Bangkok Metropolitan and the National Health Security Office of Thailand and chairs the scientific committee of the Parkinson s disease guideline in Thailand. Dr. Bhidayasiri has published over 80 articles in peer-reviewed journals in the field of movement disorders and 5 international textbooks in neurology. He also serves as a writing committee panel member of the American Academy of Neurology on the practice parameters of tardive syndromes. Dr. Bhidayasiri is the President of the Thai Parkinson s Disease and Movement Disorders Society and an educational committee member of the International Movement Disorder Society. He is a chair of the local organizing committee of the Asian Oceanian Parkinson s Disease and Movement Disorders Congress (AOPMC) which will be held in Thailand in November

46 Feb.21 15:00-15:30 Idiopathic normal pressure hydocephalus EK.Tan Idiopathic normal pressure hydrocephalus is a syndrome characterized by gait and cognitive impairment, and urinary incontinence. There is no elevated cerebrospinal fluid (CSF) pressure even though the ventricles are enlarged. Because of it varied clinical spectrum, the diagnosis may be delayed. CSF shunting helps in improving some of the symptoms in majority of the cases. External CSF drainage and spinal tap may also help in selecting patients for shunt surgery. The clinical presentation, differential diagnosis, imaging findings and clinical factors associated with surgical outcome will be discussed

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48 Feb.21 15:30-16:00 Psychogenic Parkinson disease Eduardo Tolosa MD 13 th International Parkinson disease Symposium Takamatsu 2014 Parkinsonism can be psychogenic, and psychogenic parkinsonism is about 10% of psychogenic movement disorder patients. Patients can present with any feature or combination of features of organic Parkinson s disease. There are clinical clues that can lead to the correct diagnosis, and laboratory testing with clinical neurophysiology or DAT (dopamine transporter) scanning can be helpful as well. Patients may have both organic Parkinson s disease and psychogenic parkinsonism, and this might be considered a psychologically induced aggravation of the organic disorder

49 Prof. Eduardo Tolosa MD, February 2014 FRCP Eduardo Tolosa obtained his MD degree from the University of Barcelona and received his neurological training at the University of Minnesota Hospital in Minneapolis. He is Professor of Neurology at the University of Barcelona and Director of the Parkinson Disease Research Program at the University of Barcelona Hospital. He is a founding member and past president of the Movement Disorder Society. He is also past president of the European Neurological Society. Prof. Tolosa was certified as a neurologist by the American Board of Neurology and Psychiatry and is currently a Fellow of the American Academy of Neurology, the American Neurological Association and the Royal College of Physicians. He is the recipient of the American Academy of Neurology 2014 Movement Disorders Research Award. Professor Tolosa s research interests are in movement disorders and particularly in issues related to experimental therapeutics, etiology and pathophysiology of various Parkinson syndromes. In the area of experimental therapeutics, he was involved in pioneering studies defining mechanisms underlying levodopa-related motor fluctuations, and his team has been among the first in Europe to evaluate the efficacy of novel surgical strategies for Parkinson s disease, such as subthalamic nucleus stimulation, subcutaneous dopamine agonist infusions and intraduodenal infusions of levodopa. Other areas of current research include assessment of non-motor symptoms in asymptomatic carriers of Parkinson-associated genetic mutations and the role of neuroimaging in early detection of Parkinson disease

50 Feb.21 16:20-16:50 Re-classifying Parkinson s disease by neuroimage. Shigeki Hirano, MD, PhD Abstract: Parkinson s disease (PD) is a heterogeneous disorder. Approximately 15 % of the PD patients enrolled in clinical trials with presynaptic dopaminergic imaging are assessed as a scans without evidence of dopaminergic deficits (SWEDDs). Among the multiple causes for cognitive decline in PD, cholinergic nerve loss and Amyloid deposition can be assessed by positron emission tomography (PET). The cholinergic deficit observed in PD with dementia patients is profound in the fronto-temporo-parietal regions and indicates that the cholinergic modifying therapy can be beneficial for the cognitive symptoms. Amyloid deposition is observed in the subset of PD patients which resembles the grey matter volume loss of Alzheimer s patients (Shimada H, et al. Mov Disord 2013). Substantial number of PD patients is misdiagnosed as atypical parkinsonism by autopsy findings. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), characterized by abnormal tau accumulation in the brain, are among those atypical parkinsonism that are often difficult to discriminate from PD in the early disease stage. Recently, we have developed a novel radiotracer called [ 11 C]PBB3, which enables us to detect abnormal tau deposition in vivo. (Maruyama M, et al. Neuron 2013) By using these state-of-the-art neuroimaging techniques, we are able to re-classify PD patients and improve the outcome of the future perspectives of clinical trials in PD patients

51 Biographical sketch Shigeki Hirano, MD, PhD Associate professor, Department of Neurology, Chiba University Hospital, Chiba, Japan Visitor researcher, Molecular Neuroimaging Program, Molecular Imaging Center (MIC), National Institute of Radiological Sciences (NIRS), Chiba, Japan Graduated School of Medicine, Chiba University (1998). Dept Neurology, Chiba University Hospital, residency training ( ) Institute of Neurology, University of London, Queen Square, diploma ( ) Dept Neurology, Chiba East National hospital, Resident. ( ) Graduate School of Medicine, Chiba University, doctorial course. ( ) Center for Neuroscience, Feinstein Institute for Medical Research, North shore university hospital, postdoctorial fellow. ( ) Dept Neurology, JR general hospital, consultant. ( ) Dept Neurology, Chiba University Hospital,research associate professor ( ), associate professor. ( present) Molecular neuroimaging program, MIC NIRS, visitor researcher in ( present)

52 Feb.21 共催セミナー : 日本メジフィジックス 16:50-17:30 DAT-scan in parkinsonism W. Poewe Dept. of Neurology, Innsbruck Medical University Idiopathic Parkinson s disease is the most common type of parkinsonism seen in clinical practice. Its classical motor symptoms, in particular bradykinesia and rigidity, closely correlate with nigrostriatal dopamine deficiency. When cardinal motor features are fully established and other supportive criteria for the diagnosis (including responsiveness to levodopa) are met a diagnosis is usually a straightforward clinical exercise. However, in routine clinical care misdiagnosis rates at first visit are high for parkinsonian syndromes and most difficulties arise with atypical tremor disorders, symptomatic parkinsonism, atypical parkinsonian disorders as well as, rarely, psychogenic parkinsonism. Imaging of the dopamine transporter using SPECT reveals a classical picture of predominantly putaminal striatal asymmetric tracer loss in idiopathic Parkinson s disease and other types of degenerative parkinsonism while it is normal in patients with parkinsonian symptoms due to other causes. Diagnostic specificity of DAT-SPECT imaging for differentiating degenerative parkinsonism from other types of tremor disorders is high and degenerative parkinsonism can be excluded by normal DAT-scan findings. In recent clinical trials using DAT-SPECT as a surrogate outcome between 6 % and 12 % of patients were found to display no DAT-SPECT abnormalities at baseline. The cause for this is related to a clinical misdiagnosis and there are no reports of any of these subjects (SWEDD s) to have converted to progressive degenerative parkinsonism over time. Other than differentiating non-parkinsonian tremor disorders from tremor dominant early Parkinson s disease DAT-SPECT has also been shown to be useful in correctly classifying patients with vague and unspecific signs of possible early degenerative parkinsonism. Symptomatic parkinsonism, in particular drug-induced parkinsonism can also be differentiated from idiopathic Parkinson s disease or atypical degenerative parkinsonism by the use of DAT-SPECT imaging, while the situation is slightly more complex in cases of vascular parkinsonism or cases with other types of structural basal

53 ganglia lesions. The most challenging scenario arises when it comes to differentiate idiopathic Parkinson s disease from atypical degenerative parkinsonism like MSA-P or PSP-P. All these conditions share a nigrostriatal denervation and thus produce reduced striatal DAT-binding. Our group has shown that using novel types of voxel-based analyses of DAT-SPECT images can enhance differential diagnostic performance even in this most difficult area of parkinsonian syndromes

