4THINTERNATIONAL · Hôpital du Haut-Leveque Avenue de Magellan Pessac 33604 France ......

4th International Congress on MSA sur 51

Toulouse, France – March 19-20, 2012

4

TH

INTERNATIONAL

CONGRESS ON MULTIPLE SYSTEM

ATROPHY

TOULOUSE, FRANCE, MARCH 19-20, 2012

FACULTY OF MEDICINE

NATURAL HISTORY MUSEUM

35 ALLEES JULES GUESDE, TOULOUSE



Multiple System Atrophy (MSA) is an uncommon, progressive neurological disorder, caused by cell

loss in specific areas of the brain leading to a variety of symptoms affecting especially the functions

of the motor system (cerebellar and/or parkinsonian symptoms) and the autonomic nervous

system. So far, the disease progression cannot be stopped by any medication. However, with

increasing understanding of MSA pathogenesis and availability of animal models, novel strategies

will hopefully become available which can be evaluated by multicentre research groups such as the

EMSA Study Group in Europe and the NAMSA Study Group in North-America. This congress on MSA

follows previous meetings held in Innsbruck in 2007, in Rome in 2004 and in London in 1997.

Numerous discoveries have been made in MSA research since then and this congress will be a

unique opportunity to update and share the knowledge in this field. International specialists of this

disease will give a series of invited lectures on the neuropathological and molecular features,

imaging, investigations and clinical trials related to this rare and disabling disease. The objective of

the conference is also to bring together international basic and clinical neuroscientists to generate

ideas for future research in this long-neglected field.

L’Atrophie Multi-Systématisée (AMS) est une maladie neurologique dégénérative rare et grave,

causée par la perte de cellules dans différentes zones du cerveau conduisant à divers symptômes

affectant surtout le système moteur (symptômes cérébelleux et/ou parkinsoniens) et le système

nerveux autonome. A ce jour, aucun médicament ne peut stopper l’évolution de la maladie.

Cependant, la meilleure compréhension des mécanismes de la maladie et le développement de

modèles animaux devraient aboutir à de nouvelles stratégies thérapeutiques qui sont évaluées par

des groupes de recherche multicentriques, tels que l’EMSA-Study Group en Europe et le NAMSA-

Study Group en Amérique du Nord.

Ce congrès sur l’AMS fait suite aux précédentes réunions qui se sont déroulées à Innsbruck en 2007,

à Rome en 2004 et à Londres en 1997. De nombreuses découvertes ont été faites dans ce domaine

depuis, et ce congrès sera l’occasion d’actualiser et d’échanger les connaissances dans ce domaine.

Les spécialistes internationaux de cette pathologie donneront une série de conférences invitées sur

les caractéristiques neuropathologiques et moléculaires, l’imagerie, les investigations et les essais

cliniques de cette maladie rare et très invalidante. L'objectif du congrès est aussi de réunir des

cliniciens et des scientifiques internationaux pour définir de nouvelles recherches dans ce domaine

longtemps négligé.

Venez nombreux nous rejoindre pour échanger et découvrir les grandes avancées dans le domaine

en vous inscrivant sur le site http://www.msa.univ-tlse3.fr.

http://www.msa.univ-tlse3.fr/

http://www.msa.univ-tlse3.fr/



E. Angot (Sweden) : MD, PhD P. Barone (Italy) : MD, PhD E. Benarroch (USA): MD, PhD B. Bloem (Netherlands) : MD R.G. Brown (UK): MD, PhD C. Colosimo (Italy) : MD, PhD P.O. Fernagut (France): MD, PhD T. Gasser (Germany): MD, PhD N. Giladi (Israel): MD, PhD S Gilman (USA): MD, PhD J. Holton (UK) : MD, PhD A. Iranzo (Spain): MD H. Kaufmann (USA) : MD, PhD T. Klockgether (Germany) : MD, PhD C. Mathias (UK): MD, PhD W. Meissner (France): MD, PhD

A.Pavy-Le Traon (France) : MD, PhD M. Pellechia (Italy): MD, PhD P. Peran (France): MD W. Poewe (Autria): MD, PhD N. Quinn (UK): MD, PhD O. Rascol (France) : MD, PhD A. Schrag (UK) : MD, PhD J.M. Senard (France) : MD, PhD K. Seppi (Austria): MD, PhD N. Stefanova (Austria): MD, PhD F. Tison (France): MD, PhD E. Tolosa (Spain): MD, PhD H. Watanabe (Japan) : MD, PhD G.K. Wenning (Austria): MD, PhD I. Yazawa (Japan): MD, PhD



Colosimo Carlo University Sapienza V. Dell' Universita' 30. Rome 00185 Italy Gilman Sid University of Michigan Health System Department of Neurology 300 N. Ingalls Street Room 3D15 Ann Arbor MI 48109-0489 USA Kaufmann Horacio The Dysautonomia Research Center New York School of Medicine 530 First Avenue Suite 9Q. New York NY 10016 USA Mathias J. Christopher Department of Medicine Imperial College London South Kensington Campus London SW7 2AZ UK Meissner Wassilios Service de Neurologie Hôpital du Haut-Leveque Avenue de Magellan Pessac 33604 France Pavy-Le Traon Anne Centre de Référence MSA Pavillon Riser – Neurologie Hôpital Purpan Place du Dr Baylac 31059 Toulouse Cedex 9 France Poewe Werner Department of Neurology Medical University Innsbruck AnichstraBe 35 A-6020 Innsbruck Austria

Quinn Niall Institute of Neurology Queen Square London WC1N 3BG UK Rascol Olivier Centre de Référence AMS Service de Pharmacologie CIC9302/UMR 825 Faculté de Médecine Purpan UPS Toulouse III 37 Allées Jules Guesde 31000 Toulouse France Senard Jean-Michel Service de Pharmacologie Faculté de Médecine Purpan UPS Toulouse III 37 Allées Jules Guesde 31000 Toulouse France Sobue Gen Department of Neurology Nagoya University Graduate School of Medicine 65 Tsurumai‐cho Showa‐ku Nagoya 466‐8550 Japan Tison François Service de Neurologie Hôpital du Haut-Leveque Avenue de Magellan Pessac 33604 France Tolosa Eduardo Hospital Clinic Universitari Servicio Neurologia Villarroel 170, Esc. 8, 4 Pl. Barcelona 08036 Spain Wenning K. Gregor Division of Clinical Neurobiology Medical University Innsbruck Anichstraße 35 A-6020 Innsbruck Austria



Olivier Rascol Centre de Référence AMS

Service de Pharmacologie

CIC9302/UMR 825

Faculté de Médecine Purpan UPS Toulouse III 37 Allées Jules Guesde

31000 Toulouse, France

Wassilios Meissner

Centre de Référence AMS

Service de Neurologie

Hôpital du Haut-Lévèque

Avenue de Magellan

Pessac 33604, France

Christine Brefel-Courbon

Service de Pharmacologie

Faculté de Médecine Purpan

UPS Toulouse III 37 Allées Jules Guesde


Nelly Fabre


Hôpital Rangueil 1, avenue du Pr Jean Poulhès

TSA 50032

31059 Toulouse Cedex, France

Evelyne Guillaud

Faculté de Médecine Purpan UPS Toulouse III Service de Pharmacologie

37 Allées Jules Guesde


Marie-Ange Albouy

Cellule Congrès

Direction de Soutien aux Laboratoires

Université Paul Sabatier – Toulouse III Bâtiment Administratif Central 118 Rte de Narbonne 31062 Toulouse Cedex 09, France

François Tison Centre de Référence AMS


Hôpital du Haut-Lévèque

Avenue de Magellan

Pessac 33604, France

Anne Pavy-Le Traon Centre de Référence AMS


Hôpital Purpan

Place du Dr Baylac

31059 Toulouse Cedex 9, France

Fabienne Ory-Magne

Service Neurologie A

Pavillon Riser Hôpital Purpan

Place du Dr Baylac


Pierre-Alain Joseph Service de Médecine Physique et de Réadaptation

Pôle de Neurosciences Cliniques

& EA 4136 Handicap et système nerveux CHU Université Victor Segalen Bordeaux2

F-33076 Bordeaux cedex, France

Véronique Cébadero

Centre de Référence AMS


Hôpital Purpan

Place du Dr Baylac


Antoine Lacombe

Ingénieur d’Etudes en Informatique et Télécommunication

Faculté de Médecine Purpan

UPS Toulouse III 37 Allées Jules Guesde


And the French Reference Center for MSA Toulouse & Bordeaux

And the French Competence Network of MSA : F. Durif (Clermont-Ferrand) ; T. Moreau (Dijon) ; P. Krack (Grenoble) ; A. Destee (Lille) ; Ph. Couratier (Limoges) ; E. Broussolle (Lyon) ; J.Ph. Azulay (Marseille) ; W. Camu (Montpellier) ; P. Derkinderen (Nantes) ; A. Brice (Paris) ; J.L. Houeto (Poitiers) ; C. Tranchant (Strasbourg)



March 19 08:00- 09:00

Registration Welcome

Pathogenesis of MSA – Chairs : N. Stefanova (Austria), P.O. Fernagut (France)

09:15-09:35 Update on neuropathology in MSA J. Holton (UK)

09:35-09:55 SNCA variants in MSA T. Gasser (Germany)

09:55-10:15 Are α-synucleinopathies prion-like disorders? E. Angot (Sweden)

10:15-10:35 Autonomic failure in animal models of MSA N. Stefanova (Austria) 10:35-10:55 Coffee break

10:55-11:15 Effect of microtubule depolymerization on α-synuclein accumulation I. Yazawa (Japan)

11:15-11:35 11:35-11:55

Substrates of respiratory failure in MSA Role of neurotrophic factors in animal models of MSA

E. Benarroch (USA) P.O. Fernagut (USA)

Poster Session

12:00-13:15 Guided Poster Tour : H. Kaufmann / S. Gilman (USA) Address : Faculty of Medicine (37 Allees Jules Guesde, Toulouse)

13:15-14:15 Lunch

Clinical presentation and natural history - Chairs : C. Mathias (UK), P. Barone (Italy)

14:30-14:50 Cognitive symptoms in MSA R.G. Brown (UK)

14:50-15:10 Differential diagnosis with cerebellar ataxies T. Klockgether (Germany)

15:10-15:30 Non motor symptoms in MSA : the PRIAMO study C. Colosimo (Italy)

15:30-15:50 Quality of life in MSA A. Schrag (UK) 15:50-16:20 Coffee break

16:20-16:40 The cohort of the French Reference Centre for MSA A. Pavy-Le Traon (France)

16:40-17:00 The Japanese cohort of MSA patients H. Watanabe (Japan)

17:00-17:20 Update on EMSA cohort G. Wenning (Austria)

March 20

Imaging / Biomarkers – Chairs : E. Tolosa (Spain), N. Giladi (Israel)

09:00-09:20 Update on imaging in MSA K. Seppi (Austria)

09:20-09:40 Update on biomarkers for the diagnosis of MSA W. Meissner (France)

09:40-10:00 MRI multimodal approach: a valuable marker for MSA ? P. Peran (France)

10:00-10:20 The insuline like growth factor system in MSA M. Pellechia (Italy) 10:20-10:35 Coffee break

Treatment – Chairs : N. Quinn(UK), F. Tison (France)

10:35-11:55 Management of autonomic failure : cardio-vascular aspects J.M. Senard (France)

10:55-11:15 Management of sleep and respiratory disturbances A. Iranzo (Spain)

11:15-11:35 11:35-11:55

Management of end-stage disease The rifampicin trial

B. Bloem (Netherlands) S. Gilman (USA)

11:55-12:15 Results of the MSA-RAS-202 trial W. Poewe (Austria)

12:15-12:35 On-going and future trials in MSA : emerging agents and targets End of congress

O. Rascol (France)



Les organisateurs du Congrès International sur l’Atrophie Multi-Systématisée remercient tous leurs partenaires institutionnels ou privés qui ont contribués à la réalisation de cette manifestation scientifique internationale. The organizers of “International Congress on Multiple System Atrophy” thank all their institutional or private partners who contributed to organizing this international scientific event.



ARE ALPHA-SYNUCLEINOPATHIES PRION-LIKE DISORDERS?

E. Angot1, J.S. Steiner

1,2, P. Brundin

1,2

1 Neuronal Survival Unit, Department of Experimental Medical Science, Wallenberg Neuroscience

Center, Lund, Sweden

2 Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan

“Alpha-synucleinopathy” is a group of neurodegenerative diseases characterized by the

presence of alpha-synuclein-positive inclusions within the diseased cells. In Parkinson’s

disease, these inclusions, named Lewy bodies and Lewy neurites, are located in neuronal cell

bodies and neurites, respectively. However, alpha-synuclein aggregates are not restricted to

neurons and in multiple system atrophy, glial cells are also affected.

Prion-like propagation of -synuclein has been recently proposed as a new pathogenetic event

in Parkinson’s disease, contributing to the progression of Lewy pathology along with the

disease course. This hypothesis presupposes intercellular transfer of alpha-synuclein from a

donor to a recipient cell, followed by induction of the aggregation of alpha-synuclein proteins

endogenously expressed by the recipient cell around a nucleus of transferred alpha-synuclein,

in a process called “seeding”.

Here we review the evidence supporting this hypothesis. We start with the post-mortem

analysis of transplants from Parkinson’s disease patients, from which this prion-like

hypothesis for alpha-synuclein propagation originates. Then we underline the mechanistic

insights coming from the in vitro studies, especially regarding a potential involvement of

endocytosis and seeding process. We also present the high value of experimental animal

models of this phenomenon. Finally, we question whether a similar process could play a role

in other alpha-synucleinopathies than Parkinson’s disease, such as multiple system atrophy.



SUBSTRATES OF RESPIRATORY FAILURE IN MULTIPLE SYSTEM ATROPHY

Eduardo E Benarroch

Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905

The brainstem respiratory network includes neurons involved in respiratory rhythmogenesis

and chemosensitive neurons that respond to changes in carbon dioxide and oxygen levels. The

normal respiratory rhythm depends on interactions between neurons of the parabrachial

nucleus/Kölliker Fuse complex in he pons and neurons of the ventral medullary respiratory

column, particularly the neurokinin-1 receptor (NK1R) expressing neurons of the

preBötzinger complex (preBötC), which have pacemaker-like activity and are critical for

respiratory rhythmogenesis. Respiratory chemosensitivity depends on glutamatergic neurons

of the retrotrapezoid nucleus (RTz) and serotonergic neurons in the medullary raphe, include

the nucleus raphe obscurus. Sleep-related respiratory abnormalities, including laryngeal

stridor, central sleep apnea, and dysrhythmic breathing are important manifestations of

multiple system atrophy (MSA). There is loss of NK-1R immunoreactive neurons in the

preBötC and serotonergic neurons in the nucleus raphe obscurus and ventral medullary

surface in these cases. Loss of medullary serotonergic neurons relates to sudden death in MSA

patients. The degree of neuronal loss in these respiratory areas is more severe in MSA than in

cases with dementia with Lewy bodies and comparable severity of autonomic failure. The

mechanism of laryngeal stridor in MSA is controversial , as there is inconsistent involvement

of laryngeal motoneurons of the nucleus ambiguus in this disorder.



MANAGEMENT OF END-STAGE DISEASE

Bastiaan R. Bloem

Department of Neurology, Donders Centre for Brain, Cognition and Behaviour, Radboud University

Nijmegen Medical Centre, The Netherlands

Patients with multiple system atrophy (MSA) face a poor prognosis. Disease progression is

more rapid compared to Parkinson’s disease. Moreover, many complications develop in a

much earlier disease phase, and are also more pronounced. These problems are compounded

by the fact that most symptoms and signs usually respond poorly (or even not at all) to

dopaminergic treatment. In fact, pharmacotherapy can sometimes worsen the situation, for

example when dopaminergic medication aggravates orthostatic hypotension. Consequently,

even with optimal medical management, patients with MSA are faced with progressively

increasing impairments (e.g. in speech or movement-related functions), activity limitations

(e.g. self-care and mobility) and restrictions in participation (e.g. domestic life and social

activities). In my presentation, I will discuss why allied health professionals and other forms

of non-pharmacological treatment are an important cornerstone in the management of MSA.

Such non-pharmacological treatment includes physiotherapy, occupational therapy and

speech-language therapy, as well as help delivered by dieticians, social workers or

sexologists. Allied health care has long been regarded as being much of an “art”, based on

poorly described know-how passed along by teachers and supplemented with personal

experience. However, I will discuss that allied health care is rapidly maturing as an evidence-

based profession, where therapists can increasingly base clinical decisions on evidence-based

guidelines. I will address several generic principles of allied health care, outline the specific

challenges for allied health care that occur when treating MSA patients, review the various

specific contributions of allied health, and conclude with a debate about the pros and cons of

an integrated multidisciplinary approach (including the possible role of patients and their

families in the team).



COGNITIVE SYMPTOMS IN MSA

RG Brown for the NNIPPS Study Group

King’s College London, Institute of Psychiatry, Department of Psychology (PO77), De Crespigny

Park, London SE5 8AF,UK

Cognitive impairment is recognized feature of Progressive Supranuclear Palsy with dementia

occurring in a significant proportion of patients. In MSA, however, significant cognitive

impairment is less typical and when present early in the clinical presentation argues against a

diagnosis of MSA by current criteria. Data are presented on a sample of 372 patients with

MSA from the NNIPPS cohort (mean age 61.7±8.34 years, mean disease duration 4.55±1.92

years). Cognition as assessed by the Mattis Dementia Rating Scale (DRS) was impaired in

19.5% (score <5thile) of which 10.9% were severely impaired (<1%). On the Frontal

Assessment Battery 42% scored below the cut-off. The profile of cognitive impairment on the

DRS was identical that seen in a parallel sample of patients with Progressive Supranuclear

Palsy. Logistic regression analysis identified the following predictors of impairment in MSA;

greater motor disability (OR 3.58, 95% confidence interval 1.75-72.9), less education (2.27,

1.10-4.65), male gender (1.94, 1.05-3.56), the presence of cardiovascular dysautonomia (2.64,

1.34-5.05) and the absence of genitourinary symptoms (4.02, 1.67-9.60). Severity of

impairment was modestly related to disease duration (r=0.17, p=0.002) in cross-sectional

analysis. Annual follow-up was available in 235, 148 and 106 cases over the following years

and revealed a linear increase in the prevalence cognitive impairment, with a cumulative

figure (1-survival) of 0.41. Post-mortem diagnosis was obtained in 47 cases including 10 with

cognitive impairment. A diagnosis of MSA was confirmed in 95% of those without

impairment on 70% of those with impairment. The data suggest that significant cognitive

impairment, similar to that seen in other parkinsonian syndromes, is a relatively common

feature of MSA, particularly in patients with more severe disease and/or those surviving

longest.



NON-MOTOR SYMPTOMS IN MULTIPLE SYSTEM ATROPHY: THE PRIAMO STUDY

C. Colosimo1, P. Barone

2 and the PRIAMO study group

1Sapienza University of Rome,

2 University of Salerno, Italy

The PRIAMO study is a cross-sectional longitudinal observational study aimed at describing

epidemiology and evolution of non-motor symptoms (NMS) in patients with different forms

of parkinsonism recruited in 55 Italian centers and evaluated over 24 months. In this

presentation, we are reporting the prevalence and clinical characteristics of NMS in patients

with multiple system atrophy (MSA) as compared to Parkinson’s disease (PD) and other

parkinsonian disorders. Out of 1307 consecutive patients with a diagnosis of parkinsonism,

1072 had PD, 34 had MSA, 30 had progressive supranuclear palsy (PSP), and 11 had

corticobasal degeneration (CBD). MSA had the highest total number of NMS domains and, in

particular, gastrointestinal symptoms, pain, urinary problems and postural instability due to

orthostatic hypotension were significantly more frequent in MSA than in the other groups.

Sleep disturbances were also very common with a prevalence of approximately 70% in all

diagnostic groups. Psychiatric symptoms and attention and memory impairment were

frequently observed in all diagnoses, but were most prevalent among PSP and CBD patients;

conversely, the prevalence of skin and respiratory disorders was rather low in all forms,

ranging between 10 and 30%. On the long-term follow–up MSA cases continued to have

significantly more burden due to NMS as compared to PD; in addition, based on the

modifications of UPDRS-III and HY scores, a faster disease progression in MSA than in PD

was confirmed. Atypical parkinsonian patients also reported a low quality of life (QoL), with

no significant differences among the different forms, whereas PD patients consistently had a

better QoL during the entire observation period.



RESPIRATORY DYSFUNCTION IN AN ANIMAL MODEL OF MSA

P.O. Fernagut

Institut des Maladies Neurodégénératives, CNRS UMR5293, Université Bordeaux2, 33076 Bordeaux,

France

Multiple system atrophy (MSA) frequently manifests with breathing disorders such as apnea,

or laryngeal stridor at any stages. These breathing disorders are thought to be associated with

poor prognosis and no validated treatment is available so far. These clinical features are due

to the extension of the neurodegenerative process to the pontomedullary respiratory nuclei,

such as serotoninergic medullary Raphe Pallidus, Magnus, Obscurus and pre-Bötzinger

complex. We investigated respiratory function and some of the brainstem nuclei involved in

the genesis and regulation of respiratory rhythms in a transgenic mouse model of MSA based

on oligodendroglial expression of human wild-type alpha-synuclein under the control of the

proteolipoid promoter. Analysis of respiratory function in transgenic mice indicates that this

model replicates some of the breathing and pathological characteristics seen in MSA. Our

findings corroborate the use of transgenic mouse models as a testbed for future candidate

drugs discovery in MSA breathing disorders.



SNCA VARIANTS IN MSA

T. Gasser

Department of Neurodegenerative Diseases at the Hertie Institute for Clinical Brain Research at the

University of Tübingen, Germany

Multiple systems atrophy (MSA) is a sporadic neurodegenerative disease, which is

pathologically characterized by alpha-synuclein aggregates, predominantly in the form of glial

fibrially inclusions (GCIs) in oligodendroglial cells. A recent study has shown that common

genetic variants (SNPs) in the gene encoding α-synuclein (SNCA) are associated with an

increased risk to develop MSA in a clinically diagnosed as well as in a post-mortem

confirmed cohort of patients (Scholz et al., 2009). This finding was confirmed in two further

independent studies in Caucasians (Al-Chalabi et al., 2009, Ross et al., 2010), although

different SNPs were identified in those studies. The association was not replicated in a Korean

cohort (Yun et al., 2010), suggesting population differences.

Common variants in SNCA are also the major genetic risk factors for Parkinson’s disease, a

finding that has been replicated in many studies. It is unclear, if the association signal detected

in MSA has the same structure as the one found in PD. The different minor allele frequencies,

some of the most associated variants and the different genetic models giving the strongest

association (recessive in MSA and trend in PD) may point towards different genetic

architectures and therefore potentially to different underlying pathogenic mechanisms. A

recent attempt to replicate the initial finding in MSA has been unable to confirm the finding

(Anna Sailer, unpublished results). Reanalysis of the original data indicates that the signal was

due to a small number of patients with MSA-C, suggesting etiologic heterogeneity of the

group. Insight into these differences may help to better understand the pathologic role of α-

synuclein in the pathogenesis of both diseases and eventually even have therapeutic potential.



THE RIFAMPICIN TRIAL

S. Gilman1, Ph. A. Low

2, D. Robertson

3, I. Bioggioni

4, R. Freeman

5, H. Kaufmann

6, S. Perlman

7, R.A.

Hauser8, W.P. Cheshire

9, S.L. Lessig

10 and S. Vernino

11

1 University of Michigan, Ann Arbor, MI, United States, 48105; 2Mayo Clinic, Rochester, MN, United

States, 55905; 3Vanderbilt University, Nashville, TN, United States, 37232; 4Vanderbilt University,

Nashville, TN, United States, 37232; 5 Beth Israel Deaconess Medical Center, Boston, MA, United

States, 02215; 6 New York University, New York, NY, United States, 10016; 7 UCLA Medical Center,

Los Angeles, CA, United States, 90095; 8 University of South Florida, Tampa, FL, United States,

33612; 9 Mayo Clinic, Rochester, MN, United States, 55905; 10 UCSD, La Jolla, CA, United States,

92037 and 11 UT Southwestern Medical Center, Dallas, TX, United States, 73590.

MSA is a rapidly progressive neurological disorder characterized by autonomic failure with

parkinsonism and/or cerebellar ataxia. It is defined neuropathologically by glial cytoplasmic

inclusions of aggregated misfolded alpha-synuclein with widespread neuronal degeneration.

In a transgenic mouse model of MSA, Rifampicin, a bactericidal antibiotic, inhibits formation

of alpha-synuclein fibrils and disaggregates already formed fibrils, thereby improving

behavioral abnormalities and halting or reversing neuropathological changes. We initiated a

randomized, double-blind, placebo-controlled 12-month clinical safety/efficacy study of 100

patients with possible or probable MSA, 50% consigned to active drug (Rifampicin 300 mg

twice daily), 50% consigned to placebo (Riboflavin capsules twice daily). Subjects are

recruited from 10 US sites. Inclusion criteria include subjects of either gender; ages 30 to 80

yrs; less than 4 years from time of diagnosis; expected survival of at least 3 yrs; able to give

informed consent; MMSE >24. Exclusion criteria include modified UMSARS 1 score >17;

tetrabenazine, rasagiline or selegiline; abnormal liver function tests; medications affecting

autonomic function; neuroleptics; dementia. Primary outcome measure will be the rate of

change from baseline to 12 months in total UMSARS 1 score. Secondary outcome measures

will include the change from baseline to completion in total UMSARS score; slope analysis of

rate of progression in total UMSARS score from baseline to 12 months; change from baseline

to 12 months in UMSARS subscores. 76 subjects have been recruited to date, 43% women

and 57% men, mean age 60.9 ± 8.3 (mean ± standard deviation), age range 41.7 years to 79.9

years, 48% possible MSA, 52% probable MSA. Thus far (starting April 25, 2011) there have

been 41 adverse events, including 2 serious adverse events. One subject has dropped out of

the trial. Based upon strongly positive results in the animal model, there is a chance of

slowing disease progression in subjects with MSA, a rapidly progressive, fatal neurological

disorder.



UPDATE ON NEUROPATHOLOGY IN MSA

J.L. Holton

Queen Square Brain Bank, UCL Institute of Neurology, 1 Wakefield Street, London, WC1N 1PJ, UK

Multiple system atrophy (MSA) is a sporadic adult onset neurodegenerative disease, in which

clinical features include parkinsonism, cerebellar ataxia and autonomic failure.

Neuropathological studies have shown regional neuronal loss and gliosis. The

neuropathological hallmark of MSA is the glial cytoplasmic inclusion (GCI), an

oligodendroglial inclusion containing fibrillar α-synuclein. α-Synuclein immunoreactive

inclusions are also found in neurons and MSA is regarded as a member of the group of α-

synucleinopathies that also includes idiopathic Parkinson’s disease and dementia with Lewy

bodies. The pattern of regional neuronal loss has given rise to the concept of pathological sub-

types of MSA and the prevalence of these sub-types has been shown to vary between different

ethnic populations. GCIs are believed to be important in the pathogenesis of MSA as their

density in striatonigral and olivopontocerebellar regions correlates with neuronal loss and

disease duration, although, we have limited understanding of the mechanism of GCI

formation. In this presentation the neuropathological features of MSA will be described, along

with recent advances in understanding the pathogenesis of the disease.



SLEEP DISORDERS AND ITS MANAGEMENT IN MULTIPLE SYSTEM ATROPHY

A. Iranzo

Neurology Service, Hospital Clínic and Institut d’Investigació Biomèdiques August Pi i Sunyer

(IDIBAPS), Barcelona, SPAIN

Multiple system atrophy (MSA) is a sporadic neurodegenerative disease with a shortened life

span, clinically characterized by parkinsonism, cerebellar syndrome and autonomic failure in

any combination. Insomnia and sleep fragmentation are common and may be the consequence

of associated anxiety, depression, urinary dysfunction and difficulty in turning in bed due to

rigidity, bradykinesia and poor coordination. Excessive daytime sleepiness occurs in 28% of

the subjects and is related to poor nocturnal sleep and sleep disordered breathing.

Neuropathological studies show hypocretinergic cell loss in the posterior hypothalamus but

hypocretin-1 levels in the cerebrospinal fluid are normal. Restless legs syndrome occurs in

25% of the patients.

REM sleep behavior disorder (RBD) occurs in most, if not all, of the male and female patients

with MSA and may result in injuries. In half of the MSA subjects RBD precedes the onset of

the waking motor manifestations of MSA. Seventy-seven percent of the patients are unaware

of their abnormal sleep behaviors which are only noticed by the bed partners. Recall of the

RBD-associated unpleasant dreams is present in 65%. When compared with Parkinson’s

disease patients with associated RBD, MSA patients with RBD have higher REM sleep

without atonia percentage, a greater periodic leg movement index and less total sleep time.

Clonazepam improves RBD symptoms.

Sleep and breathing disorders are very common in MSA and may antedate autonomic failure

symptoms, parkinsonism and cerebellar syndrome onset. There are two different causes of

sleep-disordered breathing in MSA. One is central alveolar hypoventilation due to

degeneration of the pontomedullary respiratory centers resulting in central sleep apnea and

Cheyne-Stokes respiration. The other cause is obstructive sleep apnea as a result of upper

airway obstruction at the pharynx and larynx levels. Stridor during sleep occurs in up to 42%

of the patients and reflects laryngeal narrowing which is detected by laryngoscopy. Detection

of stridor in MSA is very important because this condition is associated with life-threatening

episodes of respiratory failure, sudden death during sleep and short survival. Nocturnal stridor

occurs in all clinical stages and subtypes of MSA and it may be the initial symptom of the

disease. Compared to MSA subjects without stridor, patients with stridor have higher apnea-

hypopnea index, oxyhemoglobin desaturations and vocal cord abnormalities on laryngoscopy.

Stridor during wakefulness follows nocturnal stridor and indicates marked laryngeal

obstruction and potential severe respiratory failure. The origin of laryngeal obstruction in

MSA is unclear, but it is thought to be related to both 1) neuronopathy of the recurrent

laryngeal nerve leading to denervation of the vocal cord abductors and 2) overactivation of

the vocal cord adductors in response to increased upper airway resistance due to vocal cord

abductor paralysis. Continuous positive airway pressure (CPAP) is an effective non-invasive

long-term treatment for eliminating stridor and obstructive sleep apnea in MSA increasing the

mean life expectancy of the disease. In subjects with stridor during wakefulness elective

tracheostomy should be advised since this condition leads to dramatic subacute episodes of

respiratory failure.



DIFFERENTIAL DIAGNOSIS WITH CEREBELLAR ATAXIAS

T. Klockgether

Department of Neurology, University of Bonn and German Center for Neurodegenerative Diseases

(DZNE), Sigmund-Freud-Str. 25, D-53105 Bonn, Germany

In the majority of patients suffering from adult onset, progressive ataxia, ataxia manifests

without an obvious familial background. The classification and correct diagnosis of these

sporadic patients remain a challenge, as almost the entire spectrum of non-genetic and genetic

causes of ataxia has to be considered. There is a wide range of potential acquired causes of

ataxia including alcoholism, various other toxic agents, immune-mediated inflammation,

vitamin deficiency, chronic leptomeningeal deposition of iron leading to superficial siderosis,

and chronic CNS infection. Mutations of single genes may also underlie sporadic ataxia in

adults. Finally, patients may suffer from a sporadic degenerative disease, such as multiple

system atrophy of cerebellar type (MSA-C) or sporadic adult onset ataxia of unknown

aetiology (SAOA). The definition of clinical criteria and delineation of characteristic MRI

features have greatly facilitated the early and correct recognition of sporadic ataxias. In

addition, specific serological and genetic markers are available which allow a definite

diagnosis in many cases.



UPDATE ON BIOMARKERS FOR THE DIAGNOSIS OF MSA

W. Meissner

Centre de Référence Atrophie Multisystématisée et service de neurologie, CHU de Bordeaux, Pessac,

France et Institut des Maladies Neurodégénératives, CNRS UMR 5293, Université Bordeaux 2,

France

The diagnosis of MSA is based on clinical consensus criteria and post-mortem confirmation.

Hitherto, no valid biomarker is available for the diagnosis of MSA. Previous studies have

focused on proteins that are constituents of glial cytoplasmic inclusions (GCIs), the

pathological hallmark feature of MSA, markers of inflammation and metabolites of

neurotransmitter systems that are included in the neurodegenerative process in MSA. For

instance, these studies have reported increased CSF levels of neurofilament and tau protein as

well as reduced CSF concentrations of flt3 ligand, homovanillic acid, 5-hydroxyindoleacetic

acid and 3-methoxy-4-hydroxyphenylethyleneglycol. Some of these markers have allowed the

distinction between MSA, Parkinson’s disease (PD) and sporadic adult onset ataxia of

unknown aetiology, but these results require confirmation in larger studies. Moreover, results

were obtained in populations with an established clinical diagnosis of MSA. It remains

therefore unclear whether the assessed CSF markers will be helpful in patients with

incomplete MSA phenotype, a frequent challenge in clinical practice.

α-synuclein is a major constituent of GCIs in MSA and Lewy bodies in PD. CSF and plasma

levels of oligomeric α-synuclein are increased in PD patients. Moreover, CSF concentrations

are higher in patients with mild PD suggesting that they may change over time. Given the

more severe nature of underlying disease mechanisms, these observations make oligomeric α-

synuclein an excellent candidate for future biomarker development in MSA.

The presentation will discuss recent progress and promising future avenues for CSF and

plasma biomarker development in MSA.



THE COHORT OF THE FRENCH REFERENCE CENTRE FOR MSA

A. Pavy-Le Traon1, O. Rascol1, F. Tison2 and W.G. Meissner2

1Centre de référence atrophie multisystématisée, Service de neurologie, CHU de Toulouse, France

2Centre de référence atrophie multisystématisée, Service de neurologie, CHU de Bordeaux, Pessac,

France

Multiple system atrophy (MSA) is a neurodegenerative disorder presenting as a variable

combination of autonomic failure, parkinsonism, cerebellar ataxia and pyramidal tract

dysfunction. Patients are divided into MSA-P or MSA-C according to the predominant motor

feature (parkinsonism vs. cerebellar dysfunction). A cohort of 170 MSA patients has been

followed within the French Reference Center for MSA since 2008 (82 women and 88 men;

mean age: 65 +/-8 years). Every year, each patient undergoes a standard follow-up visit

including demographic data and disease characteristics: “possible” or “probable” MSA,

duration, type P or C, severity (UMSARS and SCOPA-AUT (for dysautonomia)) and MSA

Health-Related Quality of Life scale (MSA-QoL).

The mean age at onset was 59 +/-8 years; the mean disease duration was 5.4+/-2.6 y. Most

patients met criteria for probable MSA (about 90%).One hundred and nine patients were

classified as having MSA-P and 61 patients as having MSA-C. These results are in agreement

with large data series from Europe. At the last visit of these patients mean UMSARS I score

was 23+/-8 and mean UMSARS II score was 26+/-9; mean MSA-QoL was 74+/-29 (maximal

score 180 with higher total scores reflecting more impaired quality of life) confirming the

important impairment of QoL in this disabling disease. The implementation of this cohort

which also includes a yearly follow-up of some patients provides key information on MSA

natural history.



THE INSULINE LIKE GROWTH FACTOR SYSTEM IN MSA

M.T. Pellecchia,1 R. Pivonello,

2 A. Colao,

2 and P. Barone

1

1Center for Neurodegenerative Disorders, University of Salerno, Italy

2Department of Molecular and Clinical Endocrinology and Oncology, Federico II University, Naples,

Italy

Insulin-like growth factors (IGF-I and IGF-II) have several neurotrophic actions and IGF

system may be impaired in neurodegenerative disorders. We investigated the IGF system in

patients with MSA and evaluated correlations between this endocrine system and clinical

features of the disease.

Serum levels of IGF-I, IGF-II, insulin, IGF-binding protein 1 (BP1) and IGF-binding protein

3 (BP3) were measured in 25 patients with probable MSA and 25 age, sex and BMI-matched

healthy controls.

IGF-I levels were significantly higher in MSA (164,1 + 66,2 g/L) than in healthy controls

(111,7 + 60,3 g/L; p = 0.001). Insulin levels were significantly higher in MSA patients (21,9

± 14,4 U/mL) and healthy controls (13,3 ± 5,1 U/mL, p=0.048). No significant difference

was found in serum IGF-II, IGF-BP1 and IGF-BP3 levels between patients with MSA and

healthy controls. There was a trend toward significantly higher IGF-II levels in MSA patients

with UMSARS score <25 (1026,3 ± 442,6 g/L) than MSA patients with UMSARS score

>25 (796,1 ± 234 g/L , p=0.055).

The results of the present study demonstrated that IGF system is altered in MSA. The

degenerative process in MSA could lead to a compensatory increase in IGF-I and insulin in an

attempt to provide additional support to degenerating neurons.



MRI MULTIMODAL APPROACH: A VALUABLE MARKER FOR MSA?

P. Péran, A. Pavy-Le Traon, O. Rascol

Inserm U825, Toulouse, France

CIC, Toulouse, France

Centre de Référence Atrophie Multisystématisée, Service de neurologie, CHU de Toulouse, France

The diagnosis of multiple system atrophy (MSA) is difficult, particularly, in early stages of

the disease. One objective of modern neuroimaging is to identify markers that can aid in

diagnosis, disease progression monitoring, and analysis of treatments effects. Magnetic

resonance imaging (MRI) demonstrated consistent and promising results using advanced

techniques. However, most of previous work has been limited by single modality imaging. An

approach measuring MR parameters sensitive to complementary tissue characteristics (e.g.

volume atrophy, iron deposition and microstructural damage) in brains of MSA patients could

have great potential for investigating pathological changes. Indeed, a previous study showed

that multimodal MRI is able to discriminate patients with Parkinson’s disease from healthy

control subjects. The markers comprising discriminating combinations were R2* (reflecting

iron content) in the substantia nigra, fractional anisotropy (reflecting microstrutural

orientation) in the substantia nigra and mean diffusivity (reflecting microstrutural integrity) in

the putamen or caudate nucleus. These findings demonstrated that multimodal MRI of

subcortical grey matter structures is useful for the evaluation of Parkinson’s disease and,

possibly, of other subcortical pathologies as MSA.



A RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL TO ASSESS THE EFFECTS OF

RASAGILINE IN PATIENTS WITH MULTIPLE SYSTEM ATROPHY OF THE PARKINSONIAN

SUBTYPE - RESULTS OF THE MSA-RAS-202 TRIAL

W. Poewe, P. Barone, N. Giladi, S. Gilman, P. Low, O. Rascol, C. Sampaio, K. Seppi and G. Wenning

for the Rasagiline-for-MSA Investigators

Department of Neurology, Medical University of Innsbruck, Austria

Objective: To assess the effect of rasagiline in patients with Multiple System Atrophy of the

Parkinsonian subtype (MSA-P).

Background: Rasagiline is a second generation MAO-B inhibitor indicated for the treatment

of Parkinson’s disease (PD). MSA is a complex neurodegenerative disorder characterized by

Parkinsonian, autonomic and cerebellar symptoms, for which there is currently no effective

treatment.

Methods: 174 patients (39 sites 12 countries) with a diagnosis of possible or probable MSA-P

were randomized to receive rasagiline 1 mg/day or placebo (84:90) for 48 weeks. The primary

endpoint was change from baseline to study end in the Unified Multiple System Atrophy

Rating Scale (UMSARS). Safety and tolerability were assessed through AEs, and percent of

subjects who discontinued. An MRI substudy included 40 patients and assessed changes in

putaminal diffusivity as primary outcome.

Results: Of the 174 randomized patients (100M/74F), 138 completed the study and 36

prematurely terminated. Patients had relatively early and mild MSA; mean (± SD) age at

baseline was 65.0 ± 8.5 years, time from diagnosis was 0.7 ± 0.8 years and total-UMSARS

score was 37.2 ± 8.9 units. Based on modified Intention-To-Treat analysis, at week 48,

patients in the rasagiline group had progressed by an adjusted mean (± SE) of 7.2 ± 1.2 total-

UMSARS units vs. 7.8 ± 1.1 units in the placebo group. This difference was not statistically

significant (p=0.70). No differences between groups were noted in key secondary endpoints

or change of putaminal diffusivity in the MRI substudy. No new safety concerns were

observed; AEs (rasagiline vs. placebo groups) were reported in 81.0% vs. 74.4%, AEs leading

to withdrawal were reported in 16.7% vs. 7.8%, and serious AEs were reported in 34.5% vs.

25.6%. Five deaths (three in rasagiline vs. two in placebo) occurred but none were related to

study drug.

Conclusions: In this population of MSA-P patients, rasagiline at a dose of 1mg/day did not

have a significant effect as assessed using the UMSARS scale.



ON-GOING AND FUTURE TRIALS IN MSA : EMERGING AGENTS AND TARGETS

O. Rascol

French Reference Center on MSA, Toulouse University Hospital, France

Multiple system atrophy (MSA) is an aggressive orphan disorder presenting clinically as a

combination of parkinsonian, cerebellar and autonomic symptoms largely resisting to

therapies, leading to severe handicap and premature death. MSA is characterized by striato-

nigral neurodegeneration and olivo-pontocerebellar atrophy with abnormal alpha-synuclein

aggregation. Within the last few years, important progresses have been achieved both from a

pre-clinical and clinical perspective. Novel animal models, combining genetic and toxic

approaches, improved our understanding of the pathophysiology of MSA, allowing

conceptualizing novel targets and screening strategies for future therapeutic interventions. In

parallel, national and European funding supported active clinical networks of centers with

special interest in MSA. Such initiatives have been instrumental in accelerating progresses in

several crucial areas including: (1) developing consensus diagnostic criteria and clinical rating

scales to better assess patients’ symptoms, disability and health-related quality of life, (2)

setting-up large prospective clinical databases for a better understanding of the natural history

of MSA, (3) implementing large biobanks exploring new biomarkers (including neuro-

imaging and biological ones) to assess genetic and environmental factors, and to improve

diagnosis accuracy and sensitivity to changes over time. Such developments have then

allowed conducting the first large placebo-controlled randomized clinical trials in the field to

assess the efficacy and tolerability of drugs like riluzole, minocycline, fluoxetine, rasagiline,

rifampicine, lithium and others… Future symptomatic and neuroprotective approaches look

promising, including cell and gene therapy. Such progresses are expected to translate in the

future into better management and prognosis for MSA patients.



HEALTH-RELATED QUALITY OF LIFE IN MSA

A. Schrag

Institute of Neurology, University College London, UK

MSA is a devastating disease affecting motor, autonomic and emotional function with

relentless progression. Efforts to both improve symptoms, with pharmacological and non-

pharmacological measures, and to slow disease progression aim at improving impact on the

patient’s experience. Health-related quality of life (QoL) studies have therefore aimed at

outlining the most important aspects of this disease on the patient, the influence of disease-

related and other factors on patient experience, and at providing the most accurate subjective

assessment of problems from the patients’ point of view. Generic QoL instruments have

shown the profound impact of physical aspects on mobility, self-care and activities of daily

living with depression and anxiety, autonomic dysfunction and mobility as the main

predictors of poor QoL scores. The longitudinal natural history study of the EMSA-SG has

provided evidence for the reflection of physical deterioration in patient experience, which

particular deterioration of the physical aspects, self care and activities of daily living, whereas

pain and depression and anxiety remain stable. To date, only few data on change in QoL

scores in treatment trials are available. A more detailed profile of the subjective experience of

having MSA than with the generic QoL scales is provided using the MSA-QoL, which

captures the specific motor and non-motor impairments of MSA as well as emotional and

social impact. This scale has been found to have excellent psychometric properties in its

English, French and German versions, and further validation studies are being conducted.

Future clinical studies in MSA should incorporate these patient-reported scales to assess

treatment effects on patients’ subjectively experienced health.



MANAGEMENT OF AUTONOMIC FAILURE IN MSA: CARDIOVASCULAR ASPECTS

F. Despas1,2, M. Lebrin2, A. Pavy-Le Traon2, A. Pathak, J.M. Senard

Autonomic Unit, departments of clinical pharmacology and of cardiology, French reference centre for

MSA, Toulouse University Hospital, INSERM U1048, 37 allées Jules Guesde, 31000 Toulouse, France

Cardiovascular autonomic failure (AF) is frequently observed in MSA. It results from

complex modifications of autonomic nervous system (ANS) including brainstem and spinal

cord neuronal degeneration and adaptation of peripheral adrenergic receptors. Apart from

neurogenic orthostatic hypotension (NOH), other disorders have to be taken into account

before starting treatment such as postprandial hypotension, supine hypertension, increased

arterial stiffness and increased risk of cardiac rhythm disorders. Thus, MSA patients should be

considered at high risk of cardiovascular morbidity and mortality. Therapeutic decision, but

also follow-up, should only be undertaken after careful evaluation of patient’s cardiovascular

status, in the frame of a multidisciplinary approach including cardiologists and neurologists.

Concerning NOH, management should first focus on non pharmacological measures (elastic

socks), when possible eviction of drugs favouring OH, patient education and correction of the

frequently associated anemia. A lot of drugs have been proposed for the treatment of NOH

including alpha1-adrenoceptor agonists (midodrine, dihydroergotamine), noradrenaline

precursors (droxidopa), enhancers of ganglionic transmission (pyridostigmine), plasma

volume expanders (mineralocorticoids, vasopressin analogs) or blockers of noradrenaline

neuronal transporters. Up today, efficacy and long term safety of these drugs have scarcely

been evaluated and the actual consensus is that their use should be limited to patients with

symptomatic NOH. Drug selection depends on patient comorbidities, presence or not of

supine hypertension. Postprandial hypotension can be improved by food intake fractioning

and/or water intake. Despite of its high frequency, no pharmacological strategy has been

proven to be of interest in the management of supine hypertension.



UPDATE ON IMAGING IN MSA

K. Seppi

Department of Neurology, Medical University Innsbruck, Anichstrabe 35, Innsbruck, Austria

Advances in different neuroimaging techniques have allowed the detection of functional and structural

brain changes in patients with multiple system atrophy (MSA). The traditional role of neuroimaging in

MSA aimed at the differentiation of MSA from other forms of neurodegenerative parkinsonism,

especially Parkinson’s disease. Indeed, the revised MSA consensus criteria include several imaging

features. Atrophy on conventional MRI of putamen, middle cerebellar peduncle, pons or cerebellum or

hypometabolism on FDG-PET in putamen, brainstem or cerebellum were included as additional

features for possible MSA-P; and atrophy on conventional MRI of putamen, middle cerebellar

peduncle or pons or hypometabolism on FDG-PET in putamen were included as additional features for

possible MSA-C. Moreover, diffusion-weighted and diffusion-tensor imaging may detect diffusion

abnormalities in the basal ganglia and infratentorial structures in patients with MSA at an early stage

of disease. Beside diagnostic aspects, serial neuroimaging studies in MSA have been shown to have

the potential to study lesion progression in vivo. This presentation will summarize and update the state

of the art knowledge concerning neuroimaging in differentiating MSA from other forms of

neurodegenerative parkinsonism as well as in assessing progression of the disease.



AUTONOMIC FAILURE IN ANIMAL MODELS OF MSA

N. Stefanova

Division of Neurobiology, Department of Neurology, Anichstr. 35, Innsbruck, Austria

Progressive autonomic failure (AF) is a major manifestation of multiple system atrophy

(MSA). AF frequently accompanies or precedes variable motor presentations of MSA

including cerebellar ataxia and parkinsonism. The presence of AF is therefore obligatory for

the diagnosis of clinically probable MSA. The neuropathological substrate of MSA involves

system-bound neurodegeneration that is associated with α-synuclein (αSYN)-positive

(oligodendro)glial cytoplasmic inclusions (GCIs). Modelling AF related to MSA-like

pathology in rodents may represent an important preclinical tool to study underlying

pathomechanisms and identify therapeutic targets. Transgenic overexpression of α1B-

adrenergic receptors in mice generated MSA-reminiscent wide-spread neurodegeneration

linked to cardiovascular autonomic dysfunction and motor impairment, associated with the

formation of neuronal and oligodendroglial αSYN inclusions by yet unclear mechanisms.

Transgenic mice, overexpressing human αSYN under oligodendroglial promotors were

developed to reproduce the specific GCI pathology of MSA and to study the related

neurodegeneration and motor phenotype. The observations in (PLP)- SYN transgenic mice

were extended by demonstrating progressive degeneration of brain areas, closely linked to AF

and other non-motor symptoms in MSA, including locus coeruleus, nucleus ambiguus,

laterodorsal tegmental nucleus, pedunculopontine tegmental nucleus and Onuf’s nucleus.

Although the spatial and temporal evolution of central autonomic pathology in MSA is

unknown the findings in transgenic MSA mice corroborate their utility as a testbed to study

oligodendroglial SYN mediated neurodegeneration replicating both motor and non-motor

aspects of MSA.



THE JAPANESE COHORT OF MSA PATIENTS

G. Sobue, H. Watanabe, M. Ito, J. Senda, N. Atsuta, M. Katusno, F. Tanaka, M. Yoshida

Department of Neurology, Nagoya University Graduate School of Medicine, 65 tsurumai-cho Showa-

ku Nagoya, 466-8550 Japan

Multiple system atrophy (MSA) is a sporadic neurodegenetative disorder characterized by

various combinations of autonomic failure, cerebellar ataxia, parkinsonism, and pyramidal

symptoms. Based on our cohort study in 230 Japanese patients with MSA (131 men, 99

women; 208 probable MSA, 22 definite; mean age at onset, 55.4 years), MSA-C

predominated in 155 patients, and MSA-P in 75. This proportion has been identified by

several studies in Japan. In addition, our pathological cohort of 161 patients with MSA also

demonstrated that MSA-C is predominant compared to MSA-P although the frequency of the

MSA-P is relatively high in Western countries. The median time from initial symptom to

combined motor and autonomic dysfunction was 2 years (range 1-10). Median intervals from

onset to aid-requiring walking, confinement to a wheelchair, a bedridden state and death were

3, 5, 8 and 9 years, respectively. Patients manifesting combined motor and autonomic

involvement within 3 years of onset had a significantly increased risk of not only developing

advanced disease stage but also shorter survival. MSA-P patients had more rapid functional

deterioration than MSA-C patients, but showed similar survival. Onset in older individuals

showed increased risk of confinement to a wheelchair, bedridden state and death. These

progression pattern and prognosis were very similar to the results from Western countries.

Recent our prospective study of the progression of cerebral involvement in MSA using both

diffusion tensor imaging and voxel based morphometry demonstrated that MSA patients

would show more widespread cerebral involvement than previously supposed.



UPDATE ON EMSA COHORT – THE EMSA NATURAL HISTORY STUDY

G.K. Wenning and F. Krismer on behalf of the EMSA-SG

Division of Neurobiology, Department of Neurology and Neurosurgery, Medical University,

Anichstraße 35, A-6020 Innsbruck, Austria

Objective: To prospectively study the natural history of multiple system atrophy (MSA) using

validated and disease-specific rating instruments.

Background: MSA is a rapidly progressive neurodegenerative disorder of unknown

aetiopathogenesis associated with a markedly reduced life expectancy. It is characterized by

autonomic failure, parkinsonism, and cerebellar ataxia in any combination.

Methods: A total of 151 patients were recruited consecutively in a natural history study

conducted by the European MSA study group (EMSA-SG). Patients were followed up for two

years having a comprehensive neurological examination every six months. The degree of

disease progression was determined by the unified MSA rating scale (UMSARS).

Results: 141 patients fulfilled the Gilman criteria for MSA (60% MSA-P, 38% MSA-C, 2%

unclassifiable). Mean age at disease onset was 56.2 ± 8.4 years, mean disease duration at

baseline 5.5 ± 3.8 years. Median survival was 9.8 years (95% CI: 8.1 – 11.4) and survival

tended to be shorter in MSA-P patients. A Cox backward stepwise (Wald) regression model

corrected for age at disease-onset and gender identified a diagnosis of MSA-P and the

presence of incomplete bladder emptying as predictors of shorter survival. 24 months

progression rates of UMSARS activities of daily living (ADL), motor examination (ME) and

total (ADL + ME) scores were 46%, 57% and 52%, relative to baseline scores. Clinical

milestones of preterminal disease such as daily falls and wheelchair-dependency were

clustered within a short period 6 years after symptom onset. Quality of life deteriorated

relentlessly during follow-up

Conclusion: Our data confirmed the rapid progression of MSA. The identified UMSARS

progression rates will be instrumental for future interventional trials.



EFFECT OF MICROTUBULE DEPOLYMERIZATION ON α-SYNUCLEIN ACCUMULATION

I. Yazawa

Laboratory of Research Resources, Research Institute for Longevity Sciences, National Center for

Geriatrics and Gerontology, Aichi 474-8511, Japan

Multiple system atrophy (MSA) is a neurodegenerative disease in which oligodendrocytes and

neurons in the central nervous system are affected. MSA is pathologically characterized by

glial cytoplasmic inclusions and neuronal accumulation of α-synuclein. We previously

generated a transgenic (Tg) mouse model in which human α-synuclein was overexpressed in

oligodendrocytes. Our studies have revealed that oligodendrocytic α-synuclein inclusions

induced neuronal α-synuclein accumulation, thereby resulting in progressive neuronal

degeneration in mice. We demonstrated that an insoluble complex of α-synuclein and β-III

tubulin in microtubules progressively accumulated in neurons, leading to neuronal

degeneration. Neuronal accumulation of the insoluble complex was derived from binding of

α-synuclein to β-III tubulin, and was suppressed by a microtubule-depolymerizing agent.

Furthermore, the α-synuclein accumulation was increased in the presynaptic terminals of Tg

mice neurons and might reduce neurotransmitter release. Recently, using whole-cell patch-

clamp recording, we investigated the effects of neuronal α-synuclein accumulation on

synaptic function in Tg mice. We found that the frequency of miniature inhibitory

postsynaptic currents was selectively reduced in Tg mice. The microtubule-depolymerizing

agent restored normal frequencies of miniature inhibitory postsynaptic currents and enhanced

synaptic plasticity in Tg mice. These findings suggest that neuronal dysfunction in synapse

may be an important process before neuronal degeneration due to α-synuclein accumulation

develops in MSA.



VALIDATION of the German translation of the MSA-QoL

S. Duerr, A. Schrag, F. Krismer, M. Minnerop M, T. Klockgether, M. Stamelou, W. Oertel, W. Eggert,

W. Poewe, G. Wenning on behalf of EMSA-SG

Universitätsklinik für Neurologie on behalf of the EMSA SG

Introduction: The MSA health-related Quality of Life scale (MSA-QoL) is a patient-reported

Questionnaire to assess quality of life in patients with MSA.

Objective: To validate the German version of the MSA-QoL in participants in the European MSA

Study group cohort.

Methods: The MSA-QoL was translated according to standardised guidelines and piloted in a small

number of individuals. 38 (18 male) consecutive MSA patients were included in the study in Austria

and Germany. One patient had more than 10 percent missing responses requiring exclusion from the

final analysis. Data quality, scaling assumptions, acceptability, reliability and validity were assessed

similar to the original validation of the English version.

Results: Missing responses were low, item and subscale scores were evenly distributed and floor and

ceiling effects were negligible. Item-total correlations were higher than the recommended >0.30 and

internal consistency was high for all subscales. Validity was supported by moderate inter-scale

correlations between the subscales and the predicted correlations with other scales assessing objective

impairment and disability.

Discussion: The German versions of the MSA-QoL have similar psychometric properties to the

original English version. The French translation, reported by Meissner et al, also showed similar

properties. Together these results suggest that the translated versions of the MSA-QOL can be used to

assess QoL in patients with MSA.



VALIDATION OF THE FRENCH VERSION OF THE MSA HEALTH-RELATED QUALITY OF LIFE

SCALE (MSA-QOL)

S. Dupouy1, A. Foubert-Samier1, R. Debs4, A. Gerdelat-Mas4, V. Cochen De Cock4, A. Schrag5, O.

Rascol4,6, F. Tison1,2,3 and A. Pavy-Le Traon4, W.G Meissner1,2,3*

1Service de neurologie et centre de référence atrophie multisystématisée, CHU de Bordeaux, Pessac,

France

2Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France

3CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France

4Centre de référence atrophie multisystématisée, CHU de Toulouse, France

5Royal Free and University College Medical School, University College London, Department of

Clinical Neurosciences, London, UK

6Départements de Pharmacologie Clinique et Neurosciences, INSERM CIC9302, CHU de Toulouse,

France

Objective: To validate the French version of the MSA-QoL questionnaire.

Background: Multiple system atrophy (MSA) has considerable impact on health-related quality of life.

The MSA health-related Quality of Life scale (MSA-QoL) is a patient-reported questionnaire, which

has been recently designed to evaluate the quality of life in MSA. Methods: One hundred thirty-six

consecutive MSA patients were included in the study. Four patients with more than 10 percent missing

responses were excluded from the final analysis. Data quality, scaling assumptions, acceptability,

reliability and validity were assessed similar to the original validation of the English version.

Results: Missing responses were low, item and subscale scores were evenly distributed and floor and

ceiling effects were negligible. Item-total correlations were higher than the recommended >0.30 and

internal consistency was high for all subscales. Test-retest reliability was good for all subscales.

Validity was supported by moderate inter-scale correlations between the subscales and the predicted

correlations with other scales assessing motor disability, activities of daily living, quality of life and

mood.

Conclusion: The French version of the MSA-QoL displays robust psychometric properties similar to

the English version and seems suitable for assessing quality of life in French speaking MSA patients.



PATTERNS OF EXTRASTRIATAL UPTAKE OF123

I FP-CIT IN PARKINSON'S DISEASE AND

MULTIPLE SYSTEM ATROPHY.

A. Eusebio, T. Witjas, O. Mundler, J.P. Azulay, and E. Guedj

- APHM, Hôpital de la Timone, Service de Neurologie et Pathologie du Mouvement, Marseille,

France

- Aix-Marseille Univ, Institut de Neurosciences de la Timone, CNRS UMR 7289, Marseille, France

- APHM, Hôpital de la Timone, Service Central de Biophysique et Médecine Nucléaire, Marseille,

France

- Aix-Marseille Univ, CERIMED, Marseille, France

Objectives: Imaging of presynaptic dopaminergic neurons using dopamine transporter tracers

(DaT) or fluorodopa in multiple system atrophy (MSA) and idiopathic Parkinson’s disease

(IPD) has hitherto mostly been based on an ROI approach centred on the striatum. Recent

data suggest however a decreased uptake of 123I -CIT in the midbrain of MSA patients

compared to IPD. The aim of our study was to examine the extrastriatal DaT imaging pattern

in MSA and IPD through a voxel-based approach.

Methods: We performed 123I FP-CIT SPECT scans in 18 IPD, 15 MSA-P patients matched

for clinical severity (UPDRS III and Hoehn&Yahr), and 13 healthy controls matched for age.

All scans were performed with the patients’ usual medication. Voxel-based analysis of the

scans was performed using SPM.

Results: We did not find any difference in midbrain DaT binding between MSA and IPD

patients. MSA patients compared to IPD patients showed a decreased DaT binding in bilateral

inferior and medial cortex (BA10 and BA11, p < 0.0001 ; Mann-Whitney test). When

compared to healthy subjects IPD patients demonstrated a significant DaT binding increase in

this frontal area (p = 0.0065) and MSA patients showed a non-significant trend towards a

reduction in frontal DaT binding (p = 0.0653). No significant interaction was found between

this cluster and treatment of patients or with neuropsychological assessments (MATTIS).

However, a significant negative correlation was found between this cluster and the UPDRS III

ON scores in IPD patients

(r = -0.4739, p = 0.0020).

Conclusions: Our results show that dopaminergic presynaptic imaging of extrastriatal areas

shows differences between parkinsonian syndromes. Further studies are warranted to

understand the relevance of the correlation with on medication motor scores and to determine

whether this may be helpful in the diagnostic process of these conditions.



BEHAVIORAL AND HISTOLOGICAL ANALYSIS OF A PARTIAL DOUBLE-LESION MODEL OF

MSA-P

C Kaindlstorfer1, J García2,3, C Winkler2, A Marsch3, GK Wenning1, G Nikkhah3, MD Döbrössy3

1Neurological Research Laboratory, University Hospital, Anichstrasse 35, 6020 Innsbruck, Austria

2Department of Neurology, University Freiburg - Medical Center, 79106 Freiburg,Germany

3Department of Stereotactic Neurosurgery, Laboratory of Molecular Neurosurgery,University

Freiburg - Medical Center, 79106 Freiburg, Germany

Multiple system atrophy (MSA) is a neurodegenerative disease characterised by progressive

autonomic failure, cerebellar ataxia (MSA-C) and parkinsonism (MSA-P) due to neuronal

loss in multiple brain areas associated with oligodendroglial cytoplasmic α-synuclein

inclusion bodies. There are no effective treatments for MSA, and most of MSA-P patients

lose response to levodopa due to the loss of striatal dopaminergic post-synaptic receptors.

Improving the levodopa response of MSA-P patients by transplantation of primordial striatal

cell transplantation is considered a potential clinical option to manage the disease. The current

study characterized a unilateral sequential double lesion striatal rat model combining a partial

6-hydroxidopamine (6-OHDA) lesion followed by a striatal quinolinic acid (QA) lesion

mimicking early stage MSA-P pathology. Animals were assessed using tests sensitive to

simple-, skilled and sensorimotor behavior deficits. Animals received baseline testing on

spontaneous, learned or drug-induced behavioral tasks, and again on multiple occasions

following lesion surgery. Under the experimental paradigm applied, the behavioral data

showed robust lateralised deficits on all tasks, albeit the partial 6-OHDA and the double-

lesioned animals were most impaired. In summary, the study identified a behavioral deficit

profile unique to the double-lesion animals, and distinctive from the single 6-OHDA or the

QA lesioned animals. Histological analysis confirmed an approximate 40% dopamine loss in

the striatum in the 6-OHDA and double-lesion animals, as well as a similar loss of striatal

projection neurones in the QA and double-lesion animals. In a follow-up study based on the

same sequential double-lesion model, we have tested the impact of E14.5 striatal allografts on

changes in levodopa sensitivity (Stepping and Cylinder tests), dyskinesia (AIMs), and

functional recovery (drug-induced rotation, Corridor and Paw-reaching). Histological

assessment is in progress.



THE SEOUL NATIONAL UNIVERSITY HOSPITAL COHORTS OF MSA

Han-Joon Kim, Beom S Jeon, Young-Eun Kim, Ji Young Yun

Department of Neurology and Movement Disorder Center, Parkinson study group, and Neuroscience

Research Institute, College of Medicine, Seoul National University Hospital, Seoul, Korea

Here we report two large cohorts of Korean MSA patients in Seoul National University

Hospital (SNUH), which is one of the largest tertiary referral hospitals in Korea. The first one

(‘historical cohort’) is a retrospective cohort comprising 389 patients with probable MSA

according to Quinn’s criteria. Patients were registered between 1998 and 2008 and detailed

clinical information was obtained by medical record review. This cohort includes 190 men

and 199 women with an age at onset of 60.4±8.5 years. The most prevalent type of MSA at

last evaluation was MSA-P (55%), followed by MSA-PC (28%) and MSA-C (17%). All

patients in this cohort are no longer followed up at our center for various reasons. As of

December 2008, 107 patients had died with a median survival of 10 years. The second one

(‘active cohort’) is a prospective cohort of 278 MSA patients (152 men) who are currently

under regular follow-up at SNUH. Patient registration started in August 2011 and both

probable and possible MSA patients, according to the 2nd Consensus Criteria, are being

registered. Mean age is 67.2±9.1, age at onset 61.9±9.4, and disease duration 5.3±2.9 years.

Of 172 patients with probable MSA, 132 (77%) have parkinsonism and 69 (40%) have

cerebellar dysfunction. Urinary incontinence is present in 114 (66%) and orthostatic

hypotension was in 96 (56%). Of 106 patients with possible MSA, 83 (78%) have

parkinsonism and 40 (38%) have cerebellar dysfunction. Urinary symptoms were present in

98 (92%).



INTACT OLFACTION AS HALLMARK FEATURE OF MULTIPLE SYSTEM ATROPHY :

EXPERIMENTAL EVIDENCE

F. Krismer, Y. Li, N. Stefanova, G.K. Wenning

Division of Neurobiology, Department of Neurology and Neurosurgery, Medical University,

Anichstraße 35, A-6020 Innsbruck, Austria

Objective: To determine variation in olfactory behavior as well as histopathological changes

in a transgenic (tg) mouse model of multiple system atrophy (MSA).

Background: Clinicopathological as well as prospective studies involving patients with MSA

found the olfactory function to be mostly unaffected. In contrast, the majority of Parkinson’s

disease patients suffer from substantial olfactory deficits which have recently been replicated

in mouse models of PD.

Methods: Homozygous tg mice with targeted overexpression of α-synuclein as well as wild-

type controls were studied towards their olfactory function. The study was split into (1) a pilot

study investigating behavioral differences and their correlation to histopathological changes in

tg and wildtype mice at 9 months of age and in a (2) long-term study (LTS) that characterized

histopathology of the olfactory bulb longitudinally at 2, 6, 12, and 18 months. Olfactory

preference testing was performed according to previously published protocols. Animals were

exposed to two odors (peanut butter and water). The total time spent exploring the scents was

recorded using video analysis. Neuropathological analysis was performed on sections stained

with tyrosine hydroxylase (TH), human α-synuclein, glial fibrillary acidic protein, and CD11b

antibodies by a blinded examiner.

Results: In our pilot study, peanut butter was the more attractive odorant; however, there were

no significant differences between the two groups. These findings were accompanied by

unaffected TH-positive cell numbers in the olfactory bulb. Similarly, the LTS failed to

identify progressive degeneration in the olfactory bulb over time, even though a significant

increase in the number of α-synuclein positive cells was observed.

Conclusions: Our experimental data suggest a preserved olfactory function in a tg MSA

model which is in line with the human condition and may reflect the unique

oligodendrogliopathy in MSA.

Acknowledgment: This work was supported by the Austrian Science Fund (FWF): F04404-

B19



EXTENDING THE PHENOTYPE OF TRANSGENIC MSA: PRESENCE OF H- -SYN IN PNS

D. Kuzdas1, M. Theurl2, S. Quarta3, R. Irschick4, R. Kirchmair2, W. Löscher5, M. Kress3, L.

Klimaschewski4, W. Poewe5, N. Stefanova1 and G.K. Wenning1

1-Division of Neurobiology, Medical University Innsbruck, Innsbruck, Tirol, Austria, 6020, 2-

Universitätsklinik für Innere Medizin I, Medical University Innsbruck, Innsbruck, Tirol, Austria, 6020,

3-Department of Physiology and Medical Physics, Medical University Innsbruck, Innsbruck, Tirol,

Austria, 6020, 4-Department of Anatomy, Histology and Embryology, Division of Neuroanatomy,

Medical University Innsbruck, Innsbruck, Tirol, 5Universitätsklinik für Neurologie, Department of

Neurology and Neurosurgery, Medical University Innsbruck, Innsbruck, Tirol, Austria, 6020,5-

Universitätsklinik für Neurologie, Department of Neurology and Neurosurgery, Medical University

Innsbruck, Innsbruck, Tirol, Austria, 6020

Objective: To evaluate the relevance of h- -syn positive aggregates in the peripheral nervous

system (PNS) of a h- -syn overexpressing mouse model of multiple system atrophy (MSA)

using different behavioral/functional tests as well as extensive morphological

characterization.

Background: Previous work by another group showed reduced myelination and increased

axonal degeneration after peripheral nerve injury in a neuronal -syn expressing model and

awoke our interest for characterizing the PNS of the h- -syn overexpressing transgenic PLP-

MSA mouse model. The CNS of this model has been well characterized in previous studies. It

works under the control of a PLP promoter, which leads to overexpression of h- -syn in

oligodendrocytes and Schwann cells.

Methods: Immunohistochemistry was used to detect h- -syn positive aggregates in sciatic

nerve sections of the PLP-MSA model. Behavioral tests to investigate potential motor

impairment via the rotarod test, as well as pain and sensitivity tests like the Hargreaves and

Von Frey test and nerve conductance measurements were applied. Extensive morphological

analyses have been initiated comparing peripheral nerve sections from the h- -syn MSA

model with age-matched wildtype controls.

Results: Our preliminary immunohistochemistry results have shown the presence of h- -syn

aggregates in the PNS of tg MSA mice. Using confocal microscopy analysis, we found that

the presense of h-a-syn was restricted to Schwann cells. This finding confirmed our

hypothesis that the PLP-promoter does not only lead to h-a-syn expression in

oligodendrocytes, but also in Schwann cells.

Conclusions: Our results raise the possibility that polyneuropathies in MSA patients might be

related to a-syn associated Schwann cell pathology.



MULTIPLE SYSTEM ATROPHY PHENOTYPES IN A NEW YORK CITY COHORT

J. Martinez, L. Norcliffe Kaufmann, D. Roncevic, H. Kaufmann

New York University Medical Center, Dysautonomia Center, Suite 9Q, 530 First Avenue, New York

NY 10016

Background: The incidence of the cerebellar form of MSA (MSA-C) is reportedly higher than

the parkinsonian (MSA-P) form in Japan whereas the reverse was reported from European

clinical cohorts. We conducted a retrospective review of our clinical database of patients with

probable and possible MSA seen in New York City, were there is a multi-ethnic population.

Methods: Complete clinical data was extracted from the database were information was

collected on standardized case report forms. All patients were seen and rated by at least one

investigator (H.K.) according to revised consensus criteria (Gilman, 2008). Blood pressure

responses to 10 minutes of 60-degree passive head-up tilt were also reviewed.

Results: Eighty-eight patients met criteria for probable or possible MSA. Fifty-six were male

and 32 female. Mean UMSARS-I score was 19±7 and UMSARS-II score was 21±8. Sixty-

three percent were classified as having MSA-P and the remaining 37% as MSA-C. Mean age

at the time of the first visit was 60±10 years. Eight-four percent had orthostatic hypotension

with a drop of a least 20/10 mmHg in systolic/diastolic BP with the first 3 minutes of tilt and

74% had a drop of 30/15 in blood pressure within 3 minutes of tilt. Other common autonomic

features were urinary retention (88%) and erectile dysfunction in men (98%).

Discussion: The incidence of MSA-C in comparison to MSA-P in patients seen in New York

City is closer to that reported in large data series from Europe than from Japan. Further

studies are warranted to determine whether the autonomic features hold early predictive value

in the differential diagnosis of MSA from other movement disorders.



ASSESSMENT OF QUALITY OF LIFE IN MULTIPLE SYSTEM ATROPHY WITH MSA-QOL:

RELATION TO UMSARS SCORES AND PROGRESSION OVER TIME

W.G. Meissner1,2,3,4*, A. Foubert-Samier1,2, S. Dupouy1,2, A. Gerdelat-Mas5, R. Debs5, V.

Cochen De Cock5, O. Rascol5,6, F. Tison1,2,3,4 and A. Pavy-Le Traon5

1Centre de référence atrophie multisystématisée, CHU de Bordeaux, Pessac, France

2Service de Neurologie, CHU de Bordeaux, Pessac, France



5Centre de référence atrophie multisystématisée, CHU de Toulouse, France

6Départements de Pharmacologie Clinique et Neurosciences, INSERM CIC9302, CHU de Toulouse,

France

Objective: Prospective evaluation of health-related quality of life in multiple system atrophy

by using the multiple system atrophy health-related quality of life scale, a patient-reported

questionnaire specifically designed for multiple system atrophy.

Background: Multiple system atrophy has considerable impact on health-related quality of

life. Beyond scales assessing impairment of motor function and activities of daily living,

patient-reported data on health-related quality of life are increasingly being recognized as

important outcome measures for clinical trials in movement disorders.

Methods: Evaluation of health-related quality of life in 100 patients suffering from multiple

system atrophy by using the multiple system atrophy health-related quality of life scale. Data

were obtained at baseline and after a mean of 11.5 months of follow-up. Potential associations

between health-related quality of life and established markers of disease progression were

further assessed.

Results: The results confirm severe impairment of health-related quality of life in multiple

system atrophy with significant worsening during follow-up. Multivariate regression analysis

confirmed an association between total multiple system atrophy health-related quality of life

scale scores and unified multiple system atrophy rating scale activities of daily living sub-

scores. This association was also found for the amount of worsening during follow-up.

Conclusions: The multiple system atrophy health-related quality of life scale may serve as

outcome measure for future clinical trials.



RESTLESS LEGS SYNDROME IN MULTIPLE SYSTEM ATROPHY

I. Ghorayeb1,2, S. Dupouy1,2, W. Meissner1,2,3,4, F. Tison1,2,3,4

1Centre de Référence Atrophie Multisystématisée, CHU de Bordeaux, Pessac, France

2Service de Neurologie, CHU de Bordeaux, Pessac, France



Objective: To evaluate the frequency and severity of Restless legs syndrome (RLS) in patients

with Multiple System Atrophy (MSA).

Background: The pathophysiology of restless legs syndrome (RLS) is associated with central

dopaminergic system dysfunction leading to speculations that RLS may be common in those

neurodegenerative diseases with dopaminergic cell loss.

Methods: Thirty one consecutive patients with MSA underwent polysomnography (PSG) with

scoring for sleep, respiratory abnormalities and abnormal motor activities including periodic

limb movements during sleep (PLMS). RLS diagnosis was based on the presence of a

characteristic clinical history and on the International Restless Legs Syndrome Study Group

essential definition criteria. RLS severity was assessed by the International Restless Legs

Syndrome Rating Scale.

Results: Of the whole group, ten patients (31.25%) with MSA complained from RLS, their

mean severity score was 21.6 ± 5.948 indicating severe RLS. PLMS with or without

fragmentary myoclonus were found in 70% of patients with RLS.

Conclusion: Our results are in accordance with rare previous data dealing with RLS and PLM

in MSA, and suggest that RLS is more prevalent in MSA compared to the general population.

Future studies should investigate whether RLS symptoms severity in MSA is a specific

feature of the disease.



IN VIVO DETECTION OF NEUROPATHOLOGICAL DIFFERENCES BETWEEN MULTIPLE SYSTEM

ATROPHY (MSA) AND SPORADIC ADULT ONSET ATAXIAS OF UNKNOWN AETIOLOGY

(SAOA) USING MR-MORPHOMETRY

M. Minnerop (1,2), J.C. Schöne-Bake (3,4), S. Röske (2,5), M. Abele (2), D. Timmann (6), U.

Wüllner (2), K. Amunts (1,7), M. Tittgemeyer (8), T. Klockgether (2,5) B. Weber (3,4)

(1) Research Centre Juelich, Institute of Neurosciences and Medicine (INM-1), D-52425 Jülich,

Germany (2) Department of Neurology, University Hospital of Bonn, D-53105 Bonn, Germany (3)

Life and Brain, Department of NeuroCognition-Imaging, D-53127 Bonn, Germany (4) Department of

Epileptology, University Hospital of Bonn, D-53105 Bonn, Germany (5) German Centre for

Neurodegenerative Diseases (DZNE), D-53175 Bonn, Germany (6) Department of Neurology,

University of Duisburg-Essen, D-45122 Essen, Germany (7) Department of Psychiatry and

Psychotherapy, RWTH Aachen University, D-52074 Aachen, Germany (8) Max-Planck-Institute for

Neurological Research, D-50931 Cologne, Germany

Multiple system atrophy (MSA) is a sporadic, adult-onset disease characterized by

neurodegeneration with oligodendroglial cytoplasmic inclusions in basal ganglia, brainstem,

cerebellum and intermediolateral cell columns of the spinal cord. Clinically, parkinsonian and

cerebellar types of MSA (MSA-P/C) are distinguished. Sporadic adult onset ataxias of

unknown aetiology (SAOA) denote all non-hereditary degenerative adult onset ataxias

distinct from MSA-C. Early differential diagnosis is often difficult. We investigated white

matter pathology (WMP) in MSA and SAOA using diffusion-tensor-imaging.

We compared 24 MSA-patients (MSA-C/P: 18/6, m/f: 16/8, age 59.6 .6.2 years (y), disease

duration (dd) 3.8 1.9y) and 18 SAOA-patients (m/f: 8/10, age 50.1 12.0y, dd 8.1 4.9y) with

age- and sex-matched healthy controls groups, separately for all (sub-)groups. Each subject

underwent neurological and neuropsychological examinations. Diffusion weighted images

were obtained using a 3T MRI scanner with 60 gradient directions. FSL/TBSS was used for

preprocessing and statistical analysis of fractional anisotropy (FA, 2-sample t-tests,

p(FWE)<0.05).

In MSA we found reduced FA in all cerebellar peduncles (CPs), left medial lemniscus (ML)

and corticospinal tracts. In SAOA lower FA were depicted in inferior and superior CPs, right

ML and callosal body. Correlation studies with clinical data are under way.

Our DTI analyses demonstrate distinct cerebellar WMP in MSA, affecting middle CPs which

are spared in SAOA. This extends earlier findings of cerebellar and extracerebellar grey and

white matter loss (GML/WML) in both MSA and SAOA. Detection of disease-specific

morphometric pattern provides deeper insights in neuropathological differences in vivo and

may improve the accuracy of clinical diagnosis.



MEDICATION USE IN PATIENTS WITH MULTIPLE SYSTEM ATROPHY OR PARKINSON’S

DISEASE COMPARED TO A GROUP OF PATIENTS CONSULTING A GENERAL PRACTITIONER

S. Perez-Lloret (1), M.V. Rey (1), A. Pavy-Le Traon (1,2), W. Meissner (3), F. Ory-Magne (1), C.

Brefel- Courbon (1), L .Ratti (1), N. Fabre (1), F. Tison (3), O. Rascol (1,2)

1-Service de Pharmacologie Médicale et Clinique du CHU de Toulouse, Université Paul Sabatier

2-Centre de référence pour l'atrophie multi-systématisée Service de Neurologie, CHU Toulouse,

France

3-Centre de référence pour l’atrophie multi-systématisée, Service de Neurologie, CHU Bordeaux

Institut des Maladies Neurodégénératives CNRS UMR 5293, Université Bordeaux 2

Objective: To compare drug utilization between MSA, Parkinson's disease (PD) patients or

unselected patients consulting a general practitioner (GP).

Methods: 147 MSA patients (according to Gilman criteria) were assessed at the MSA

reference Center between 2008 and 2011. 653 PD patients (according to UKPDSBB criteria)

and 98 patients assisting to a GP for reasons not related to PD or MSA were recruited from

the same geographical area. Data were analyzed by chi-square test followed by pairwise

comparisons by bonferroni-adjusted z-test for proportions.

Results: MSA patients were younger as compared to PD or GP patients (65±1 vs 68±1 or

71±1 years p<0.001). Proportion of males was similar in the 3 groups (MSA: 50% vs PD:

49% or 46%, p=0.9). MSA patients were more frequently exposed to drugs for bowel

disorders (MSA: 19% vs PD: 6% or GP: 10% p<0.001), to urinary antispasmodics (MSA:

18% vs PD: 2% or GP: 1% p<0.001) to drugs used for orthostatic hypotension such as

midodrine or fludrocortisone (MSA: 42% vs PD: 3% vs GP: 0%, p<0.001) ot to

antihypertensives (MSA: 22% vs PD: 40% vs GP: 58% p<0.001). MSA patients were less

frequently on antiparkinsonian as compared to PD (73% vs 88% p<0.05). Finally, MSA

patients were more frequently on antidepressants (MSA: 48% vs PD: 18% or GP: 10%

p<0.001).

Conclusions: Medication use patterns differed patients with MSA, PD or those assisting to a

GP.



MILD COGNITIVE IMPAIRMENT IN MULTIPLE SYSTEM ATROPHY: A COMPARATIVE STUDY

WITH PARKINSON'S DISEASE

M. Petrova, S .Skelina, R. Pavlova, M. Raycheva and L. Traykov

Department of Neurology, Medical University-Sofia, Sofia, Bulgaria

Objective : To compare the pattern of mild cognitive impairment (MCI) in patients with

Multiple System Atrophy and Parkinson's disease.

Background : Similarly to Parkinson's disease (PD), Multiple System Atrophy (MSA) was

found to be associated with increased risk of cognitive impairment. However, the exact

pattern of MCI in patients with MSA (MSA-MCI) and its differences from the pattern of MCI

in PD (PD-MCI) are still unclear and subject of considerable controversy.

Methods : We studied 18 MSA-MCI patients, 21 PD-MCI patients and 26 normal controls.

All patients underwent a comprehensive clinical, neuropsychological and psychiatric

assessment.

Results : Compared to controls, MSA-MCI patients demonstrated most prominent deficits in

digit span backward, Stroop test part 3, MCST, phonemic and semantic verbal fluency.

Besides the deficits in above-mentioned tests, patients with PD-MCI also showed

significantly worse scores on total free and delayed recall of the Free and Cued Selective

Reminding Test, as well as on Trail Making Test B-A. However, there was not a significant

difference between both MCI groups in MMSE and DRS as well as in tests measuring short

term memory, visiospatial/constructional abilities and language.

Conclusions : The presence of MCI in MSA patients was associated with clear dysfunction in

some aspects of attention/executive functions, such as working memory, initiation and

strategic searching, inhibition and concept-formation. The most prominent difference between

the both MCI groups was revealed in retrieval of episodic memory, significantly more

impaired in patients with PD. The possible relationship between MCI and incipient dementia

in individuals with MSA remains to be investigated in follow-up studies.



MEDICATION USE IN THE PATIENTS OF THE FRENCH MULTIPLE SYSTEM ATROPHY (MSA)

REFERENCE CENTER

M.V. Rey, S. Perez LLoret, A. Pavy-Le Traon, W. Meissner, F. Ory-Magne, C. Brefel- Courbon, L.

Ratti, N. Fabre, F. Tison, O. Rascol

1-Service de Pharmacologie Médicale et Clinique du CHU de Toulouse, Université Paul Sabatier

2-Centre de référence pour l'atrophie multi-systématisée Service de Neurologie, CHU Toulouse,

France

3-Centre de référence pour l’atrophie multi-systématisée, Service de Neurologie, CHU Bordeaux

Institut des Maladies Neurodégénératives CNRS UMR 5293, Université Bordeaux 2

Objective: To describe medication use in MSA patients and to relate it with different

characteristics of the disease.

Methods: Patients were assessed at the French MSA reference Center. The following

variables were collected: MSA diagnosis (“probable” vs “possible” according to Gilman

criteria), disease duration, autonomic dysfunction (SCOPA-Aut), disease severity (UMSARS

I+II), clinical subtype (MSA-P vs MSA-C) and any medication use (coded by ATC). Data

were analyzed by chi-square test, only significant differences are reported.

Results: 147 MSA patients were recruited (mean age 65.3±0.7, 50% males, 61% MSA-P,

82% “probable” MSA, mean UMSARS-score 48.9±1.3, mean disease duration

5.1±0.2).Overall, MSA patients received 8.2±0.4 medications. Seventy-three % patients

received at least one antiparkinsonian (mainly levodopa: 67%), 33% midodrine and 10%

fludrocortisone. More severely affected patients (UMSARS>47) received more frequently

antithrombotics (27% vs 14% p<0.05) antidepressants (61% vs 38% p<0.01,) or drugs for

bowel disorders (30% vs 10% p<0.01). More patients with MSA-P (versus -C) received

antiparkinsonian (90% vs 46% p<0.01), antihypertensive (28% vs 12% p<0.05) or analgesic

(19% vs 4% p<0.01) medications. More patients with “probable” MSA (versus “possible”)

received midodrine (39% vs 7%, p<0.01) and less alpha-blockers (5% vs 19%, p<0.02).

Patients with SCOPA-Aut score > 22 were more frequently on fludrocortisone (18% vs 3%,

p<0.01) or antidepressants (57% vs 41%, p<0.04). Patients with disease duration>5 years

were more frequently on alpha-adrenergics blockers for urinary problems (14% vs 3%,

p<0.01).

Conclusion: In MSA, medication use significantly differs according to disease characteristics.



NEURONAL -SYNUCLEIN BINDS TO β-III TUBULIN TO ACCUMULATE IN AN MSA MODEL

Y. Suzuki, K. Nakayama, and I. Yazawa

Laboratory of Research Resources, Research Institute for Longevity Sciences, National Center for

Geriatrics and Gerontology, Aichi 474-8511, Japan

Multiple system atrophy (MSA) is a neurodegenerative disease in which oligodendrocytes and

neurons in the central nervous system are affected. Abnormal accumulation of α-synuclein in

oligodendrocytes and neurons are characteristic in MSA. The accumulations might be the

primary lesions that eventually compromise neuronal function and viability. To clarify how

oligodendrocytic α-synuclein inclusions cause neuronal degeneration, we generated a

transgenic mouse for an MSA model in which human wild-type α-synuclein was

overexpressed selectively in oligodendrocytes. We established primary culture cells derived

from the brain of transgenic mice, and revealed that insoluble mouse α-synuclein was

progressively accumulated in neurons, leading to neuronal dysfunction and degeneration. In

this study, we demonstrate that α-synuclein binds to β-III tubulin to form an insoluble

complex in the primary cultured cells. The neuronal accumulation of the insoluble complex

was suppressed by treatment of microtubule-depolymerizing agent in primary culture cells.

These results indicate that binding of α-synuclein to β-III tubulin principally developed

neuronal accumulation of α-synuclein. Next, we generated a series of truncated β-III tubulin

proteins to determine β-III tubulin domains responsible for the interaction of α-synuclein.

Full-length and truncated β-III tubulins fused to glutathione S-transferase were coexpressed

with α-synuclein in COS-7 cells, and the formation of the overexpressed protein complex was

confirmed by a pull-down assay. Our data suggest that the interaction between α-synuclein

and β-III tubulin plays an important role in neuronal α-synuclein accumulation in an MSA

model.

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