2 · clinical diagnostic criteria is also a classical symptom in pd dementia, such that the only...
TRANSCRIPT
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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 …………………………………………………………… 103
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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
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Information
Registration Information
Registration: on-site only available
Pre-registration is appreciated.
No discount for pre-registration is available
Registration Times:
Feb 21(Fri) 08:20-18:40
Feb 22(Sat) 08:30-17:30
Feb 23(Sun) 08:30-15:40
Registration Fee:
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.)
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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
-Molecular dissection of X-linked
Dystonia-Parkinsonism
R.Kaji
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
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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
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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
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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
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Day 3 : Feb.23 (Sun) Program
Japanese Session
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
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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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International Parkinson’s Disease Symposium
in Takamatsu 2014
February 21
Abstract
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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
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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.
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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.
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Bioskech
Prof. Eduardo Tolosa MD, FRCP
February 2014
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.
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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-01307 Dresden
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
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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.
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Heinz Reichmann, MD, PhD, FRCP, FAAN – biosketch
Heinz Reichmann MD PhD graduated from the University of Freiburg, Germany in
1979. 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 1990. 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 2014.
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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 bio-
resources 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.
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Biosketch
Dr.Sigeo Murayama,MD,PhD
1979. Graduate from the Faculty of Medicine, the University of Tokyo (UT).
1989. Ph.D. of UT: “Immunocytochemical and ultrastructural studies of Pick’s disease.”
1991. Medical Board, State of North Carolina (UNC, Professor Kinuko Suzuki)
1999. Chairman, Department of Neuropathology, Tokyo Metropolitan Geriatric Hospital
and Institute of Gerontology (TMGHIG)
2001. Director, Brain Bank for Aging Research, TMGHIG
2009. PI, Japanese Brain Bank Network for Neuroscience Research
2013. Chairman, Department of Neurology and Bio- resource Center, TMGHIG.
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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
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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.
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Biosketch
Takayoshi Shimohata, M.D., Ph.D., FAAN
Address (Work) Department of Neurology, Brain Research Institute, Niigata University
1-757 Asahi-machi-dori Niigata, Niigata 951-8585, Japan
Phone: +81-25-227-0670
Fax: +81-25-223-6646
e-mail: [email protected]
EDUCATION and PROFESIONAL TRAINING
1992 M.D. Niigata University, Medical School, Niigata, Japan
Japanese Medical License Registration (No. 345353)
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
1997-2001 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
2004-2006 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
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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 13th
Naito conferences on molecular biological approaches for intractable
diseases (II)
2001 The 5th
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 15th
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
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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
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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 1985.
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 2010. 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.
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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.
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Curriculum Vitae
Name Ryuji Kaji MD, PhD 59 y.o. M
Birth Date Nov 2nd
, 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 770-8503, JAPAN
phone 81-88-633-7206 fax 81-88-633-7208
e-mail: [email protected]
Education:
1979 Graduated from Kyoto University School of Medicine (M.D.)
Residency in Neurology and Medicine at Tokyo Metropolitan
Geriatric Hospital
1981-85 PhD course in Medical Science (1985, PhD degree)
1985-86 Post-doctoral fellow in Department of Neurology,
Hospital of the University of Pennsylvania
Positions:
1986-87 Visiting Professor of Neurology at the Hospital of the
University of Pennsylvania
1987-88 Assistant Professor of Neurology at the Louisiana State
University Medical Center
1989-91 Assistant, Department of Neurology, Kyoto University School of
Medicine
1991-2000 Lecturer, Department of Neurology, Kyoto University Graduate
School of Medicine
2000- Current Position
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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;465:223-226.
2. 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;105:12551-12556.
3. 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):1785-1787.
4. 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):393-406.
5. 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):7-17. .
6. 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):203-11.
7. Kaji R, Murase N, Urushihara R, Asanuma K. Sensory deficits in dystonia and
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their significance. Adv Neurol 2004;94:11-7. .
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 2006.
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).
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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).
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Tohru Matsuura, brief biosketch
2000-2002 Instructor, Dept. of Neurology, Baylor College of Medicine, USA
2002-2005 Assistant Prof., Dept. of Molecular & Human Genetics, Baylor College of
Medicine, USA
2005-2009 Associate Prof., Div. of Neurogenetics, Nagoya University Graduate
School of Medicine, Japan
2009-2013 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 3rd
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.