54 Feb.21 17:30-18:10 Treatment strategy for MSA and neurodegenerative parkinsonian syndromes O. Rascol University of Toulouse, France One of the key clinical diagnostic criteria to differentiate Parkinson disease (PD) from MSA and other neurodegenerative parkinsonian syndromes like progressive supranuclear palsy (PSP) relies on the symptomatic response to levodopatherapy.: it is good in PD patients and poor in the others. Defining the good or poor quality of levodopa responsiveness remains however quite subjective, and in-between ambiguous and partial responses are common. Testing dopaminergic drugs to improve, at least partially, motor parkinsonian symptoms of MSA and PSP remains therefore a frequent first-line empirical therapeutic strategy, considering the absence of other efficacious alternatives It is difficult to assess in a given patient the usefulness of such dopaminergic medications on the long term, and to define the best dose offering some benefit without risking unnecessary side effects. No treatment can slow down the progressive worsening over time of neurodegenerative parkinsonian syndromes. In MSA, some symptoms, like those related to autonomic dysfunction including orthostatic hypotension and urinary dysfunction for example, can be managed with some efficacy using non-pharmacological and pharmacological interventions. But the level of evidence supporting such strategies is weak. Unfortunately, there are no efficacious medications to manage most of the other disabling symptoms contributing to the severe handicap of MSA and PSP patients, including ataxia, falls, cognitive impairment, oculomotor problems, dysarthria, dysphagia Multidisciplinary approaches combining pharmacological and non-pharmacological interventions (physiotherapy, speech therapy, palliative care and others) are used empirically to cope with patient s distress and minimize the burden of their caregivers

55 Recent progresses in our understanding of the pathophysiology of MSA and PSP, synucleinopathies and taupathies, have opened new perspectives towards novel targets for symptomatic and disease modifying therapeutic strategies. Several randomized clinical trials have been conducted to test such hypotheses in the last few years. Unfortunately, none of them have provided yet positive results

56 Bioskech Doctor Olivier Rascol is Professor of Clinical Pharmacology in Toulouse University Hospital since He obtained his MD in Neurology (Toulouse, 1985) and his PhD in Neurosciences (Paris, 1992). Dr Rascol is running the Toulouse Clinical Investigation Centre since 1994 and the Toulouse European Space Clinic since He is also running a Research Group on Motricity in the Research Unit INSERM U825 and is the coordinator of the French Reference Center for Multiple System Atrophy (Atypical Parkinsonism). Dr Rascol is the chair of the national network of the 56 French Clinical Investigation Centers since 2008 and the chair of the NS-Park Neurosciences Network of the French CIC since From 2011, Dr Rascol is now coordinating the National French Clinical Research Infrastructure Network F-CRIN. As a neuropharmacologist, Dr Rascol s main fields of interest are Parkinson s disease and movement disorders, drug development for Parkinson s disease and functional neuroimaging. Dr Rascol has been actively involved in the development of several marketed antiparkinsonian medications (ropinirole, rasagiline). He is currently running several research programs for disease progression and symptomatic management of PD (motor signs, dyskinesias and on-off problems, non-motor signs such as pain and sleep problems) with new dopaminergic (dopamine agonists, dopamine reuptake inhibitors, MAO-B inhibitors ) and non-dopaminergic (serotonergic, glutamatergic, alpha-adrenergic ) drugs in collaboration with several academic and industry research centres in the US and in Europe. He is acting in this field as an external advisor for French and European scientific organisations, patients associations, drug agencies and international pharmaceutical companies. He is at the board of the Evidence-Based Medicine MDS Task Force in charge of the continuous assessment of all antiparkinsonian treatments. He is involved in the process of editing French (HAS) and European (EFNS / MDS-ES) guidelines for the treatment of Parkinson s disease. As the chair of the French CIC Network and of the National F-CRIN Clinical Research infrastructure, Dr Rascol has been deeply involved within the last few years in the management and organisation of clinical research in France. Dr Rascol is member of several French and American neurological and pharmacological societies. He was the Secretary of the international Movement Disorders Society

57 ( ) and is a member of the WFN Research Committee on Parkinsonism and Related Disorders. Dr Rascol is chair of the European Section of the Movement disorders Society Dr Rascol is working or has worked as associate-editor for the Journal Fundamental and Clinical Pharmacology and is or has been a member of the editorial board of Lancet Neurology, Neurology, the European Journal of Neurology, the Journal of Neural Transmission, Evidence Medicine. Dr Rascol has published 350 articles in International Scientific journals (New England Journal of Medicine, Lancet, Lancet neurology, Annals of Neurology, Neurology, Archives of Neurology, Brain, Movement Disorders ). His H factor is 50. He has also been invited to give more than 250 lectures in various European, North and South American and Asian universities or national and international meetings. Prof. Olivier RASCOL, MD, PhD Departments of Clinical Pharmacology and Neurosciences CIC-1436/INSERM UMR825 Faculty of Medicine Purpan University UPS of Toulouse III 37 Allees Jules Guesde Toulouse, France

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59 International Parkinson s Disease Symposium in Takamatsu 2014 February 22 Abstract

60 Feb.22 共催セミナー : 協和発酵キリン 08:30-09:00 Premotor multiple system atrophy (MSA) Hirohisa Watanabe Background: Current diagnostic criteria for MSA focus on the combination of motor and autonomic manifestations. However, MSA patients often show isolated autonomic failure or motor symptoms in the early course of illness, and some patients may die during this premotor MSA phase. Design/Methods: We investigated 102 consecutive cases (54 men and 48 women) of pathologically confirmed MSA. The diagnosis of MSA was based upon the presence of α-synuclein- and Gallyas-positive glial cytoplasmic inclusions (GCIs), and GCIs were confirmed in all cases. The mean age at death was 65.5±7.4 years. The mean disease duration was 6.9±4.0 years. To investigate the pathological spectrum of MSA, we used the grading scales of the olivocerebellar (OPC) and striatonigral (SN) systems, as described previously (Jellinger, et al. 2005). We defined the patients with mild or no OPC and SN pathology and no evidence of clinical motor features as premotor MSA. Results: Six of the 102 cases (5 men and 1 women) showed extremely mild pathology in both the OPC and SN, but showed significant cell loss and gliotic changes in the dorsal motor nuclei of the vagus and ventrolateral medulla, the intermediolateral column of the thoracolumbar spinal cord, and Onuf's nucleus. Clinically, 4 of the 6 patients did not show cerebellar ataxia and parkinsonism, but showed >1 significant autonomic symptom (urinary symptoms, 4; orthostatic hypotension, 3; and respiratory symptoms, 2). These 4 patients showed shorter survival ( 2y) than the other MSA types and sudden death. Discussion/Conclusions: Recognition of premotor MSA patients who demonstrate sudden death prior to fulfilling the current diagnostic criteria for MSA is needed. We also discussed the characteristic findings in patients with mono system atrophy

61 Name: Hirohisa Watanabe, Sex: Male, Nationality: Japan Career Summary: 1993 Graduate from University of Mie (MD) 2002 Completed Nagoya University Graduate School of Medicine (PhD) 2009 Lecturer, Nagoya University Graduate School of Medicine 2013 Research Professor of Brain and Mind Research Center, Nagoya University

62 Feb.22 09:00-09:30 Premotor symptoms in PD Kazushi Takahashi Department of Neurology, Saitama Medical University, Saitama Non-motor symptoms are common in patients with newly diagnosed Parkinson s disease (PD), and some even predate the emergence of the classic motor features. The premotor phase of PD is characterized by several important non-motor features, including constipation, olfactory dysfunction, REM sleep behavior disorder (RBD), depression, etc. In addition, several reports link other non-motor symptoms such as excessive daytime sleepiness, color vision abnormalities, apathy, fatigue and central pain of PD as possible premotor features. We investigated 469 Japanese PD patients in our multicenter study (Keio Parkinson's Disease Database), using the Japanese version of the RBD screening questionnaire. Probable RBD was detected in 146 patients (31.1%) and the RBD symptoms of 53 patients preceded the onset of PD motor symptoms. The basis of this prodromal stage is that the pathological process related to Lewy bodies, may start outside of the substantia nigra. Therefore, a special focus is being put on non-motor symptoms, which are known to antecede motor symptoms of PD, as clinical premotor markers. With the probable exception of RBD, non-motor clinical markers can be sensitive for an impending diagnosis of PD, but these features are common and non-specific. The combination of non-motor clinical markers and more specific markers (e.g., imaging, biochemical or genetic markers) may achieve sufficient utility in PD diagnosis and prediction in future. As an example, in the protocol of PPMI (The Parkinson s Progression Markers Initiatives), the inclusion criteria of prodromal subjects is defined as follows; subjects must have at least one of the following characteristics: hyposmia and/or RBD, and confirmation of DAT (dopamine transporter) SPECT scan deficit (mild to moderate) similar to early PD subjects. It is essential to determine sensitivity, specificity, relative risk and predictive value with regards to the development of PD for each marker, alone as well as in combination. The most effective way to suffice these aims is a prospective longitudinal population-based study design

63 CURRICULUM VITAE February 2014 Kazushi Takahashi, M.D. Department of Neurology, Saitama Medical University, Education: Undergraduate: Keio University School of Medicine, Tokyo, Graduate: Keio University Graduate School of Medicine, Tokyo, Japan Professional Training and Employment: Resident, Department of Neurology,Keio University School of Medicine, Tokyo, 1992 Board Certified Neurologist by JSN Instructor, Department of Neurology,Keio University School of Medicine, Tokyo, Research Associate in Cerebrovascular Research Center, University of Pennsylvania,U.S.A Department of Neurology, National Hospital Organization Tokyo Medical Center, Tokyo A/P Department of Neurology,Keio University School of Medicine, Tokyo, Chief, Department of Neurology,Tokyo Metropolitan Neurological Hospital 2014-present Professor, Department of Neurology,Saitama Medical University, Saitama, Japan Academic Society: Movement Disorder Society American Academy of Neurology Society for Neuroscience U.S.A nternational Society for Cerebral Blood Flow and Metabolism Japanese Society of Internal Medicine Japanese Society of Neurology Japanese Society of Cerebral Blood Flow and Metabolism Research: Keio Parkinson's Disease Database Project (Japanese multicenter study) Non-motor symptoms in PD Neuroprotection against ischemic brain damage Being able to diagnose that a patient has PD at an earlier time point than is currently possible, would be allowed to introduce potential disease-modifying therapies at a time when it could have fundamental and long-lasting effects

64 Feb.22 09:30-10:00 Genetic in MSA Jun Mitsui Department of Neurology, Graduate School of Medicine, The University of Tokyo Multiple system atrophy (MSA) is a progressive neurodegenerative disease clinically characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although MSA has been defined as a nongenetic disorder until recently, several multiplex families have been described, indicating that strong genetic factors confer susceptibility to the disease. However, the pathogenic mechanisms underlying this disease remain unknown, making it difficult to develop effective therapies. Recently, whole-genome sequence analysis in combination with linkage analysis revealed that mutations in the COQ2 gene have been associated with familial MSA in two Japanese families. COQ2 encodes for an enzyme involved in the biosynthetic pathway of coenzyme Q 10 (CoQ 10 ). Indeed, CoQ 10 levels in frozen brain tissues from a patient with familial MSA carrying homozygous M78V-V343A in COQ2 were substantially lower than those of control subjects. To investigate the involvement of COQ2 variants in sporadic MSA, the mutational analysis of COQ2 to a Japanese series, a European series, and a North American series were further extended. Of the COQ2 variants, V343A was exclusively observed in the Japanese population. The allele frequency of V343A in Japanese MSA patients was significantly higher than that in Japanese controls (4.8% vs. 1.6%). Other than V343A, various rare variants in COQ2 were found in the case-control series. To determine the functional effect of each variant on CoQ 10 biosynthesis, functional complementation analysis by transforming the yeast coq2 null strain with non-mutated or mutated human COQ2 cdnas were carried out. According to the functional assays, nine variants were revealed to be deleterious. On combining all three case-control series, eight variants were identified in 758 MSA patients, whereas only one variant was found in 1,129 controls. Functionally impaired variants of COQ2 were associated with an increased risk of MSA

65 in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. Biographical sketch Education Faculty of Medicine, The University of Tokyo M.D Graduate School of Medicine, The University of Tokyo Ph.D Employment Resident, Internal Medicine, The University of Tokyo Hospital Resident, Internal Medicine, Mitsui Memorial Hospital Neurology, The University of Tokyo Hospital Neurology, Yokohama Rosai Hospital Neurology, The University of Tokyo Hospital Project Research Associate, Department of Neurology, The University of Tokyo Hospital Publications Mitsui J, Mizuta I, et al. Mutations for Gaucher disease confer a high susceptibility to Parkinson disease. Arch Neurol. 2009; 66: Sidransky E, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson s disease. N Engl J Med. 2009; 361: Mitsui J, et al. Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines. Am J Hum Genet. 2010; 87: Hashimoto Maeda M, Mitsui J, Soong BW, et al. Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease. Ann Neurol. 2012;71:84-92 Mitsui J, et al. Mutations in COQ2 in familial and sporadic multiple-system atrophy. N Engl J Med. 2013; 369:

66 Feb.22 10:00-10:30 Biochemical biomarkers for Parkinson s disease and related disorders Takahiko Tokuda, M.D. Department of Molecular pathobiology of Brain Diseases (Neurology), Kyoto Prefectural University of Medicine Parkinson's disease (PD) is a progressive and disabling neurodegenerative disorder, in which diagnosis, measurement of progression, and response to therapeutic intervention currently rely upon clinical observation. However, there remains a critical need for validated biomarkers to make diagnosis and evaluate disease progression and therapeutic responses. Definitive diagnostic tests and objective measures of progression would improve clinical management and would be useful in clinical trials to enroll adequate patients and monitor therapeutic effects. Biomarkers may also provide insight into pathogenesis, and might therefore suggest possible novel targets for therapeutic intervention. Over recent years, analysis of neuronal and other markers in cerebrospinal fluid (CSF) or plasma has become increasingly accepted as an aid for diagnosis of neurological disorders. There is ample biochemical, pathological, and genetic evidence that the metabolism of α-synuclein (α-syn) plays a crucial role in the pathogenesis of PD. We developed a specific ELISA system and found that PD patients had significantly lower α-syn levels in their CSF than the control groups. We then investigated the levels of α-syn oligomers in CSF using our own ELISA that can specifically detect α-syn oligomers. The levels of α-syn oligomers in CSF were higher in the PD group compared to the control group. The receiver operating characteristic (ROC) curve analysis showed a sensitivity of 75.0% and a specificity of 87.5%, with an area under the curve (AUC) of for the diagnosis of PD. Our results demonstrate that levels of α-syn oligomers in CSF can be a useful biomarker for diagnosis of PD. We have recently developed a proteomic profiling strategy for PD using mass spectrometry analysis for magnetic-bead-based enrichment of CSF proteins and

67 subsequent multivariate statistical analyses. Cerebrospinal fluid was obtained from patients with PD, multiple system atrophy (MSA), and other neurological diseases as controls. The samples were from the first cohort and the second cohort. CSF proteins were purified with C8 magnetic beads, and spectra were obtained by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. Support vector machine (SVM) methods are used to select features to classify diseases. By building a SVM classifier, 3 groups were classified effectively with good cross-validation accuracy. The model accuracy was well preserved for both cases, training by the first cohort and validated by the second cohort and vice versa. A proteomic pattern classification method can increase the accuracy of clinical diagnosis of PD and MSA. I would also like to review recent progress in biochemical biomarkers for PD and premotor PD in may talk

68 Biographical Sketch NAME: Takahiko Tokuda, M.D., Ph.D. ACADEMIC EDUCATION: Graduated Shinshu University School of Medicine (Matsumoto, Japan) with an M.D Obtained a Ph.D. (Dr. of Medical Science), Shinshu University School of Medicine RESEARCH AND PROFESSIONAL ACTIVITIES: Passed the Examination of National Board (Certificate No ) Entered Dept. of Neurology, Shinshu University School of Medicine, Japan Visiting Scholar, Dept. of Molecular Biology, Tokyo Institute of Psychiatry, Tokyo, Japan Postdoctoral fellow, Dept. of Pathology, New York University School of Medicine, USA Assistant Professor, Dept. of Neurology, Shinshu University School of Medicine, Japan Associate Professor, Dept. of Neuroplasticity, Division of Molecular and Cell Biology, Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine Assistant Professor, Dept. of Neurology, Kyoto Prefectural University of Medicine, Japan 2011-present Associate Professor, Dept. of Molecular Pathobiology of Brain Diseases (Neurology), Kyoto Prefectural University of Medicine, Japan BOARD CERTIFICATION: Jul 1988 Board Certified Member of the Japanese Society of Neurology (#1130) Sep 1990 Board Certified Member of the Japanese Society of Internal Medicine (#2123) Dec 1992 Fellow of the Japanese Society of Internal Medicine (#1953) Nov 2010 Certified Doctor, Japan Society for Dementia Research (#270) PROFESSIONAL AND SOCIETY MEMBERSHIPS: Membership: 1984 The Japanese Society of Neurology 1984 The Japanese Society of Internal Medicine 2000 The Japan Society for Dementia Research 2008 The Japanese Society of Neurological Therapeutics 2009 MDSJ (Movement Disorder Society, Japan) 2011 The Japanese Society of Normal Pressure Hydrocephalus Board Member 2009 Representative, The Japanese Society of Neurology 2010 Councilor, The Japan Society for Dementia Research 2012 Director, The Japanese Society of Normal Pressure Hydrocephalus MAJOR RESEARCH INTERESTS 1. Biomarkers for neurodegenerative diseases (Parkinson s disease and related disorders, Alzheimer s disease, ALS etc.) 2. Protein chemistry of biofluids and brains of neurodegenerative diseases 3. Drosophila models of familial ALS

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70 Feb.22 11:00-11:30 Emergencies in Parkinson`s disease:the phenomena and their management Eldad Melamed,M.D. Neurology,Sackler Faculty of Medicine Tel Aviv University Tel Aviv, Israel Parkinson`s disease (PD) is considered as a slowly progressive neurological disorder with gradual accumulation of motor and non-motor manifestations. Nevertheless,there are occasional emergency situations in PD patients that may become increasingly more frequent as the disease advances and disability deteriorates. Firstly,most common causes of Emergency Room (ER) admissions of these patients include acute infections (usually pulmonary or urinary), syncopal episodes due mainly to orthostatism,and fall-induced traumatic injuries, with or without fractures. Emergency states that can occur in PD patients include sudden,expected or unpredictable,pronloged parkinsonian crises (long-duration "off" periods). These may be due to a variety of causes e.g. infection,administration of inappropriate drugs that interfere with absorption and central action of levodopa,unjustified discontinuation of anti-pd treatment,trauma, surgery and anaesthesia.such episodes may lead to severe disability,various complications,and may even be life-risking.other emergencies include severe prolonged dyskinesias, and neuroleptic malignant-like syndrome mostly due to sudden withdrawal of levodopa.acute prolonged psychosis represents another common and important emergency.neurologists treating PD patients should be aware of these acute phenomena and be able to identify their causes and rapidly start therapeutic countermeasures.because surgery and anaestesia are a common trigger for the emergence of such problems, preventive preplanning of risk management and therapeutic adaptations should be performed before and following elective and,if possible, also acute procedures

71 Professor Eldad Melamed, M.D- Brief C.V Professor and Chairman- Department of Neurology, Rabin Medical Center- Beilinson Campus, Petah Tiqva, Israel( ) Professor of Neurology- Sackler School of Medicine, Tel Aviv University, Tel Aviv Head-The Norma and Alan Aufzien Chair for Research in Parkinson s disease, Tel- Aviv University, Sackler School of Medicine( ) President- Israel Neurological Association ( ) Chairman - Advisory Board, Israel Parkinson s Disease Association ( ) Member- Scientific Advisory Board, Michael J. Fox Foundation for Research of Parkinson s Disease (2003) Founder- Brainstorm Cell Therapeutics Ltd. (2005) Elected -Honorary Member of the Movement Disorder Society (2007) Graduated with M.D. degree (1968)- Hebrew University and Hadassah Medical School, Jerusalem, Israel Residency in Neurology ( ), Department of Neurology, Hadassa University Hospital, Jerusalem Postdoctoral fellowship in Cerebral Blood Flow, National Hospital, Queen' s Square, London, England and Bispebjerg Hospital, Copenhagen, Denmark (1976) Postdoctoral Fellowship in Neurochemistry and Neuropharmacology, Massachusetts Institute of Technology, Cambridge- Boston, U.S.A ( ) Sebulsky - Royce Professor of Neurology, Hadassah Hospital and Hebrew University, Jerusalem (1983) Visiting Professor, Movement Disorders, King's College, London, England (1986) Visiting Professor, Mount Sinai School of Medicine, New- York, U.S.A (2002)

72 Feb.22 11:30-12:00 Acute confusional state in Parkinson s disease Kenichi Kashihara, MD Department of Neurology, Okayama Kyokuto Hospital Patients with Parkinson s disease (PD) often fell in acute confusional state. Variety factors which induce acute brain dysfunction or chronic organic brain pathology may cause confusion in PD patients. These factors may be classified into several groups; direct PD-related morbidity, indirect PD-related morbidity such as bone fracture, pneumonia, and ileus, non-pd related morbidity such as cancer, medications, stereotactic brain surgery, and psychosocial problems. According to the report of Aminoff et al (Parkinsonism Relat Disord, 2011), such factors include hospitalization (being in an unfamiliar place), infection, changes in medications, changes in the environment, lingering effects of anesthesia or preexisting dementia. Disturbed physical condition such as dehydration, vitamin B1 deficiency, hypotension, liver failure, renal failure, and hyponatremia also induce confusion. When PD patients showed confusion, infections should first be excluded (Aminoff et al, Parkinsonism Relat Disord, 2011). Medications with central system effects should then be checked as the cause. Responsible drugs include anti-cholinergic drugs, amantadine, dopamine agonists, the other drugs for dopamine replacement therapy, pain killer or sleeping pills such as narcotics, anxiolytics, hypnotics, and antidepressants. Treatment of the underlying physical disturbance, such as infection, is the first thing to do to manage the acute confusional state. If the confusion has started soon after changing medication, return the medication as it was. Anti-cholinergic drugs, amantadine, selegiline, or dopamine agonists, if any, have to be considered to reduce or stop. Addition of cholinesterase inhibitors or memantine may be effective to improve confusional state. The use of atypical antipsychotic may be considered if the other management is not successful. Rehabilitation or physical exercise during day time may enhance the attention level, result in good sleep at night, and eventually improve confusional state of patients. For PD patients in admission, encourage a family member to spend as much time as

73 possible in the hospital room to get rid of confusion. Dr. Kenichi Kashihara graduated from Okayama University Medical School in 1981 and defended his PhD thesis in 1985 at Okayama University, Japan. Then, he had undergone the training as the neurologist at Kochi Municipal Central Hospital and National Sanatorium Sanyoso Hospital. Since 1986, He has worked at the Department of Neuropsychiatry, and since 1994, at the Department of Neurology, Okayama University medical School, Okayama, Japan. He spent two years at the Department of Pharmacology, Health Sciences Center, University of Arizona, AZ, USA between 1989 and Presently, he is a head at the Department of Neurology of Okayama Kyokuto Hospital, Okayama, Japan. He is a member of Neurology, Stroke, Epilepsy and Movement Disorder Society of Japan and international Movement Disorder Society. His research has focused on the pharmacological and clinical aspects of Parkinson s disease. He is a past secretary of the Movement Disorder Society of Japan. He is certificated as the specialist of neurology, stroke, and epilepsy from the corresponding Japanese societies

74 Feb.22 12:00-12:30 Management of PD Patients Undergoing Surgery Louis Tan National Neuroscience Institute, Singapore Managing patients with Parkinson s disease (PD) in the peri-operative hospital setting can be particularly challenging. Suboptimal management can lead to medical complications, prolonged hospital stays, delayed recovery and development of post-operative morbidity or mortality. Challenges in managing PD patients in the peri-operative hospital setting include: 1. Disruption of dopaminergic medication schedules resulting in poor symptom control, 2. Nil by mouth status resulting in an inability to serve oral dopaminergic drugs, 3. Reduced mobility with resultant deconditioning and medical complications that lead to delayed recovery, 4. Medication interactions and their side effects. Complications related to PD such as dysphagia, pneumonia, urinary retention, constipation, falls, and psychiatric symptoms may arise. In addition, other general complications such as hospital acquired infections and deep vein thrombosis may occur. Steps can be taken to prevent these complications in the peri-operative period by ensuring that dopaminergic medications are continued in one form or other, being vigilant to detect and prevent complications, and instituting early rehabilitative therapy. Knowing and anticipating these complications will enable PD patients to have a shorter hospitalisation, faster recovery and quicker return to their pre-morbid function

75 A/Prof Louis Tan Chew Seng MBBS, MRCP (UK), FAMS (Neurology), FRCP (Edin) Senior Consultant, Department of Neurology; Director, Clinical Research (NNI-TTSH Campus), Neuroscience Academic Clinical Program; National Neuroscience Institute Co-Director Parkinson s Disease and Movement Disorders Centre USA National Parkinson Foundation International Centre of Excellence Dr Louis Tan is a Senior Consultant Neurologist with the National Neuroscience Institute, Singapore (TTSH campus) and also the Co-Director of the Parkinson s Disease and Movement Disorders Centre there. In 2006, the Centre received the distinction of being an International Centre of Excellence for the United States based National Parkinson Foundation (NPF) for Parkinson-related research, comprehensive care and community outreach. He is an Adjunct Associate Professor of Duke-NUS Graduate Medical School, Singapore. He is the Chair of the Asian and Oceanian Section of the Movement Disorder Society and the past-chair of the MDS Education Committee. Upon graduating from the National University of Singapore and completing his neurology training at Tan Tock Seng Hospital, he underwent a movement disorders fellowship at the Parkinson s Institute in Sunnyvale, California. His areas of specialty and research interests are Parkinson s disease and movement disorders. He is also interested in the interested in the epidemiology, clinical studies and clinical trials in Parkinson s disease and other movement disorders

76 Feb.22 Luncheon seminar : 日本ベーリンガーインゲルハイム 12:30-13:30 Hyposmia and cholinergic deficiency in Parkinson Disease Atsushi Takeda, M.D., Ph.D. Deputy Director, National Hospital Organization: Sendai-Nishitaga Hospital Dementia is one of the most debilitating symptoms of Parkinson disease (PD). However, the development of dementia is still difficult to predict at early stages. Forty-four patients with PD without dementia underwent the odor stick identification test (OSIT-J) for Japanese, memory and visuoperceptual assessments, 18 F-fluorodeoxyglucose positron emission tomography scans and magnetic resonance imaging scans at baseline and 3 years later 1. A subgroup of PD patients who exhibited severe hyposmia at baseline showed more pronounced cognitive decline at the follow-up survey. By the end of the study, 10 of 44 PD patients had developed dementia. Surprisingly, all of them showed severe hyposmia at baseline. The multivariate logistic analysis identified severe hyposmia and visuoperceptual impairment as independent risk factors for subsequent dementia within 3 years. The patients with severe hyposmia had an 18.7-fold increase in their risk of dementia for each 1 SD (2.8) decrease in the score of OSIT-J. We also found an association between severe hyposmia and a characteristic distribution of cerebral metabolic decline, which was identical to that of dementia associated with PD. Furthermore, volumetric magnetic resonance imaging analyses demonstrated close relationships between olfactory dysfunction and the atrophy of focal brain structures, including the amygdala and other limbic structures. Our findings suggest that brain regions related to olfactory function are closely associated with cognitive decline and that severe hyposmia is a prominent clinical feature that predicts the subsequent development of dementia with PD. Now, we conduct a double blinded randomized control trial of donepezil on PD with severe hyposmia to prevent a later development of dementia. This study was named DASH-PD (donepezil application on severe hyposmic-pd) study (UMIN )

77 REFERENCES 1. Baba T., Kikuchi A., Hirayama K., Nishio Y., Hosokai Y., Kanno S., Hasegawa T., Sugeno N., Konno M., Suzuki K., Takahashi S., Fukuda H., Aoki M., Itoyama Y., Mori E., Takeda A., Severe olfactory dysfunction is a prodromal symptom of dementia associated with Parkinson s disease: a 3-year longitudinal study, Brain 135: , &type=summary&language=E Atsushi Takeda, M.D. & Ph.D. Born: Hirosaki, Japan Office Address: Deputy Director National Hospital Organization: Sendai-Nishitaga Hospital Kagitorihoncho, Taihaku-ku, Sendai , JAPAN Telephone: +81 (22) Fax: +81 (22) atakeda@ nishitaga.hosp.go.jp EDUCATION: M.D., Tohoku University, School of Medicine, Sendai, JAPAN Ph.D, Tohoku University, Graduate school of Medicine, Sendai, JAPAN PROFESSIONAL TRAINING: Resident in Neurology, Tohoku University Hospital, Sendai, JAPAN Research Fellow, Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, Ohio, USA FACULTY APPOINTMENTS: Instructor, Department of Neurology, Tohoku University Hospital, Sendai,JAPAN Instructor, Department of Neurology, Tohoku University Graduate school of Medicine, Sendai, JAPAN Assistant Professor, Tohoku University Graduate school of Medicine, Sendai, JAPAN 2007-present Associate Professor, Tohoku University Graduate school of Medicine, Sendai, JAPAN 2013-present Deputy Director, National hospital organization: Sendai-Nishitaga Hospital, JAPAN

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79 International Parkinson s Disease Symposium in Takamatsu 2014 February 23 Abstract

80 Feb.23 08:30-09:00 PDD update: What's role of AD pathology? 森秀生 順天堂大学越谷病院神経内科 認知症はパーキンソン病 (PD) 患者の 20-40% でみられるとされているが パーキンソン病患者を長期に調査したシドニー研究によると PD と診断されてから 20 年後には 80% の患者に認知症がみられている このことは認知症がパーキンソン病の経過とともにみられるパーキンソン病の症状であり 認知症を伴うパーキンソン病 (PDD) は特別なグループではないことを示している PD の認知症の病理学的背景としては老人斑 神経原線維変化 (NFT) といったアルツハイマー病 (AD) 病変 マイネルト基底核の神経細胞脱落 黒質の内側部の神経細胞脱落などが主張されてきたが 近年では大脳皮質のレヴィ小体 (LB) が重視されている PDD の病理学的背景は 小阪 DLB の分類による大脳皮質に多数の LB がみられるびまん性新皮質型か大脳皮質の LB の分布が辺縁系に限られる辺縁型 ( 移行型 ) が大部分であり これはレヴィ小体型認知症 (DLB) と共通している びまん性新皮質型や辺縁型ではしばしば AD 病変が伴ってみられる 小阪は早くからその点に着目し びまん性のタイプでは老人斑や NFT が高度の群が一般的だとしてびまん性型の Common form と名付け AD 病変が見られない群を Pure form と呼んでいる (Kosaka K 1990 J Neurol) AD 病変の合併の頻度の高さはα ーシヌクレインと AD 病変の関連を示唆するものであるが 実験的にα ーシヌクレインとタウが相互に線維化を促進すること (cross-seed) が報告されている (Giasson BI 2003 Science) α ーシヌクレイン遺伝子 (SNCA) の多重化による PD (PARK4) では二重化 (duplication) よりも三重化 (triplication) の方が認知症を早期から伴いやすいが 三重化の家系では老人斑や NFT はみられていない 私どもが検索した進行期に認知症をともなった二重化の例 (Obi T et al. 2008) でも老人斑や NFT はごく少数しかみられていない これらの多重化の例では大脳皮質に多数の LB が出現しており 多数の大脳皮質の LB のみでも認知症になりえることを裏付けている しかし 一方 大脳皮質に広範に LB が出現する例でも半数では神経学的異常を伴っていず incidental Lewy body disease であるとする報告 (Parkkinen L et al Acta Neuropathol ) もあり 大脳皮質の LB のみが PD の認知症の原因とするする説に反するものである AD 病変の合併が認知症を加速しているとする研究もある AD 病変と LB 病変は相乗効果をもたらすこと

81 も考えられるが AD 病変と LB(α ーシヌクレイン病変 ) の程度とは相関することが多い ので AD 病変の影響を分析するにはこの点も考慮する必要がある 森秀生 昭和 51 年に順天堂大学医学部卒業し 順天堂大学神経学講座 ( 脳神経内科 主任教授楢林博太郎 ) に入局 昭和 58 年には東京都老人総合研究所臨床病理学部に勤務し神経病理学を専攻 その間この間 61 年 ~63 年まで米国国立衛生研究所 (NIH) の米国国立老化研究所 (NIA) の Research fellow として留学 平成 2 年には 順天堂大学神経学講座 ( 脳神経内科 主任教授水野美邦 ) に復帰 平成 11 年より同助教授 平成 18 年より平成 18 年順天堂大学医学部附属順天堂越谷病院神経内科勤務し 平成 20 年より同神経内科教授に就任し現在にいたる 日本神経学会認定神経内科専門医 日本認知症学会認定認知症専門医の資格を有している 専門医学会役員として日本神経学会評議員 日本神経学会会誌 臨床神経学 編集委員 編集幹事 日本神経病理学会評議員 日本パーキンソン病 運動障害疾患学会 (MDSJ) 役員 (secretary-elect) 日本神経病理学会関東地方会世話人に当たっている

82 Feb.23 09:00-09:30 PD depression:update 永山寛 日本医科大学大学院医学研究部門神経内科学分野 Parkinson 病 (PD) は運動症状の他に多彩な非運動症状を呈し その一つであるうつは報告により頻度に大きな差はあるものの 概ねPDの40-50% に認められると考えられている しかし対象としたうつや診断 評価方法が多彩であること うつ アパシー アンヘドニアといった用語の並列がPDのうつの解釈を困難にしている そのため 症状 発症機序 治療といった一連の流れの解釈が求められる DMS-IV TR2による大うつ病性障害の診断基準では 抑うつ気分 と 興味 喜びの減退 のどちらかが軸となるが PDに合併するうつではこのうち 興味 喜びの減退 が主体となり さらに高度な不安 自殺念慮 幻覚 妄想は少なく 日内変動も少ないとされている この 興味 / 喜びの減退 は 従来から用いられているアンヘドニア アパシーといわれる語に相当するが 最近の知見では PDに認められるうつはアパシーとは各々独立した存在である可能性も示されている さらにはアパシーには明確な定義がないこと アパシーは症候群でありアンヘドニアを含みうる概念であることも これらの概念の解釈を困難にしている またwearing offがある患者では off 期にうつや不安といった気分変動を来し levodopaの投与で改善する このことから PDのうつの一部は PDの病態そのものと関連していることが示唆されるが 最近の検討では この様なPD の病態生理に関連して発症したうつはPDのうつの半数以上になることが示唆されている 治療に関しては 従来からまずは運動症状に対する十分な治療を行うこと 希死念慮が著しい場合には, 精神科医にコンサルトをすることが明示されているが それでも症状の改善が認められない場合は薬物療法を試みる これまでに三環系抗うつ薬 (nortiptyline amitriptyline) SSRI (sertraline fluvoxamine) ドパミンアゴニスト (pergolide pramipexole) の有用性が示されており 最近の報告では SSRI 選択的セロトニン ノルアドレナリン再取込み阻害薬 (paroxetine venlafaxine) も二重盲検で PD のうつに関しての有用性を示し Class I evidence を提供している ドパミンアゴニストに関しては 病態に即した D 3 受容体に親和性の高い薬剤の有用性が報告されており 特に pramipexole は SSRI と同程度にうつを改善した報告や プラセボとの二重盲験で有意な直接の効果でのうつ改善効果を示している また adenosine A 2A 受容体拮抗薬で

83 ある istradefylline の有用性が期待される報告もある 氏名永山寛 ( ながやまひろし ) 日本医科大学大学院医学研究部門神経内科学講師 : 平成 5 年 3 月日本医科大学卒業 平成 5 年 5 月 平成 7 年 1 月日本医科大学付属病院精神神経科 日本医科大学付属第一病院で研修 平成 7 年 2 月 平成 11 年 6 月東京都多摩老人医療センター ( 現 : 東京都多摩北部地域病院 ) 神経内科 平成 11 年 7 月 日本医科大学神経内科助手 平成 12 年 3 月学位 ( 医学博士 ) 取得 平成 22 年 4 月 日本医科大学神経内科講師 専門分野 : Parkinson 病 末梢神経 筋疾患研究テーマ : MIBG 心筋シンチを用いた Parkinson 病及び類縁疾患の診断 Levodopa の薬物動態評価を用いた Parkinson 病の治療 Parkinson 病の精神症状の評価と治療 Parkinson 病の気分障害

84 Feb.23 09:30-10:00 Why do PD patients fall? ( なぜパーキンソン病患者は転倒するのか?) 大熊泰之 順天堂大学医学部附属静岡病院脳神経内科 目的 : パーキンソン病における転倒の特徴と機序を理解し, 予防に繋げる. Take home messages: 1. 近年, パーキンソン病における転倒に関する前方視的研究が多数報告されるようになった. 2. それらによると,6-12 ヶ月の転倒発生率は 40-70% である. 前年の転倒の既往, 重症度, すくみ足, バランスの異常, 認知症, 注意力障害, 転倒の恐怖などが将来の転倒予測因子とされている. 3. 転倒の頻度はヤール3 4 度で高くなり,5 度で減少するとみられる. 実際の転倒原因を前方視的に調べた報告は未だに少ない. 一般的にパーキンソン病の転倒は屋内で起こることが多く, ある程度薬の効いている時間帯に多い. すくみ足など内因性の転倒が多いのも特徴である. 4. 転倒, すくみ足と dual tasking( 二重課題 ) の関係が重視されている. 5. パーキンソン病の転倒とアセチルコリン系の機能低下との関係が注目されている. ドネペジルが転倒を減少させたとする論文が報告されたが, 追試が必要である. 6. 加速度計を用いた転倒, すくみ足の客観的な検出が試みられている. 参考文献 1. Okuma Y and Yanagisawa N. The clinical spectrum of freezing of gait in Parkinson s disease. Mov Disord 23 (Suppl 2): , Bloem BR, et al. Falls and freezing of gait in Parkinson s disease: a review of two interconnected, episodic phenomena. Mov Disord 19: , Yoneyama M, Mitoma H, Okuma Y. Accelerometry-based long term monitoring of movement disorders: from diurnal gait behavior to nocturnal bed mobility. J Mech Med BIol 13: No , Okuma Y. Freezing of gait and falls in Parkinson s disease. J Parkinson s Disease 2014, in press

85 昭和 57 年 3 月 順天堂大学医学部卒業 57 年 5 月 順天堂大学神経学講座に入り, 順天堂大学病院, 東京都立神経 病院, 国立精神神経センター国府台病院, 国立療養所富士病院などで研修 平成 4 年 10 月から6 年 12 月まで カナダ, カルガリー大学臨床神経科学部門留学 (visiting scientist) 7 年 1 月 順天堂大学神経学講座助手 7 年 6 月 順天堂大学浦安病院内科 ( 神経内科 ) 助手 9 年 4 月 順天堂大学神経学講座助手 ( 医局長 ) 10 年 4 月 順天堂大学神経学講座講師 12 年 6 月 順天堂伊豆長岡病院 ( 現静岡病院 ) 脳神経内科科長講師 13 年 8 月 順天堂伊豆長岡病院 ( 現静岡病院 ) 脳神経内科科長助教授 21 年 4 月 順天堂大学医学部附属静岡病院脳神経内科科長教授 現在に至る 賞罰 : 平成 20 年 5 月順天堂大学医学部同窓会学術奨励賞 ( 附属病院における症例報告指導の実践 ) 専攻領域 : 臨床神経学, パーキンソン病等運動障害, 臨床神経生理学 ( 脳波 筋電図 ) 特に興味を持っていること : パーキンソン病における歩行 バランス障害 転倒機序の解明

86 Feb.23 10:30-11:00 Rehabilitation in PD from walking to speech: state-of-the-art 市川忠 埼玉県総合リハビリテーションセンター神経内科 リハビリテーションは従来 治療訓練による効果の蓄積を経験的に集約することで その効果を立証してきた. 最近では生化学的手法おび機能画像による科学的根拠や比較試験等の結果によるエビデンスにより, その効果の科学的根拠を示す報告が増加している. 本稿ではパーキンソン病においても 様々な障害に対するリハビリテーションについての最新の科学的知見を紹介する リハビリテーションにおける可塑性と神経保護リハビリテーションによって中枢神経ではシナプスは機能的変化, さらには形態的変化が生じる. この変化は可塑性そのものであり, 近年 BDNF が可塑性の指標となっている. またリハビリテーションで獲得した機能改善の保持には, パーキンソン病での神経変性から神経保護作用があることが望ましい. パーキンソン病リハビリの具体的手法パーキンソン病のリハビリテーションの主たる目的は運動機能の改善である. 視覚や聴覚を用いた外部キューが運動開始や運動リズムを改善することは, すでに広く知られている. 外部キューを取り入れた訓練により歩行の改善, 立ち上がり動作の改善がみられる. また振動覚刺激による立位安定性向上効果についても検討がされている. すくみ足はパーキンソン病症状で最 QOL を低下させる症状の一つであるが, 抵抗下歩行運動ですくみ足が改善するという報告もある. 体幹前屈にたいしても外腹斜筋へのリドカインの繰り返し筋肉注射とリハビリテーションにより体幹前屈が長期間改善すると報告されている. 運動により認知機能が改善することも最近報告が増加しており, 今後運動障害だけでなく認知機能を改善する運動プログラムの開発が期待される. 発語, 嚥下機能に対するリハビリテーションは QOL および呼吸器系合併症予防の点で重要である. 発語 ( 話 ) では Lee Silvermann Voice Training (LSVT) が代表的な手法となっている. 大きく, 長く発生することで, 咽頭喉頭運動機能改善を図る手法であるが, 胸郭コンプライアンスの改善, 痰の核出改善にもつがながり患者予後を改善す

87 ると考えられる. 嚥下のリハビリテーションでは標準的な間接, 直接の嚥下訓練に加えて, カプサイシンゼリーを用いた訓練や表面電気刺激を用いた訓練によって咽頭通貨時間を短縮し, 誤嚥リスクを低減するとしている. まとめパーキンソン病においてリハビリテーションは副作用の懸念なく症状改善が図れる有用な方法である. リハビリテーション継続のための意欲の持続をどう図るか, また訓練手法の平準化などの課題がある

88 Feb.23 11:00-11:30 Exercise and cognition in PD and AD 栗﨑玲一 (Ryoichi Kurisaki) 国立病院機構熊本南病院神経難病センター神経内科 近年, 認知機能に対する運動の効果について注目されている. 過去の様々な疫学調査により, 運動が認知症のリスクを減らすことが明らかとなってきた. 多くの介入研究も行われており, 在宅運動プログラムの導入や有酸素運動などが軽度認知障害 (MCI) 高齢者の認知機能の改善に有用などとする報告がある. 本邦においても, 既に自治体単位での認知症予防を目指した運動介入試験等も行われており, 認知症疾患ガイドラインでも運動療法が認知症の予防 治療に有効である可能性について言及されている. 運動が認知機能を改善するメカニズムの解明は動物実験等によって進んでおり, 運動による脳由来神経栄養因子 (BDNF) やグリア細胞由来神経栄養因子 (GDNF) などの神経栄養因子の発現などが機序として考えられている. パーキンソン病 (PD) の長期経過中に出現する認知機能低下は臨床上の大きな問題である. PD の認知機能に対する運動療法の効果に関してもいくつかの報告があるが, 運動の PD における神経保護効果を証明した大規模な前向き無作為化比較試験は現在まで行われていない. これは神経保護効果の信頼性の高いバイオマーカーがまだ存在しないことも一因であろう. しかしアルツハイマー病 (AD) や MCI に関連した多くの間接的証拠からは, 運動は PD における認知機能の改善においても有用であることが推察される. AD, PD における認知機能低下の進展阻止を考える上で, 運動は重要なテーマである

89 栗﨑玲一 (Ryoichi Kurisaki) 平成 11 年 3 月 熊本大学医学部卒業 平成 11 年 4 月 熊本大学神経内科入局 平成 14 年 4 月 国立療養所熊本南病院 ( 現 : 国立病院機構熊本南病院 ) 平成 23 年 4 月 国立病院機構熊本南病院神経難病センター神経内科病棟医長 現在に至る

90 Feb.23 共催セミナー : ノバルティスファーマ 11:30-12:00 Pathogenesis in PD; Update 波田野琢, 服部信孝 順天堂大学神経学講座 パーキンソン病 (PD) のほとんどは孤発性で発症し, 原因は未だに不明である. 年齢とともに有病率は上昇するため孤発型 PD においては 加齢は重要な発症因子である. また, 多くの検討から環境因子が関わる事も示されている. しかし,90 代になると有病率は低下し, 必ずしも加齢や環境因子のみでは説明出来ず, 遺伝的素因も重要であることが示唆されている. また,5-10% 程度は明らかな単一遺伝子の影響を受けて発症する事が知られており, これらの原因遺伝子を同定しその遺伝子がコードする蛋白を解析することで PD の神経細胞死のメカニズムを明らかにする試みが行われている. 現在, 遺伝子座は 17 カ所つきとめられており, 原因遺伝子は 13 同定されている. この中で,α-synuclein (SNCA/PARK4) は Lewy 小体の構成成分であり PD のメカニズムに重要な蛋白である. 正常な α-synuclein の機能は未だ不明で, どのように病気に関わるのかよくわかっていない. 推定されている機能のなかで, シナプス小胞への結合と解離は重要であり膜輸送に関連していることが示唆される.VMAT2 の発現が低下し膜輸送に異常をみとめるマウスではドパミン神経細胞の障害と α-synuclein の蓄積が確認されており膜輸送の破綻はこの蛋白の凝集を引き起こす可能性も示されている. α-synuclein 以外に LRRK2 および DJ-1 もシナプス小胞に局在している事が示されており,PD の病態に膜輸送が関与している可能性がある. 常染色体劣性遺伝性 PD (ARPD) で最も頻度が高い parkin も重要な蛋白であり, ユビキチン プロテアソームシステムにおける E3 リガーゼとして機能している事が示されている. ユビキチンシステムのなかでプロテアソームを介した蛋白分解系に parkin が関わる事が予想され, 基質となる蛋白が数多く同定された. しかしいずれも parkin ノックアウトマウス脳では蓄積が確認されず, プロテアソームシステムに直接関わるかどうかは依然議論の余地がある. 興味深いことに ARPD のもう一つの遺伝子である PINK1 をノックアウトしたショウジョウバエモデルは parkin をノックアウトしたものと酷似しており,parkin と PINK1 は同じカスケードにより神経細胞へ影響を及ぼす事が推定されている. 実際にこの二つの蛋白は培養細胞において膜電位の低下したミトコンドリアのオートファジー ( マイトファジー ) に関わる. 家族性 PD 関連蛋白の機能解析を進めることで PD 発症の共通メカニズムが正確に突き止められれば治療につながる事が期待できる

91 波田野琢 39 歳昭和 49 年 1 月 19 日生 1999 年 3 月順天堂大学医学部卒業 1999 年 4 月順天堂大学脳神経内科入局 2003 年 4 月から 2007 年 3 月順天堂大学医学部大学院卒業 2007 年 4 月順天堂大学脳神経内科助教 2008 年 1 月順天堂大学脳神経内科外来医長 2009 年 1 月順天堂大学脳神経内科病棟医長 2011 年 4 月順天堂大学脳神経内科准教授 受賞歴 2010 年世界運動障害学会 ( ブエノスアイレス ) ビデオ症例検討会 (Video Olympic) 銀賞 研究テーマ ; 家族性パーキンソン病蛋白の機能解析, パーキンソン病の薬物療法 所属学会日本神経学会, 神経治療学会, 日本内科学会, 日本認知症学会 Movement disorders society Japan, Movement disorders society 専門医神経内科専門医, 指導医, 認定内科医, 認知症専門医

92 Feb.23 Luncheon seminar : グラクソ スミスクライン 12:00-12:40 Pathogenic mechanisms of levodopa-induced dyskinesias 冨山誠彦 青森県立中央病院神経内科 Wearing-off やジスキネジアなどの運動合併症の背景には, レボドパの血中における治療濃度域の狭小化が関係している. 即ちドパミン神経変性の進行に伴って治療濃度域の下限が上昇するとオフ状態が出現し, 逆に上限が低下するとジスキネジアの発症リスクが高まる. レボドパ治療に伴うジスキネジアの発現には, 主にドパミン脱神経とレボドパ投与といった二つの要因により, 血中レボドパの治療濃度域上限が低下することが関係している. 線条体におけるドパミン濃度調節は主にドパミン神経が担っているが, セロトニン神経も AADC および VMAT を有しており, レボドパをドパミンに変換し, 貯蔵してシナプス間隙に放出する機能を持つ. しかしセロトニン神経終末には, ドパミン神経細胞のようにシナプス間隙のドパミン調節機構である D2 受容体 ( ネガティブフィードバック ) やドパミントランスポーター ( ドパミンの再取り込み ) がない. ドパミン神経脱落の進行に伴いレボドパは主にセロトニン神経でドパミンに変換される様になるが, セロトニン神経による線条体へのドパミンの放出は無調節でありかつドパミンの再取り込みが行われないため, 線条体のドパミン受容体はレボドパ血中濃度の変動に応じた非生理的な波状刺激にされされることになる. このようなドパミン神経脱落に伴う線条体のレボトパ投与後のドパミン濃度の非生理的な変動により, ドパミンへの親和性が低い D1 受容体も波状的な刺激を受けることになる. この結果 D1 受容体を発現する直接路を形成する線条体神経細胞が皮質からのグルタミン投射に対して過敏性を獲得し, 同神経細胞 (GABA 作動性である ) の GABA 合成が亢進する. そのため基底核出力核 ( 淡蒼球内節および黒質網様部 ) にある直接路の線条体神経細胞終末に GABA が過剰に蓄えられ, 終末が肥大する. これがジスキネジアの priming 状態を表すものと考えられる. この状態でレボドパが投与されて線条体のドパミン濃度が上昇し D1 受容体を介して直接路神経細胞が興奮すると, その終末から基底核出力核へ GABA が大量に放出され, 基底核出力核の発火が過抑制される. その結果, 基底核出力核は GABA 作動性であるので, その投射先である視床運

93 動核が脱抑制され活動性が亢進し, そして視床 ( グルタミン酸作動性 ) の投射先である 運動皮質が最終的に過大に興奮しジスキネジアが出来する. 以上がレボドパ誘発ジ スキネジアの発症メカニズムと推定される. とみやままさひこ 冨山 誠彦昭和 36 年静岡市生まれ 昭和 61 年 弘前大学医学部卒業 弘前大学第三内科入局 平成 2 年 弘前大学大学院医学研究科修了 弘前大学第三内科医員 平成 5 年 スペイン国高等学術研究院 バルセロナ生医学研究所ポストドクトラルフェロー 平成 9 年 青森県立中央病院神経内科副部長 平成 10 年 弘前大学医学部附属病院第三内科助手 平成 17 年 弘前大学医学部附属病院神経内科助手 平成 18 年 弘前大学医学部附属病院神経内科講師 平成 19 年 弘前大学医学部神経内科助教授 平成 20 年 青森県立中央病院神経内科副部長 平成 21 年 青森県立中央病院脳卒中ユニット部長 所属学会日本脳卒中学会 ( 代議員 評議員 専門医 ) 日本神経学会 ( 代議員 専門医 ) 日本内科学会 ( 認定医 ) 日本パーキンソン病 運動障害学会日本神経科学会米国神経科学会パーキンソン病 運動障害学会 専門は神経内科学 : 特にパーキンソン病をはじめとする神経変性疾患と脳卒中

94 Feb.23 共催セミナー : 日本メドトロニック 12:40-13:10 DBS in PD : update パーキンソン病に対する脳深部刺激療法 斎木英資 北野病院神経内科 パーキンソン病に対する外科治療は遠く 1930 年代に源流をもち 定位脳手術装置の導入 高周波を用いた電気凝固による選択的治療 脳深部刺激を用いた可逆的手法と発展してきた その歩みは内服治療の発達と平行しており 常に競い合うように進んできた歴史を持つ 外科治療はその性格上 常に有害事象のリスクを伴うことから対象は内服治療では改善不十分な症状もしくは病態であり これは現在でも変わらない 今日行われるのは大半が視床下核脳深部刺激療法 (STN-DBS) 次いで淡蒼球内節脳深部刺激療法 (GPi-DBS) である STN-DBS の効果の特徴は OFF 症状の改善であり これによる薬剤の肩代わり効果である GPi-DBS は STN-DBS に比べて OFF 症状の改善効果に劣るため薬剤の肩代わり効果は一般的に得られにくいが ジスキネジアの直接抑制効果に優れ STN-DBS に比べて刺激合併症のリスクが低い STN-DBS では 10 年の経過が報告されており 長期効果が確認されている 最近では より若年で発症した患者に対する早期の STN-DBS が生活の質改善に有用であることも報告されている 一方 内服治療も新規薬剤が相次いで承認され パーキンソン病の治療手段はこれまでになく多様かつ選択の自由度が増している 本講演ではこれらの内服および外科治療のエビデンスを踏まえて現在の DBS のパーキンソン病治療における位置づけについて再考するとともに 患者 家族に対するインフォームド コンセントのあり方についても検討する また 外科的治療における神経内科医の役割についても議論する

95 バイオスケッチ 1989 年筑波大学卒業 1994 年 国立療養所宇多野病院にて研修中に視床凝固術を見学し 神経内科医としてパーキンソン病に対する定位脳手術に携わるようになる 99 年より DBS 治療 2005 年より公益財団法人田附興風会医学研究所北野病院神経内科 DBS 前のインフォームド コンセントから適応判定 術中の生理学的評価ならびに試験刺激による植え込み部位検討 術後の刺激導入 薬剤腸性 その後のフォローアップを一貫して行う 定位脳手術患者の全例について手術に立ち会う方針を続けている

96 Feb.23 共催セミナー : 大塚製薬 13:10-13:40 Dopamine agonist withdrawal syndrome (DAWS) 下泰司 服部信孝 順天堂大学医学部脳神経内科 運動障害疾患病態研究治療講座 近年は Continuous dopaminergic stimulation の概念に基づいた 持続的なドパミン受容体刺激がパーキンソン病 (PD) 治療において重要とされており 運動合併症の発現予防という観点から効果が期待されている その中ではドパミン受容体作動薬 (DA) は重要な役割を担っているが さまざまな問題点も明らかになってきた その中の一つに DAWS がある DAWS は DA を減量 ~ 中止する際に出現するさまざまな症状の総称であり Rabinak らにより 2010 年にまとめられた その症状は精神症状 ( 鬱 不安感 drug craving) や感覚異常 自律神経症状 ( 起立性低血圧など ) まで多岐にわたる DAWS が発現する背景には Impulse control disorders の存在が重要である また 視床下核脳深部刺激療法後 DA を減量するときにも生じる 近年は PD 以外の疾患 ( むずむず脚症候群 microprolactinoma) における DA 減量の過程でも生じることが示されている 治療は使用していた DA の投与再開であり levodopa には反応しないことが分かっている DAWS は Psychostimulant ( アンフェタミン コカイン たばこ産物など ) からの離脱症状に類似しており その発現には中脳辺縁系 ( Ventral tegmental area(vta)~ Nucleus accumbens~ Ventral pallidum や前頭葉を含む経路 ) におけるドパミンが重要な役割をなしていると考えられている 中脳黒質緻密部及び VTA のドパミンニューロンは通常外部からの刺激がない限り 10Hz 以下の持続的な発火を示し 報酬を示唆する刺激に一過性に興奮性の反応を示す しかし VTA にあるドパミンニューロンは 嫌悪刺激や恐怖刺激に対しては一過性の抑制性の反応を示すものも多い このようにドパミンニューロンは さまざま状況下で その後に生じる出来事を予測してその発火パターンを変え 行動学習などに影響を与えている Psychostimulant からの離脱症候群では 薬物投与下でシナプス間隙のドパミンが高濃度に存在して常に受容体を刺激している状態からの突然の離脱により 外部刺激に対して適切に対応できなくなっているドパミンニューロンの活動及びシナプス間隙のドパミン濃度がさらに変化することによって引き起こされていることが示唆されている

97 DAWS のメカニズムを このようなドパミンの役割をふまえて考察することは重要で ある

98 Feb.23 共催セミナー : 大日本住友製薬 13:40-14:10 How can we do the individual treatment in PD? Miho Murata Department of Neurology, NCNP パーキンソン病患者一人一人に適切な治療をすることは 神経内科医の理想であるが なかなか難しいことも確かである 患者が一人一人異なるように医師も一人一人異なるので この方法に王道はないと思われるので ここでは私見をのべさせていただく パーキンソン病患者一人一人に適切な医療を行うためには 1) まずは 治療法の基本を押さえる 1 PD 病症状は少なくともある程度は必ず改善することを認識する 2 発症年齢 罹患期間による一般的な特徴を理解する 3 薬剤の基本的な性質を理解する 2) 現在の状態の把握 1 運動症状 非運動症状 ( 含検査所見 ) の把握と客観的な現在の問題点 2 患者本人 ( 及び家族 ) にとっての問題点 3 患者本人 ( 及び家族 ) の価値観 環境 4 1~3を認識したうえでの現在の問題点の把握 3) 現在認める症状はドパミン欠乏による症状なのかを検討 1 ドパミン欠乏による症状であれば 十分に薬剤を使用して改善する 2 規則正しく服薬できているかの確認 3 運動不足 ( 廃用 ) による部分はないか 4 心理的要因により悪化して見えている部分はないか それぞれの例と対応策を述べる

99 村田美穂 国立精神 神経医療研究センター神経内科部長 パーキンソン病 運動障害疾患センターセンター長 1984 年 筑波大学医学専門学群卒業 1984 年 筑波大学附属病院内科研修医 神経内科レジデント 1992 年 筑波大学大学院医学研究科修了 1992 年 東京大学医学部付属病院神経内科 2004 年 国立精神 神経センター ( 現国立精神 神経医療研究センター ) 神経内科医長 2005 年 国立精神 神経センター ( 現国立精神 神経医療研究センター ) 神経内科部長 2010 年 国立精神 神経医療研究センター パーキンソン病 運動障害疾患センター長併任

100 Feb.23 14:10-14:40 Guideline in practice 平山正昭 名古屋大学医学系研究科医療技術学専攻准教授 パーキンソン病を含めた神経変成疾患は 高齢化社会により着実に有病率が増加している しかし 神経変成疾患は難病といわれるように専門的知識に基づいた正確な診療と治療が必要となる しかし すべての分野における医療情報は日々膨大となりその取得は困難な状況となりつつある 効率良く正確な情報を得て, 患者のライフス夕イルに即した医療を一定レベルで実践するという目的で提唱されてきたのが EBM (evidence based medicine) といえる 日本神経学会でも 2002 年のパーキンソン病に始まり多くの神経疾患でガイドラインが策定され 2011 年にはパーキンソン病ガイドラインの改訂も行われている ガイドラインは その多くを EBM に基づき行われているが EBM を重視するあまりいくつかの臨床診療における問題点も生じてきている そのため 改訂版では 2002 年度にあったフローチャート主体でなくクリニカルクエッションを多くするなどのガイドラインの使用に自由度を持たせる工夫がなされた 本講演では 問題点を指摘しつつ実践的なガイドラインの活用について提議したいと考える ガイドラインは 高水準のエビデンスに基づいた基準に基づき治療の推奨度を期している しかし神経疾患に EBM の概念をすべて適応できるかは問題である 第一に高血圧や高脂血症などに対する RCT よるエビデンスとはほぼ恒常的な病的状態への薬物療法などの操作の効果をみることによって得られるものである 神経疾患などのように個体差が大きな進行性の病態に対して同様に適用できるものかどうか定かでない 第二に臨床試験の時代的背景による問題点があげられる 例えば L-dopa は 最も強力な治療薬として考えられているが古い時代の試験のためエビデンスレベルは低いものが多い さらに抗コリン薬に至っては十分な効果に関する治験よりもその副作用に関する報告の方が多い 一方ドパミンアゴニストは RCT が多いため新しい薬物ほどよりエビデンスレベルが高いという結果となる すなわち RCT が高いイコール効果が高いとは言い切れない さらに 神経疾患の場合には 血圧測定や血液検査といった客観的指標ではなく 評価基準が臨床症状となる UPDRS は医師間による差異が少なく, 信頼性の高いが評価基準であるが必ずしも患者の ADL や Q0L とは一致しない MDS-UPDRS は評価者間の違いを軽減するためインターネットでの教育を行っている 精度の高い治験に参加する上でも日本人神経内科医の取得が望ましい

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