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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” (2012-2016). Prof Wu is former Chair of
the Neurology department at NTUH (2004-2010) and funding president of “Taiwan
Movement Disorders Society” (2007-2009). She is organizer of 3rd Asian and
Oceanian Parkinson’s Disease and Movement Disorders Congress in Taipei in 2011.
She served as Chair of “Asian and Oceanian Section of The Movement Disorder
Society” from 2011-2013. 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.
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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
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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(1987-2008)
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(1990-2013)
President- Israel Neurological Association (1987-1993)
Chairman - Advisory Board, Israel Parkinson’s Disease Association
(2003-2012)
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 (1971-1976), 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 (1978-1980)
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.
[email protected], [email protected]
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 1994. 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 2005. Awarded the fellowship of the
Royal College of Physicians of London in 2008 and the Royal College of Physicians of
Ireland in 2010.
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 2014.
- 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.
- 47 -
- 48 -
Feb.21
15:30-16:00
Psychogenic Parkinson disease
Eduardo Tolosa MD
13th
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, FRCP
February 2014
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 (1998 - 1999)
Institute of Neurology, University of London, Queen Square, diploma (1999 - 2000)
Dept Neurology, Chiba East National hospital, Resident. (2000 - 2002)
Graduate School of Medicine, Chiba University, doctorial course. (2003-2006)
Center for Neuroscience, Feinstein Institute for Medical Research, North shore
university hospital, postdoctorial fellow. (2006 - 2008)
Dept Neurology, JR general hospital, consultant. (2008-2011)
Dept Neurology, Chiba University Hospital,research associate professor (2011 -
2012), associate professor. (2012 - present)
Molecular neuroimaging program, MIC NIRS, visitor researcher in (2008 - 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 1993. 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 1998. 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 2010. 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 -
(2006-2009) 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 2013-2015. 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
31000 Toulouse , France
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- 59 -
International Parkinson’s Disease Symposium
in Takamatsu 2014
February 22
Abstract
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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”
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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
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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.
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CURRICULUM VITAE February 2014
Kazushi Takahashi, M.D.
Department of Neurology, Saitama Medical University,
Education:
Undergraduate: 1981-1987 Keio University School of Medicine, Tokyo,
Graduate: 1987-1991 Keio University Graduate School of Medicine, Tokyo, Japan
Professional Training and Employment:
1987-1991 Resident, Department of Neurology,Keio University School of Medicine,
Tokyo,
1992 Board Certified Neurologist by JSN
1991-1992 Instructor, Department of Neurology,Keio University School of Medicine,
Tokyo,
1995-1999 Research Associate in Cerebrovascular
Research Center, University of Pennsylvania,U.S.A.
1999-2005 Department of Neurology, National Hospital
Organization
Tokyo Medical Center, Tokyo
2005-2012 A/P Department of Neurology,Keio University School of Medicine, Tokyo,
2012-2014 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.
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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 Q10 (CoQ10). Indeed, CoQ10 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 CoQ10 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
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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. 2001
Graduate School of Medicine, The University of Tokyo Ph.D. 2010
Employment
2001-2002 Resident, Internal Medicine, The University of Tokyo Hospital
2002-2003 Resident, Internal Medicine, Mitsui Memorial Hospital
2003-2004 Neurology, The University of Tokyo Hospital
2004-2005 Neurology, Yokohama Rosai Hospital
2005-2006 Neurology, The University of Tokyo Hospital
2010- 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: 571-576
Sidransky E, et al. Multicenter analysis of glucocerebrosidase mutations in
Parkinson’s disease. N Engl J Med. 2009; 361: 1651-61
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: 75-89
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: 233-44
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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
0.859 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
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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.
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Biographical Sketch
NAME: Takahiko Tokuda, M.D., Ph.D.
ACADEMIC EDUCATION:
1984. 3. Graduated Shinshu University School of Medicine
(Matsumoto, Japan) with an M.D.
1992. 6. Obtained a Ph.D. (Dr. of Medical Science),
Shinshu University School of Medicine
RESEARCH AND PROFESSIONAL ACTIVITIES:
1984.5. Passed the Examination of National Board (Certificate No. 283777)
1984. 6. Entered Dept. of Neurology, Shinshu University School of Medicine, Japan
1993-1995 Visiting Scholar, Dept. of Molecular Biology, Tokyo Institute of Psychiatry,
Tokyo, Japan
1997-1999 Postdoctoral fellow, Dept. of Pathology, New York University School of
Medicine, USA.
2001-2002 Assistant Professor, Dept. of Neurology, Shinshu University School of Medicine,
Japan
2002-2005 Associate Professor, Dept. of Neuroplasticity, Division of Molecular and Cell
Biology, Institute on Aging and Adaptation, Shinshu University Graduate School
of Medicine
2005-2011 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.
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Professor Eldad Melamed, M.D- Brief C.V
Professor and Chairman- Department of Neurology,
Rabin Medical Center- Beilinson Campus, Petah Tiqva, Israel(1987-2008)
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(1990-2013)
President- Israel Neurological Association (1987-1993)
Chairman - Advisory Board, Israel Parkinson’s Disease Association
(2003-2012)
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 (1971-1976), 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 (1978-1980)
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
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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 1991. 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.
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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.
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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.
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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,
18F-fluorodeoxyglucose positron emission tomography scans and magnetic resonance
imaging scans at baseline and 3 years later1. 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 (UMIN000009958)2.
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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 135:161-169, 2012.
2. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R00
0011661&type=summary&language=E
Atsushi Takeda, M.D. & Ph.D.
Born: 1960.10.6 Hirosaki, Japan
Office Address: Deputy Director
National Hospital Organization: Sendai-Nishitaga Hospital
2-11-11 Kagitorihoncho, Taihaku-ku, Sendai 982-8555, JAPAN
Telephone: +81 (22) 245-2111 Fax: +81 (22) 243-2530
E-Mail: atakeda@ nishitaga.hosp.go.jp
EDUCATION:
1979-1985 M.D., Tohoku University, School of Medicine, Sendai, JAPAN
1988-1992 Ph.D, Tohoku University, Graduate school of Medicine, Sendai, JAPAN
PROFESSIONAL TRAINING:
1985-1988 Resident in Neurology, Tohoku University Hospital, Sendai, JAPAN
1998-2000 Research Fellow, Division of Neuropathology, Institute of Pathology,
Case Western Reserve University, Cleveland, Ohio, USA
FACULTY APPOINTMENTS:
1992-1999 Instructor, Department of Neurology, Tohoku University Hospital,
Sendai,JAPAN
2000-2006 Instructor, Department of Neurology, Tohoku University Graduate
school of Medicine, Sendai, JAPAN
2006-2007 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
- 78 -
- 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. 2008 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 D3 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 A2A 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):426-430, 2008
2. Bloem BR, et al. Falls and freezing of gait in Parkinson’s disease: a review of two
interconnected, episodic phenomena. Mov Disord 19: 871-884, 2004
3. 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.2-1350041, 2013
4. 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
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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
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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
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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。
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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。
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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。
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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。
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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。
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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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Acknowledgement
We greatly acknowledge their generous supports.
Supporters by joint seminaer
Dainippon Sumitomo Pharma
GlaxoSmithKline
Kyowa Kirin
Nippon Boehringer-Ingelheim
Novartis Pharma
Otsuka Pharmaceutical Co.
Nippon Medtronic
Nippon Mediphysics
Supporters
Janssen Pharma
FP Pharmaceutical Co
Abbie
Supporters
Eisai Co.
Hisamitsu Pharma
Nihon Pharmaceutical Co
Takeda Pharmaceutical Co
Ono Pharmaceutical Co
Supported by
Kagawa Prefecture Government
Takamatsu Parkinson Disease Foundation
Endorsed by
Japanese Society of Neurology
International Parkinson and Movement Disorders
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Important information
Save the date
February 2015
iPDSTakamatsu The 14th International Parkinson Disease Symposium in Takamatsu
18TH International Congress of Parkinson’s disease and
Movement Disorders June 8-12,2014
4th Asian and Oceanian Parkinson's Disease and Movement
Disorders Congress (AOPMC) November 28-30,2014
55th Annual Meeting of the Japanese Society of Neurology ; “ Keep
Pioneering” May 21-24,2014 Fukuoka, Japan: