Handbook of Clinical Neurology pptx

Alvarez Movement Disorders Unit, Centro Internacional de Restauracio´n Neurolo´gica CIREN, La Habana, Movement Disorders Unit, Department of Neurology, Tel-Aviv Sourasky Medical Center,

ObituaryWilliam C Koller, MD, PhD1945–2005

William C Koller died unexpectedly on October 3, 2005, in Chapel Hill, North Carolina,while this volume, which he was co-editing, was in preparation Bill was born in Milwau-kee on July 12, 1945, where he graduated with a BS degree from Marquette Universityin1968 He went on to Northwestern University in Chicago, where he received a Mastersdegree in pharmacology in 1971, a PhD in pharmacology in 1974, and an MD in 1976.After completing his internship and residency at Rush Presbyterian St Luke’s MedicalCenter in Chicago, he held positions at the Rush Medical College, University of Illinois,Chicago VA, Hines VA, and Loyola University In 1987, he was appointed Professorand Chairman of Neurology at the University of Kansas Medical Center, where heremained until 1999, when he moved to the University of Miami and became the NationalResearch Director for the National Parkinson Foundation He subsequently moved on to direct the Movement Dis-orders clinical program at the Mount Sinai Medical Center in New York, and then to the University of North Car-olina, where he laid the foundation for yet another superb clinical and academic program

Bill was a world-renowned neurologist who specialized in Parkinson’s disease, essential tremor and relateddisorders He published more than 270 peer-reviewed manuscripts, over 160 review papers and numerous books.His research interests included the epidemiology and experimental therapeutics of parkinsonism and essentialtremor, and his work contributed enormously to the current treatment of these disorders His collaborations wereworldwide and many current experts in movement disorders worked with him at one time or another He was

a Fellow of the American Academy of Neurology, Treasurer of the Movement Disorder Society (1999–2000),Executive Board Member of the Parkinson Study Group (1996–1999), President of WE MOVE (2001–2002),

a founding member of the Tremor Research Group and founder of the International Tremor Foundation

Dr Koller will be especially remembered for his humor, warmth and the youthful vigor and enthusiasm that hebrought to his work He was the consummate physician, befriending many of his patients who were encouraged tocall him on his cell phone at any time Whether lecturing in South America, fishing on the boat he shared withseveral colleagues, traveling with one of his sons to an international meeting or seeing patients in the clinic, Bill’ssmile and the sparkle in his eye endeared him to all who knew him The movement disorders community has lost

a valued colleague, mentor and friend He is survived by his wife and three sons

Kelly LyonsMatthew B Stern

Photo courtesy of Professor Lindsey and

the European Parkinson’s Disease Association.

TheHandbook of Clinical Neurology was started by Pierre Vinken and George Bruyn in the 1960s and continuedunder their stewardship until the second series concluded in 2002 This is the fifth volume in the new (third) ser-ies, for which we have assumed editorial responsibility The series covers advances in clinical neurology and theneurosciences and includes a number of new topics In order to provide insight to physiological and pathogenicmechanisms and a basis for new therapeutic strategies for neurological disorders, we have specifically ensuredthat the neurobiological aspects of the nervous system in health and disease are covered During the last quar-ter-century, dramatic advances in the clinical and basic neurosciences have occurred, and those findings related

to the subject matter of individual volumes are emphasized in them The series will be available electronically

on Elsevier’s Science Direct site, as well as in print form It is our hope that this will make it more accessible

to readers and also facilitate searches for specific information

The present volume deals with Parkinson’s disease and related disorders This group of disorders constitutesone of the most common of neurodegenerative disorders and is assuming even greater importance with the aging

of the population in developed countries The volume has been edited by Professor William Koller (USA) andProfessor Eldad Melamed (Israel) It is with particular sadness that we must record the sudden and untimely death

of Professor Koller while the volume was coming to fruition An experienced clinician, neuroscientist, author andeditor, he was a friend of many of the contributors to this volume, as well as of the series editors, and we shallgreatly miss him It is our hope that he would have been proud of this volume, which he did so much to craft

As series editors, we reviewed all of the chapters in the volume and made suggestions for improvement, but wewere delighted that the volume editors had produced such a scholarly and comprehensive account of the parkin-sonian disorders, which should appeal to clinicians and neuroscientists alike When the Handbook series wasinitiated in the 1960s, understanding of these disorders was poor, any genetic basis of them was speculative, sev-eral of the syndromes described here had not even been recognized, the prognosis was bleak and the therapeuticoptions were almost unchanged since the late Victorian era Advances in understanding of the biochemical back-ground of parkinsonism during the 1960s and early 1970s led to dramatic pharmacological advances in the man-agement of Parkinson’s disease and profoundly altered the approach to other degenerative disorders of the nervoussystem The pace of advances in the field has continued, and the exciting new insights being gained have man-dated a need for a thorough but critical appraisal of recent developments so that future investigative approachesand therapeutic strategies are based on a solid foundation, the limits of our knowledge are clearly defined and

an account is provided for practitioners of the clinical features and management of the various neurological orders that present with parkinsonism

dis-It has been a source of great satisfaction to us that two such eminent colleagues as the late William Koller andProfessor Eldad Melamed agreed to serve as volume editors and have produced such an important compendium,and we thank them and the contributing authors for all their efforts We also thank the editorial staff of the pub-lisher, Elsevier B.V., and especially Ms Lynn Watt and Mr Michael Parkinson in Edinburgh for overseeing allstages in the preparation of this volume

Michael J AminoffFranc¸ois BollerDick F Swaab

James Parkinson described Parkinson’s disease in his memorableEssay on the Shaking Palsy in 1817 Since then,and particularly in recent years, there has been tremendous progress in our understanding of this complex and fas-cinating neurological disorder Briefly, we have learned that it is not only manifest by motor symptoms but alsothat there is a whole range of non-motor features, including autonomic, psychiatric, cognitive and sensory impair-ments We now know how to distinguish better clinically between Parkinson’s disease and the various parkinso-nian syndromes Likewise, it is now well established that in this disorder not only the substantia nigra but manyother central as well as peripheral neuronal cell populations are involved Novel diagnostic imaging technologieshave become available The nature of the Lewy body, the intracytoplasmic inclusion body that is a characteristicelement of Parkinson’s disease pathology, is being unraveled

There are new insights in the etiology and pathogenesis of this illness Experimental models are now available

to understand better modes of neuronal cell death and help develop new therapeutic approaches There has beendramatic progress in discovering the genetic causes of dominant and recessive forms of hereditary Parkinson’s dis-ease with the identification of mutations in several genes There is new knowledge in the intricate circuitry of thebasal ganglia and the physiology of the connections in the healthy state and in Parkinson’s disease There is moreunderstanding of the role of dopamine and other neurotransmitters in the control and regulation of movement bythe brain

All of the above led to the development of many novel pharmacological treatments to improve the motor aswell as non-motor phenomena There is better understanding of the mechanisms responsible for the complicationscaused by long-term levodopa administration Futuristic approaches using deep brain stimulation with electrodesimplanted in anatomically strategic central nervous system sites are now in common use to improve basic symp-toms and the side-effects of levodopa therapy Potentially effective neuroprotective strategies are in development

to modify and slow disease progression Likewise, cell replacement therapy with stem cells offers great promise.The best of experts in the field joined in this book and contributed chapters that make up an exciting coverage

of all the exhilarating developments in the many aspects of Parkinson’s disease This volume will certainly expandthe current knowledge of its readers and it is also hoped that it will stimulate further research that will eventuallylead to finding both the cause and the cure of this common and disabling neurological disorder

William C KollerEldad Melamed

Dr William Koller died suddenly, unexpectedly and prematurely on October 3, 2005, before this volume went topress His loss is painful to all his friends and colleagues His leadership, wisdom and expertise were the maindriving force behind the creation of this very special book It is the belief of all involved that Dr Koller wouldhave been pleased and proud of this volume in its final form We hope it will be a tribute to his memory

List of contributors

L Alvarez

Movement Disorders Unit, Centro Internacional

de Restauracio´n Neurolo´gica (CIREN), La Habana,

Movement Disorders Unit, Department of

Neurology, Tel-Aviv Sourasky Medical Center,

Department of Neurology and Neuroscience, Weill

Medical College of Cornell University, New York,

NY, USA

P J Be´dard

Centre de Recherche en Neurosciences, CHUL,

Faculte´ de Me´dicine, Universite´ Laval, Quebec,

Canada

A Berardelli

Department of Neurological Sciences and

Neuromed Institute, Universita` La Sapienza,

Sobell Department of Motor Neuroscience

and Movement Disorders, Institute of Neurology,

University College London,

London, UK

R BhidayasiriThe Parkinson’s and Movement Disorder Institute,Fountain Valley, CA, USA

R E BreezeDepartment of Neurosurgery, University of ColoradoSchool of Medicine, Denver, CO, USA

C Brefel-CourbonDepartment of Clinical Pharmacology, ClinicalInvestigation Centre and Department ofNeurosciences, University Hospital, Toulouse, France

D J BrooksMRC Clinical Sciences Centre and Division ofNeuroscience and Mental Health, Imperial CollegeLondon, Hammersmith Hospital, London, UK

R E BurkeDepartments of Neurology and Pathology, ColumbiaUniversity, New York, NY, USA

D J BurnInstitute of Ageing and Health, University ofNewcastle upon Tyne, Newcastle upon Tyne, UK

M G Cerso´simoProgram of Parkinson’s Disease and Other MovementDisorders, Hospital de Clı´nicas, University of BuenosAires, Buenos Aires, Argentina

A ChadeThe Parkinson’s Institute, Sunnyvale, CA, USA

K R ChaudhuriRegional Movement Disorders Unit, King’s CollegeHospital, London, UK

Y ChenMorris K Udall Parkinson’s Disease Research Center

of Excellence, University of Kentucky College ofMedicine, Lexington, KY, USA

K L Chou

Department of Clinical Neurosciences, Brown

University Medical School and NeuroHealth

Parkinson’s Disease and Movement Disorders Center,

Warwick, RI, USA

C Colosimo

Dipartimento di Scienze Neurologiche, Universita` La

Sapienza, Rome, Italy

Y Compta

Neurology Service, Hospital Clinic, University of

Barcelona, Barcelona, Spain

E Cubo

Unit of Neuroepidemiology, National Centre for

Epidemiology, Carlos III Institute of Health, Madrid,

Spain

B Dass

Department of Neurological Sciences, Rush University

Medical Center, Chicago, IL, USA

M R DeLong

Department of Neurology, Emory University, Atlanta,

GA, USA

G Deuschl

Department of Neurology,

Christian-Albrechts-University, Kiel, Germany

V Dhawan

Regional Movement Disorders Unit, King’s College

Hospital, London, UK

The´re`se Di Paolo

Centre de Recherche en Endocrinologie Mole´culaire

et Oncologique, CHUL, Faculte´ de Pharmacie,

Universite´ Laval, Quebec, Canada

R Djaldetti

Department of Neurology, Rabin Medical Center,

Petah Tiqva and Sackler Faculty of Medicine,

Tel Aviv University, Tel Aviv, Israel

M Emre

Department of Neurology, Behavioral Neurology and

Movement Disorders Unit, Istanbul Faculty of

Medicine, Istanbul University, Istanbul, Turkey

G Fabbrini

Dipartimento di Scienze Neurologiche, Universita` La

Sapienza, Rome, Italy

C FoxNational Center for Voice and Speech, Denver, CO, USA

S H FoxToronto Western Hospital, Movement DisordersClinic, Division of Neurology, University of Toronto,Toronto, Ontario, Canada

J FrankDepartment of Neurology, Mount Sinai MedicalCenter, New York, NY, USA

C R FreedUniversity of Colorado School of Medicine, Denver,

CO, USA

A FriedmanDepartment of Neurology, Medical University,Warsaw, Poland

J H FriedmanDepartment of Clinical Neurosciences, BrownUniversity Medical School and NeuroHealthParkinson’s Disease and Movement Disorders Center,Warwick, RI, USA

V S C FungDepartment of Neurology, Westmead Hospital,Sydney, NSW, Australia

J Galazka-FriedmanFaculty of Physics, Warsaw University of Technology,Warsaw, Poland

C GallagherDepartment of Neurobiology, University ofWisconsin School of Medicine and Public Health,Madison, WI, USA

D M GashMorris K Udall Parkinson’s Disease Research Center

of Excellence, University of Kentucky College ofMedicine, Lexington, KY, USA

G GerhardtMorris K Udall Parkinson’s Disease Research Center

of Excellence, University of Kentucky College ofMedicine, Lexington, KY, USA

O S GershanikDepartment of Neurology, Centro Neurolo´gico-HospitalFrances, Laboratory of Experimental Parkinsonism,ININFA-CONICET, Buenos Aires, Argentina

C G Goetz

Department of Neurological Sciences, Rush University

Medical Center, Chicago, IL, USA

J G Goldman

Department of Neurological Sciences, Rush University

Medical Center, Chicago, IL, USA

D S Goldstein

Clinical Neurocardiology Section, National Institute of

Neurological Disorders and Stroke, National Institutes

of Health, Bethesda, MD, USA

J.-M Gracies

Department of Neurology, Mount Sinai Medical

Center, New York, NY, USA

J T Greenamyre

Department of Neurology, Emory University, Atlanta,

GA, USA

J Guridi

Department of Neurology and Neurosurgery,

University Clinic and Medical School and

Neuroscience Division, University of Navarra and

CIMA, Pamplona, Spain

T D Ha¨lbig

Department of Neurology, Mount Sinai School of

Medicine, New York, NY, USA

N Hattori

Department of Neurology, Juntendo University School

of Medicine, Tokyo, Japan

M A Hely

Department of Neurology, Westmead Hospital,

Sydney, NSW, Australia

C Henchcliffe

Department of Neurology and Neuroscience, Weill

Medical College of Cornell University, New York,

NY, USA

B Ho¨gl

Department of Neurology, Medical University of

Innsbruck, Innsbruck, Austria

X Huang

Departments of Neurology and Medicinal Chemistry,

University of North Carolina School of Medicine,

Chapel Hill, NC, USA

J S HuiDepartment of Clinical Neurology, University ofSouthern California, Los Angeles, CA, USA

J JankovicParkinson’s Disease Center and Movement DisordersClinic, Department of Neurology, Baylor College ofMedicine, Houston, TX, USA

P JennerNeurodegenerative Disease Research Center, School

of Health and Biomedical Sciences, King’s College,London, UK

M KastenThe Parkinson’s Institute, Sunnyvale, CA, USA

H KaufmannDepartment of Neurology, Mount Sinai School ofMedicine, New York, NY, USA

W C KolleryDepartment of Neurology, University of NorthCarolina, NC, USA

A D KorczynSieratzki Chair of Neurology, Tel-Aviv UniversityMedical School, Ramat-Aviv, Israel

J H KordowerDepartment of Neurological Sciences, Rush UniversityMedical Center, Chicago,

IL, USA

V KoukouniSobell Department of Motor Neuroscience andMovement Disorders, Institute of Neurology,University College London, London, UK

A E LangToronto Western Hospital, Movement DisordersClinic, Division of Neurology, University of Toronto,Toronto, Ontario, Canada

M LeeheyDepartment of Neurology, University of ColoradoSchool of Medicine, Denver, CO, USA

A J LeesReta Lila Weston Institute of Neurological Studies,University College London, London, UK

yDeceased.

F A Lenz

Department of Neurosurgery, Johns Hopkins Hospital,

Baltimore, MD, USA

N Lev

Laboratory of Neuroscience and Department of

Neurology, Rabin Medical Center, Petah-Tikva,

Tel Aviv University, Tel Aviv, Israel

M F Lew

Department of Neurology, University of Southern

California, Los Angeles, CA, USA

M Lugassy

Department of Neurology, Mount Sinai Medical

Center, New York, NY, USA

R B Mailman

Departments of Psychiatry, Pharmacology, Neurology

and Medicinal Chemistry, University of North

Carolina School of Medicine, Chapel Hill, NC, USA

C Marin

Laboratori de Neurologia Experimental, Fundacio´

Clı´nic-Hospital Clı´nic, Institut d’Investigacions

Biome´diques August Pi i Sunyer (IDIBAPS), Hospital

Clinic, Barcelona, Spain

P Martı´nez-Martı´n

Unit of Neuroepidemiology, National Centre for

Epidemiology, Carlos III Institute of Health, Madrid,

Spain

I McKeith

Institute for Ageing and Health, Newcastle University,

Newcastle upon Tyne, UK

K St P McNaught

Department of Neurology, Mount Sinai School of

Medicine, New York, NY, USA

E Melamed

Department of Neurology, Rabin Medical Center,

Petah Tiqva and Sackler Faculty of Medicine, Tel

Aviv University, Tel Aviv, Israel

M Merello

Movement Disorders Section, Raul Carrea Institute for

Neurological Research, FLENI, Buenos Aires, Argentina

F E Micheli

Program of Parkinson’s Disease and Other Movement

Disorders, Hospital de Clı´nicas, University of Buenos

Aires, Buenos Aires, Argentina

Y MizunoDepartment of Neurology, Juntendo University School

of Medicine, Tokyo, Japan

H MochizukiDepartment of Neurology, Juntendo University School

of Medicine, Tokyo, Japan

J C Mo¨llerDepartment of Neurology, Philipps-Universita¨tMarburg, Marburg, Germany

J.-L MontastrucDepartment of Clinical Pharmacology, ClinicalInvestigation Center, University Hospital, Toulouse,France

E B Montgomery JrNational Primate Research Center, University ofWisconsin-Madison, Madison, WI, USA

J G L MorrisDepartment of Neurology, Westmead Hospital,Sydney, NSW, Australia

J A ObesoDepartment of Neurology and Neurosurgery,University Clinic and Medical School andNeuroscience Division, University of Navarra andCIMA, Pamplona, Spain

W H OertelDepartment of Neurology, Philipps-Universita¨t Marburg,Marburg, Germany

D OffenLaboratory of Neuroscience and Department ofNeurology, Rabin Medical Center, Petah-Tikva, TelAviv, University, Tel Aviv, Israel

F Ory-MagneDepartment of Neurosciences, University Hospital,Toulouse, France

B OwlerDepartment of Neurosurgery, Westmead Hospital,Sydney, NSW, Australia

D P PerlMount Sinai School of Medicine, New York, NY, USA

R F PfeifferDepartment of Neurology, University of TennesseeHealth Science Center, Memphis, TN, USA

S Przedborski

Departments of Neurology, Pathology and Cell

Biology, Columbia University, New York, NY, USA

J M Rabey

Department of Neurology, Assaf Harofeh Medical

Center, Zerifin, Israel

A Rajput

Division of Neurology, Department of Medicine,

University of Saskatchewan, Saskatoon, SK, Canada

A H Rajput

Division of Neurology, Department of Medicine,

University of Saskatchewan, Saskatoon, SK, Canada

L O Ramig

Department of Speech, Language and Hearing

Sciences, University of Colorado-Boulder Department

of Speech, and National Center for Voice and Speech,

Denver, CO, USA

J Rao

Department of Neurology, Louisiana State University

Health Sciences Center, New Orleans, LA, USA

O Rascol

Department of Clinical Pharmacology, Clinical

Investigation Centre and Department of

Neurosciences, University Hospital, Toulouse, France

Clinical Neurochemistry, Department of

Psychiatry and Psychotherapy, National Parkinson

Foundation (USA) Center of Excellence Research

Laboratories, University of Wu¨rzburg, Wu¨rzburg,

Germany

M C Rodrı´guez-Oroz

Department of Neurology and Neurosurgery,

University Clinic and Medical School and

Neuroscience Division, University of Navarra and

CIMA, Pamplona, Spain

C Rouillard

Centre de Recherche en Neurosciences, CHUL,

Faculte´ de Me´dicine, Universite´ Laval, Quebec,

Canada

P SamadiCentre de Recherche en Endocrinologie Mole´culaire etOncologie, CHUL, Faculte´ de Pharmacie, Universite´Laval, Quebec, Canada

S SapirDepartment of Communication Sciences and Disorder,Faculty of Social Welfare and Health Studies,University of Haifa, Haifa, Israel

A H V SchapiraUniversity Department of Clinical Neurosciences,Royal Free and University College Medical School,University College London, London, UK

J ShahedParkinson’s Disease Center and Movement DisordersClinic, Baylor College of Medicine, Department ofNeurology, Houston, TX, USA

T SlaouiDepartment of Neurosciences, University Hospital,Toulouse, France

M B SternDepartment of Neurology, University of PennsylvaniaSchool of Medicine, Philadelphia, PA, USA

F StocchiDepartment of Neurology, IRCCS San RaffaelePisana, Rome, Italy

N P StoverDepartment of Neurology, University of Alabama atBirmingham, Birmingham, AL, USA

C M TannerThe Parkinson’s Institute, Sunnyvale, CA, USA

E TolosaNeurology Service, Hospital Clinic, University ofBarcelona, Barcelona, Spain

C TrenkwalderParacelsus Elena-Klinik, Center of Parkinsonism andMovement Disorders, Kassel, and University ofGo¨ttingen, Go¨ttingen, Germany

D D TruongThe Parkinson’s and Movement Disorder Institute,Fountain Valley, CA, USA

W TseDepartment of Neurology, Mount Sinai MedicalCenter, New York, NY, USA

J Volkmann

Department of Neurology,

Christian-Albrechts-University, Kiel, Germany

H C Walker

Department of Neurology, University of Alabama at

Birmingham, Birmingham, AL, USA

R H Walker

Movement Disorders Clinic, Department of

Neurology, James J Peters Veterans Affairs Medical

Center, Bronx, and Department of Neurology, Mount

Sinai School of Medicine, New York, NY, USA

R L Watts

Department of Neurology, University of Alabama at

Birmingham, Birmingham, AL, USA

D Weintraub

Departments of Psychiatry and Neurology, University

of Pennsylvania School of Medicine, Philadelphia, PA,

USA

T WichmannDepartment of Neurology and Yerkes NationalPrimate Center, Emory University,

Atlanta, GA, USA

M B H YoudimDepartment of Pharmacology, Technion-BruceRappaport Faculty of Medicine, Eve Topf and NPFNeurodegenerative Diseases Centers, RappaportFamily Research Institute, Haifa, Israel

W M ZawadaDivision of Clinical Pharmacology, Department ofMedicine, University of Colorado School of Medicine,Denver, CO, USA

W ZhouDivision of Clinical Pharmacology, Department ofMedicine, University of Colorado School of Medicine,Denver, CO, USA

Jean-Michel Gracies, Winona Tse, Mara Lugassy and Judith Frank (New York, NY, USA)

Fabrizio Stocchi (Rome, Italy)

Thomas D H€albig and William C Koller (New York, NY and Chapel Hill, NC, USA)

Olivier Rascol, Tarik Slaoui, Wafa Regragui, Fabiene Ory-Magne,

Christine Brefel-Courbon and Jean-Louis Montastruc (Toulouse, France)

Moussa B H Youdim and Peter F Riederer (Haifa, Israel and W€urzburg, Germany)

Yaroslau Compta and Eduardo Tolosa (Barcelona, Spain)

36 Antiglutamatergic drugs in the treatment of Parkinson’s disease 127Marı´a Graciela Cers
osimo and Federico Eduardo Micheli (Buenos Aires, Argentina)

Carlo Colosimo and Giovanni Fabbrini (Rome, Italy)

Mary Baker and Jill Rasmussen (Sevenoaks and Redhill, UK)

Susan H Fox and Anthony E Lang (Toronto, ON, Canada)

40 Levodopa-induced dyskinesias in Parkinson’s disease 185Jose A Obeso, Marcelo Merello, Maria C Rodrı´guez-Oroz, Concepci
o Marin, Jorge Guridi and

Lazaro Alvarez (Pamplona and Barcelona, Spain, Buenos Aires, Argentina and La Habana, Cuba)

Kelvin L Chou and Joseph H Friedman (Warwick, RI, USA)

Frederick A Lenz (Baltimore, MD, USA)

J Volkmann and G Deuschl (Kiel, Germany)

Curt R Freed, W Michael Zawada, Maureen Leehey,

Wenbo Zhou and Robert E Breeze (Denver, CO, USA)

45 Gene therapy approaches for the treatment of Parkinson’s disease 291Biplob Dass and Jeffrey H Kordower (Chicago, IL, USA)

Ronald F Pfeiffer (Memphis, TN, USA)

David J Burn and Andrew J Lees (Newcastle upon Tyne and London, UK)

Natividad P Stover, Harrison C Walker and Ray L Watts (Birmingham, AL, USA)

V Dhawan and K Ray Chaudhuri (London, UK)

Nirit Lev, Eldad Melamed and Daniel Offen (Petah-Tikva and Tel-Aviv, Israel)

Federico Eduardo Micheli and Marı´a Graciela Cers
osimo (Buenos Aires, Argentina)

Yacov Balash and Amos D Korczyn (Tel-Aviv and Ramat-Aviv, Israel)

Alex Rajput and Ali H Rajput (Saskatoon, SK, Canada)

J Carsten Mo¨ller and Wolfgang H Oertel (Marburg, Germany)

John G L Morris, Brian Owler, Mariese A Hely and

Victor S C Fung (Sydney, NSW, Australia)

56 Calcification of the basal ganglia 479Jennifer S Hui and Mark F Lew (Los Angeles, CA, USA)

Oscar S Gershanik (Buenos Aires, Argentina)

Vasiliki Koukouni and Kailash P Bhatia (London, UK)

Ruth H Walker (Bornx and New York, NY, USA)

Ian McKeith (Newcastle upon Tyne, UK)

Daniel D Truong and Roongroj Bhidayasiri (Fountain Valley and Los Angeles, CA,

USA and Bangkok, Thailand)

Section 5 Treatment of Parkinson’s disease

Chapter 30Physical therapy in Parkinson’s diseaseJEAN-MICHEL GRACIES*, WINONA TSE, MARA LUGASSY AND JUDITH FRANK

Department of Neurology, Mount Sinai Medical Center, New York, NY, USA

The movement disturbances characteristic of Parkinson’s

disease (PD), such as hypometria, akinesia, rigidity and

disturbed postural control, can significantly impact

func-tion and quality of life Typical disabilities resulting from

these motor impairments range from dressing or rising

from a chair to maintaining balance and initiating gait

(Morris et al., 1995, Morris and Iansek, 1996) Since

the emergence of levodopa in the late 1960s,

pharmaco-logic therapy has been the primary strategy to manage

these symptoms and has been considered the

‘gold-stan-dard’ therapy However, medication regimens are unable

to control the disease satisfactorily in the long term, as

dyskinesias, fluctuations of the medication efficacy and

cognitive difficulties invariably occur after a number of

years (Olanow, 2004) Over the past decades, there has

been increasing awareness as to the potential role of

phy-sical exercise and investigations have been carried out to

evaluate techniques that may alleviate functional

disabil-ities in patients with PD Despite this rising interest,

sur-veys show that only 3–29% of PD patients regularly

consult with a paramedical therapist, such as a physical,

occupational or speech therapist (Deane et al., 2002)

A large variety of physical therapy methods have

been evaluated in PD The approach to therapy in an

individual patient, however, may be governed at the

most basic level by the stage of the disease In

indivi-duals with mild to moderate disease, who are

ambula-tory and have retained a certain degree of physical

independence, therapy may focus on the teaching of

exercises directly designed to delay or prevent the

aggravation of the motor impairment in PD, with the

goal of maintaining or even increasing functional

capacities At the other end of the spectrum, in an

indi-vidual with compromised ambulation and significant

disability due to advanced PD, the therapeutic focus

may shift from the teaching of exercises to the

teaching of compensation strategies allowing vation of as much functional independence as possible.These strategies include adaptation of the home envir-onment, both to lessen the effects of motor impairmentand to optimize safety

preser-30.1 Physical exercises in mild to moderate stages of Parkinson’s disease

Most studies investigating physical exercises have beencarried out in subjects with mild to moderate PD, i.e up

to Hoehn and Yahr stages 3 (Dietz et al., 1990, Kuroda

et al., 1992, Comella et al., 1994; Bond and Morris,

2000, Marchese et al., 2000, Hirsch et al., 2003)

30.1.1 Metabolic and neuroprotective effects

of physical exercise in Parkinson’s diseaseExercise intensity may affect dopaminergic metabolism

in PD In unmedicated PD patients, 1 hour of strenuouswalking reduces the dopamine transporter availability inthe medial striatum (caudate) and in the mesocorticaldopaminergic system as measured using positron emis-sion tomography (PET) scans, which has been consideredhighly suggestive of increased endogenous dopaminerelease (Ouchi et al., 2001) In addition, exogenous levo-dopa seems to be better absorbed during moderate-inten-sity endurance exercise, as measured using maximallevodopa concentrations in plasma (Reuter et al., 2000;Poulton and Muir, 2005)

The beneficial effect of exercise on the dopaminemetabolism in PD patients has recently been supported

by a number of compelling studies in animal models.Rats exposed to either 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP) or 6-hydroxydopamine (6-OHDA)

to induce behavioral and neurochemical loss analogous

*Correspondence to: Jean-Michel Gracies, Department of Neurology, Mount Sinai Medical Center, One Gustave L Levy Place,Annenberg 2/Box 1052, New York, NY 10029-6574, USA E-mail: jean-michel.gracies@mssm.edu, Tel: 1-(212)-241-8569,Fax: 1-(212)-987-7363

Parkinson’s disease and related disorders, Part II

W C Koller, E Melamed, Editors

# 2007 Elsevier B V All rights reserved

to PD lesions that are then exercised show significant

sparing of striatal dopamine compared to lesioned

ani-mals that remain sedentary (Fisher et al., 2004; Poulton

and Muir, 2005) Further, one study showed that exercise

after MPTP exposure increases dopamine D2 transcript

expression and downregulates the striatal dopamine

transporter (Fisher et al., 2004) However, behavioral

effects of training were inconsistent in these studies

(Tillerson et al., 2003; Mabandla et al., 2004; Poulton

and Muir, 2005) Rodents with unilateral depletion of

striatal dopamine display a marked preferential use of

the ipsilateral forelimb After casting of the

unaf-fected forelimb in unilaterally 6-OHDA-lesioned rats,

the forced use of the affected forelimb spares its

func-tion as well as the dopamine remaining in the lesioned

striatum (Faherty et al., 2005) There was a negative

correlation in this study between the time from lesion

to immobilization, i.e to forced use and the degree of

behavioral and neurochemical sparing This may

sug-gest the importance of initiating an exercise regimen

early in the course of PD

Furthermore, two recent studies have shown that

exposing animals to an environment prompting

exer-cise and activity prior to MPTP lesion, or to unilateral

forced limb use prior to contralateral lesioning with

6-OHDA, may prevent the emergence of the

beha-vioral and neurochemical deficits that normally

fol-low the administration of 6-OHDA (Cohen et al.,

2003; Faherty et al., 2005) In one of these studies,

animals receiving a unilateral cast had an increase in

glial cell-line derived neurotrophic factor (GDNF)

pro-tein in the striatum corresponding to the contralateral

overused limb The prevention of parkinsonian deficits

by prior exercise was suggested partly to involve

GDNF changes in the striatum (Cohen et al., 2003)

30.1.2 Training techniques

Several types of exercise techniques have been

evalu-ated with regard to their impact on motor deficits in

mild to moderate PD Few studies have been

con-trolled and much of the evidence is anecdotal or relies

on open trials The strongest line of evidence to date

supports the benefit of lower-limb resistance training

in PD patients, particularly for balance and gait

30.1.2.1 Resistance training

Major goals of physical therapy in PD should be the

reduction of rigidity, the improvement of postural

control and the prevention of falls as most PD patients

experience balance disturbances and increased risk

of falls in the course of their illness (Koller et al.,

1989; Pelissier and Perennou, 2000; Ochala et al.,

2005) It has been shown that musculotendinous ness decreases following strength training in healthyelderly individuals (Ochala et al., 2005) In a recentopen-label study, 40 Hoehn and Yahr III PD patientsand 20 healthy age-matched controls underwent a30-day program comprising a variety of physicaltherapies including regular physical activity, aerobicstrengthening, muscle positioning and lengtheningexercises (Stankovic, 2004) Physical therapy resulted

stiff-in significant improvement stiff-in tandem stance, one-legstance, step test and external perturbation – all tests

of balance – in the PD group

Important risk factors for falls in PD are the muscleatrophy and the decrease in physical conditioningthat may result from activity reduction (Scandalis

et al., 2001) There is a proven relationship betweendecreased lower-limb muscle strength and impairedbalance in PD, as muscle weakness in the lower extre-mities may limit the ability to mount appropriate pos-tural adjustments when balance is challenged (Toole

et al., 1996) A controlled study addressed the effects

of lower-limb resistance training in PD, in whichpatients were randomized to two groups The firstgroup underwent 30-minute sessions three times aweek for 10 weeks of standard balance rehabilitationexercises, including practicing standing on foam andweight-shifting exercises The second group under-went the same balance training and, in addition,received tri-weekly high-intensity resistance trainingsessions focusing on plantar flexion, as well as kneeextension and flexion Subjects who received balancetraining only increased their lower-extremity strength(composite score from knee extensor, flexor and plan-tar flexor strength) by 9%, whereas subjects whounderwent additional resistance training increasedtheir strength by 52% Balance training only increasedthe subjects’ ability to maintain balance This effectwas significantly greater and lasted longer in the groupundergoing additional lower-limb resistance training(Hirsch et al., 2003)

Improvement in lower-limb muscle strength in PDmay also improve gait In an open protocol, 14 PDpatients and 6 normal controls underwent an 8-weekcourse of resistance training, twice a week, withexercises including leg press, calf raise, leg curl,leg extension and abdominal crunches Lower-limbstrength and gait were assessed in the practicallydefined levodopa ‘off’ state (i.e off medication for

at least 12 hours) before and after the training period,showing gains in strength in the PD patients that weresimilar to those of the control subjects and improve-ment on quantitative measures of gait such as stridelength, gait velocity and postural angles (Scandalis

et al., 2001)

30.1.2.2 Attentional strategies and sensory cueing

It is a common clinical observation that increased

attention or effort may allow improvements of

remark-able magnitude in motor tasks performed by PD

patients (Muller et al., 1997) This observation has

contributed to the development of cueing, an

increas-ingly prevalent concept in the field of physical therapy

in PD, in which external visual or auditory cues are

used to enhance attention and thus performance It

has been hypothesized that the basal ganglia, which

normally discharge in bursts during the preparation

of well-learned motor sequences, provide phasic cues

to the supplementary motor area, activating and

deac-tivating the cortical subunits corresponding to a given

motor sequence (Morris and Iansek, 1996) In PD

however, the internal cues provided by the basal

gang-lia are no longer appropriately supplied Thus,

restora-tion of phasic activarestora-tion of the premotor cortex might

be facilitated by external means

30.1.2.2.1 Auditory cueing

Use of auditory cueing has gained popularity over the

past decade (Rubinstein et al., 2002) In the upper

limb, auditory cues for button-pressing tasks have

shown that added external auditory information

dra-matically reduces initiation and execution time and

improves motor sequencing (Georgiou et al., 1993;

Kritikos et al., 1995) Another study showed that a

sin-gle external auditory cue to start a movement was

associated with a more forceful, more efficient and

more stable movement than if the movement was

accomplished only when the patients were ‘ready’

(internal cue) (Ma et al., 2004)

Musical beats, metronomes and rhythmic clapping

have been used as cueing techniques to improve gait

in PD patients (Thaut et al., 1996; McIntosh et al.,

1997) The use of metronome stimulation has been

shown to reduce acutely the number of steps and the

time to complete a walking course, compared to uncued

walking in PD patients (Enzensberger et al., 1997)

A study of a 3-week home-based gait-training program

revealed that PD patients trained with rhythmic auditory

stimulation in the form of metronome pulsed patterns

embedded into the beat structure of music improved

gait velocity, stride length and step cadence compared

to subjects receiving gait training without rhythmic

auditory stimulation or no gait training at all (Thaut

et al., 1996) Additional research further indicated that

these gait improvements occur regardless of whether

the patient is on or off medication at the time of training

(McIntosh et al., 1997) The effects of auditory cueing

by metronome on gait may depend on the frequency

used for the metronome beat, which may have to be

slightly faster than the baseline walking cadence to beefficacious PD patients using such rhythmic cues set

at rates of 107.5 and 115% of their baseline walkingcadence are able to increase the cadence and meanvelocity of their gait correspondingly (Howe et al.,2003; Suteerawattananon et al., 2004) In contrast,Cuboand colleagues (2004)found that the use of the metro-nome set at the baseline walking cadence slowed ambu-lation and increased the total walking time withouthaving any significant effect on freezing However,the latter results were obtained in the ‘on’ state, whichdoes not allow any conclusions as to the effects of suchtreatment in the off state, when patients typicallyexperience the most slowness and freezing Anotherspecific situation in which sensory cueing may not

be associated with functional improvements is that inwhich patients initiate walking at their maximal speed.Sensory cueing then interferes with movement speedand performance, which suggests competition betweenthe external and internal signals of movement command

in situations in which strong internal signals may beadequate to achieve optimal movement performance(Dibble et al., 2004) In the clinical setting, auditorycueing is most often used in the form of rhythmic audi-tory stimulation during gait, in which patients pace theirwalking to either a metronome beat or a rhythmic beatembedded in music

30.1.2.2.2 Combination of auditory cueing withattentional strategies

Auditory cueing may also be involved in attentionalstrategies such as the use of verbal instruction sets

In one controlled study in PD, gait was analyzed ing trials of natural walking interspersed with rando-mized conditions in which subjects were verballyinstructed to increase arm swing, or step size or walk-ing speed In addition to being able to improve any ofthese variables in response to specific instructions,hearing only one of these instructions was associatedwith an improvement in the other gait variables as well(Behrman et al., 1998) Conversely, giving an addi-tional concurrent task (cognitive or an upper-limbmotor task) to a walking patient worsens gait in PD

dur-as it may distract attention directed towards gait This

is the situation of dual task, which is a classical cause

of movement deterioration in PD (Brown et al., 1993)and more specifically of gait deterioration (Bond andMorris, 2000; Hausdorff et al., 2003) Experimentalsituations combining such dual tasks (reducing atten-tion) with verbal instructions to focus on walking(increasing attention) or on auditory cues tended toreverse the deterioration and restore better walking(Canning, 2005; Rochester et al., 2005)

30.1.2.2.3 Visual cueing

Since classic experiments by Martin (Martin and

Hurwitz, 1962), a number of studies have shown that

stride length can be improved by visual cueing, in the

form of horizontal lines marked on the floor, over which

the patient is encouraged to step In a series of

experi-ments,Morris et al (1996)demonstrated that PD patients

using such horizontal floor markers as visual cues were

able to normalize their stride length, velocity and

cadence, an effect that persisted for 2 hours after the

intervention It was noted that although transverse lines

of a color contrasting with the floor and separated by

an appropriate width are effective for this purpose,

zig-zag lines or lines parallel to the walking direction are

not These visual cues might function by supplying a

now deficient well-learned motor program with external

visual information on the appropriate stride length

(Rubinstein et al., 2002) Similar improvement in stride

length and gait velocity is possible using light devices

attached to the chest to provide a visual stimulus on the

floor over which the patient must step (Lewis et al.,

2000) However, such light devices increase attentional

demand and perceived effort of walking, which suggests

that static cues are more effective in improving gait

while minimizing effort Finally, there are suggestions

that benefit from cueing techniques might be optimal in

earlier stages of the disease (Lewis et al., 2000)

30.1.2.2.4 Combination of visual cueing with

attentional strategies

Gait improvement also occurs when, instead of using

horizontal markers on the floor, an attentional strategy

is used with instructions to visualize the length of stride

that subjects should take while walking (Morris et al.,

1996) Whether gait is assisted by direct visual cueing

or by such attentional visualization strategy, the benefit

is reversed when patients are given additional tasks to

do while walking, distracting attention from the gait

(Morris et al., 1996) Thus, direct visual cues and

visuali-zation exercises may both function by focusingattention

on the gait, such that walking ceases to be a primarily

automatic task delegated to the deficient basal ganglia

(Morris et al., 1996)

30.1.2.2.5 Combination of visual and auditory cues

Suteerawattananon et al (2004) have studied the effect

of combining visual and auditory cues to determine the

effect of such a combination on gait pattern in PD In

this study the auditory cue consisted of a metronome

beat 25% faster than the subject’s fastest gait cadence

Brightly colored parallel lines placed along a walkway

at intervals equal to 40% of the subject’s height served

as the visual cue The auditory cueing significantly

improved cadence whereas the visual cue improvedstride length However, the simultaneous use of visualand auditory cues did not improve gait significantlymore than each cue alone

30.1.2.3 Active appendicular and axialmobilization, stretch

Axial mobility may affect function in PD There is asignificant association between reduced axial rotationand functional reach (maximal reach without taking astep forward) independent of disease state (Schenkman

et al., 2000) A controlled study confirmed that physicalintervention targeted on improving spinal flexibilityimproves functional reach in PD (Schenkman et al.,

1998) An open study suggested that active mobilizationexercises of the trunk and lower limbs improved trans-fers (from supine to sitting and sitting to supine), supinerolling and rising from a chair (Viliani et al., 1999)

It has been hypothesized that muscle stiffness alonemay be a factor of functional impairment in PD, particu-larly in the lower limb with respect to shortened stridelength and altered gait pattern (Lewis et al., 2000).Aggressive stretch programs might decrease musclestiffness However, stretch alone as a therapy techni-que has not been systematically evaluated as a method

to improve motor function in PD In one controlledstudy an improvement in rigidity was observed ascompared to baseline after a therapy program invol-ving passive stretch as well as other motor tasks andbalance training This effect had disappeared by 2months after study completion, which suggests thatstandard therapy programs should probably be contin-ued in the long term, or at least repeated frequently(Pacchetti et al., 2000)

30.1.2.4 Treadmill trainingTreadmill training has been increasingly used in therehabilitation of patients with spinal cord injury, hemi-paresis and other gait disorders (Hesse et al., 2003).However, treadmill training may be expensive for somepatients and the specific literature on treadmill training

in PD must be analyzed with particular caution Somestudies have recently suggested that treadmill trainingmight increase walking speed and stride length in PD(Miyai et al., 2000, 2002; Pohl et al., 2003) However,although these studies compared treadmill with non-treadmill training, they were not controlled for the walk-ing speed used in the training In particular the non-tread-mill training did not involve specific requirements of gaitvelocity, step cadence or stride length Under these cir-cumstances, the positive effects seen after treadmill usemay have been the effects of higher energy demands,

or a higher walking speed used on the treadmill training

(Miyai et al., 2000, 2002; Pohl et al., 2003) In a study

which did control for walking speed by having subjects

walk first on the ground and then on a treadmill set at

the same speed, both PD patients and age-matched

con-trols showed shorter stride lengths and higher stride

fre-quency in the treadmill condition (Zijlstra et al.,

1998) These effects were more pronounced in the

PD patients This is consistent with previous findings

that, in healthy subjects, walking on a treadmill results

in smaller steps than when walking on the ground at

the same speed (Murray et al., 1985) This is

particu-larly relevant to the PD patient population, in which

decreased stride length and impaired stride length

regu-lation are fundamental characteristics (Morris et al.,

1996) Thus, the typical shortening of stride length in

PD may in fact be accentuated when walking on a

treadmill (Zijlstra et al., 1998)

30.1.3 Long-term effects of physical therapy

The exact duration of the effects of programs of

physi-cal exercise in PD remains unknown Most studies on

physical therapy in PD have been open and had

fol-low-up periods of less than 8 weeks, making the

long-term persistence of beneficial effects difficult to

deter-mine (Deane et al., 2001) However, in one recent

open-label trial 20 PD patients followed a

comprehen-sive rehabilitation program three times a week for

20 weeks Following the program, there was a

signifi-cant improvement in Unified Parkinson’s Disease

Rating Scale (UPDRS) activities of daily living and

motor sections scores, self-assessment Parkinson’s

Dis-ease Disability scale, 10-meter walk test and Zung scale

for depression, which was still seen at the 3-month

fol-low-up, suggesting that a sustained motor improvement

can be achieved with a long-term rehabilitation program

in PD (Pellecchia et al., 2004) A few previous open

studies have similarly suggested motor improvements

lasting 6 weeks to 6 months after physical therapy

was discontinued (Comella et al., 1994; Reuter et al.,

1999; Pellecchia et al., 2004) This might underscore

the importance of physical therapy not as one event

lim-ited in time, but as a continuous or repetitive effort, so

that its benefits might be maintained and perhaps

strengthened over time

Other long-term benefits from exercise in PD have

been suggested, involving in particular an increased

sense of well-being and an improved quality of life

(Reuter et al., 1999) One observational study reported

that mortality was higher by a hazard ratio of 1.8

amongst PD patients who did not exercise regularly

com-pared with patients who did However, the odds ratios

were not adjusted for major health factors, such as

cardi-ovascular disease, lung disease, smoking or obesity

In addition to having greater effects on motor functionthan physical therapy without cueing (Thaut et al., 1996;McIntosh et al., 1997), the use of cueing may extendthe duration of the effects of therapy (Rubinstein

et al., 2002) In a recent single-blind, prospective study,

20 PD patients were randomized to two physical apy groups (Marchese et al., 2000) The first groupunderwent a 6-week program of posture control exer-cises, passive and active stretch and walking exercises,whereas the second group combined the same regimenwith a variety of visual, auditory and proprioceptivecueing techniques Although both groups showedimprovement on activities of daily living and motorability (UPDRS) at the end of the program, the groupwithout sensory cue training had returned to baseline

ther-at a 6-week follow-up, whereas the group trained withcueing techniques was still improved at that visit.Although it remains uncertain whether all the involvedtypes of sensory cueing or only specific types wereassociated with this benefit, the learning of new motorstrategies associated with cueing may have caused thelasting improvement (Marchese et al., 2000)

30.1.4 Emotional arousal, group therapy and use ofmotivational processes

Attempts at increasing cortical excitability in PD haveinvolved, in addition to external sensory inputs, theuse of emotional arousal A recent open-label study sug-gested improved precision of arm movements as a con-sequence of exposure to stimulating music (Bernatzky

et al., 2004).Pacchetti and colleagues (2000)comparedstandard physical therapy (passive stretching exercises,motor tasks, gait and balance training) with musictherapy, involving choral singing, voice exercises andrhythmic and free body expression, both administered

in weekly group sessions in a randomized, prospectivecontrolled study The improvement of bradykinesia,emotional well-being, activities of daily living andquality of life scores was greater in the music therapygroup, whereas rigidity was the only measure that wasmore improved in the standard physical therapy group.These effects dissipated at a 2-month follow-up Theimprovement in bradykinesia associated with musictherapy may have resulted from external rhythmic cues

or from the affective arousal induced by the music,influencing motivational processes (Pacchetti et al.,

2000)

It has been theorized that physical therapy in groupsessions might enhance socialization and motivation,but group therapy has not been systematically comparedwith individual therapy and group therapy studies havenot been controlled In their study, Pacchetti and

colleagues (2000)evaluated training in a group setting,

both in the physical therapy and music therapy arms

The authors did not observe any increase in emotional

function or quality of life in the physical therapy

group In open label studies of group physical therapy

in PD, subjects have reported subjective impressions

of benefit in motor symptoms and quality of life, but

there was no improvement in quantitative measures

of motor function (Pedersen et al., 1990; Lokk, 2000;

Deane et al., 2002)

30.2 Recommendations for physical exercise in

mild to moderate Parkinson’s disease

30.2.1 Schedule

Although most protocols of the literature have involved

supervised exercise sessions one to three times per

week (Deane et al., 2002), we recommend that the

exer-cise schedule be intensified and expanded from

orga-nized physical therapy sessions into a daily event,

with a time window (1–1.5 hours) consistently devoted

to this activity every day Controlled studies have

indeed demonstrated that PD patients can improve formance on complex motor tasks with intense repeatedpractice – an effect that persists days after the practicetrials have ended (Soliveri et al., 1992; Behrman

per-et al., 2000) Similar principles of rapid repetition can

be applied to daily physical exercise

It has been suggested that such exercises should beperformed during the levodopa ‘on’ state, in order tooptimize their execution (Koller et al., 1989) However,this is not supported by evidence and the opposite strat-egy may also be suggested, i.e the performance of phy-sical exercises during the early morning ‘off’ phase forexample, which might improve dopamine availabilityand possibly delay the need for the first daily pill(Reuter et al., 2000; Ouchi et al., 2001) Finally, forexercises to be effectively replicated at home, it is prob-ably optimal to teach them as early as possible in thecourse of the disease

30.2.2 Suggested exercises

We recommend alternating between two types of cises in a practice session (Figs 30.1 and 30.2).Active

exer-STRETCHES & EXERCISES UPPER BODY

Lift the weight (bag) forward up & down Repeat with each arm until fatigued

Lift the weight (bag) to the side, up & down Repeat with each arm until fatigued

Stretch shoulder with hand behind wall (e.g in a doorway)

5 mins Each side.

Stretch shoulder with elbow leaning against wall as high as

possible.

5 mins Each side

Fig 30.1 Stretches and exercises for the upper body

exercises should consist of vigorous series of

light-resistance rapid alternating movements focused on

strengthening muscles that ‘open’ the body (extensors,

abductors, external rotators, supinators and shoulder

flexors) Passive exercises should involve limb and

trunk posturing focused on lengthening muscles that

‘close’ the body (flexors, adductors, internal rotators,

pronators) Following a series of active exercises with

passive posturing for a few minutes also allows

cardi-orespiratory rest

In the upper body, the active resistance exercises

may involve light weight-lifting, particularly focusing

on active shoulder abductions and shoulder flexions,

as these movements are associated with spinal extensor

recruitment (Moseley et al., 2002), which should

contri-bute to strengthening these muscles (Fig 30.1) The

spinal extensors are typically hypoactive in PD and

strengthening them should improve trunk posture

These exercises should be vigorous so as to provoke a

clear sense of fatigue at the end of the series (Rooney

et al., 1994) In this population we recommend

choos-ing weights so as to avoid uschoos-ing maximal or near

max-imal intensity training (Khouw and Herbert, 1998) in

order to limit the risk of muscle and tendon strain in

elderly patients Therefore, the weight recommendedshould cause fatigue optimally after 10–20 repeats asopposed to fewer than 10 repeats On the contrary,stretching postures should focus on stretching the mus-cle groups that tend to ‘close’ the body: horizontaland vertical adductors, internal rotators at the shoulder,flexors and pronators at the elbow, flexors at the wristand fingers Ideally, each active exercise should be pur-sued for about a minute whereas each posture of passivestretch should be maintained for about 5 minutes oneach side

In the lower body, stretching postures (passiveexercises) should again focus on muscles such asthe hamstrings and hip adductors that tend to adopt ashortened position in PD because of hypoactivity intheir antagonists The active exercises should primarilyfocus on sit-to-stand (training trunk and lower-limbextensors) and walking practice (Fig 30.2)

30.2.2.1 Sit-to-standPatients should repeat a series of sit-to-stand exercisesevery day, if possible with arms crossed, ideally as manytimes as possible in a continuous series so as to achieve

Stretch by bending forward

5 mins on each side

Stand from sitting position without using hands.

Repeat as many times as possible until fatigued.

Walk the same distance in as few steps as possible.

Stand with support and stretch legs for 5 mins STRETCHES & EXERCISES LOWER BODY

Fig 30.2 Stretches and exercises for the lower body

a sense of fatigue in the primary muscles involved (hip,

knee and spinal extensors) This should lead to

strengthen-ing of these muscles, which should improve sit-to-stand

ability and walking balance

30.2.2.2 Walking

Patients should not focus on the speed achieved while

walking but on their stride length Ideally the patient

selects a specific distance that should be covered every

day and counts the steps taken to walk that distance

Each day, the patient should try to walk the same

dis-tance using as few steps as possible (Fig 30.2) When

stride length improvement over that distance is

maxi-mized (i.e the number of steps taken cannot be further

decreased), the same process should be repeated on a

longer distance In terms of walking in conditions

other than a flat ground, treadmill walking has not

been compared to walking in a swimming pool in

controlled studies However, we would hypothesize

that walking against the viscous resistance of water

should maximize hip flexion and ankle push-off

train-ing and thus better improve stride length than treadmill

walking, which might lead to opposite results

(see above)

30.3 Compensation strategies in advanced

stages of Parkinson’s disease

30.3.1 Role of discipline

As PD progresses and motor function deteriorates,

patients become significantly less mobile and therefore

less able to perform daily self-initiated exercises such

as active movements against resistance and walking

Although the goal of physical therapy remains to

optimize functional independence, the method

gradu-ally shifts towards teaching strategies to patients

and care-givers to compensate for worsening motor

impairments Omitting some of these strategies may

jeopardize activities such as walking or swallowing,

with potentially serious consequences The emphasis

on a strict patientdiscipline and on the importance of

its enforcement by the care-giver thus becomes even

more important than in the early stages, as the patient

must now consistently apply the compensation

strate-gies learned in therapy

One fundamental compensatory strategy in advanced

PD involves increasing the amount of attention and

effort the patient directs toward any given motor

activity Tasks such as walking, talking, writing and

standing up are no longer automatic and should

no longer be taken for granted The individual with

advanced PD must learn to want to perform each of

these activities and actively concentrate on them,

possibly even to rehearse them mentally as a new taskeach time, as opposed to justdoing them This corre-sponds to a major change in the approach to dailyactivities Such change can be facilitated through

a clear understanding by the therapist and/or thecare-giver of: (1) the fundamental difference betweenautomatic and consciously controlled movements;and (2) the need to switch to conscious movementcontrol for virtually all daily motor activities, particu-larly those that we tend to view as the most natural,such as talking, writing, standing up and walking

We provide examples of these changes in daily gies below

strate-However, teaching and maintaining such disciplinecan become a highly challenging proposition in advanced

PD, depending on the presence of depression and ticularly mental deterioration (impairment in executivefunctions) and on the degree of patient motivation toimprove quality of life (Gracies and Olanow, 2003).Depression is a common feature of PD, particularly

par-in advanced stages (Gracies and Olanow, 2003;McDonald et al., 2003) and is characterized by hope-lessness and pessimism, as well as decreased motiva-tion and drive (Brown et al., 1988) This mayundermine the motivation to practice or to changedaily living strategies Apathy and abulia (lack ofdrive and initiative) can also be prominent symptoms

in PD, independent of depression, and occur withgreater frequency than in patients of similar disabilitylevel from other causes (Pluck and Brown, 2002).Most importantly, the gradual emergence of demen-tia, in particular frontal dysexecutive features (perse-verations, impulsivity), may hamper the ability topursue a strict but slower routine of conscious rehear-sal when performing daily activities that used to beautomatic In these cases, the care-giver oftenbecomes the primary focus of the teaching and theperson effectively responsible for implementing thediscipline of the compensation strategies

30.3.2 Strategies for freezing episodes

In advanced PD, episodes of freezing, characterized by

an interruption of motor activity especially whenencountering obstacles or constricted spaces, can con-stitute a significant problem, occurring in up to one-third of patients (Giladi et al., 1992) Managementmay consist primarily of behavioral strategies Asmentioned in the previous section, one can teach thepatient how to substitute external auditory, visual, orproprioceptive cues to replace the deficient internalmotor cues normally provided by the basal ganglia(Morris et al., 1995) Specific attentional strategiesmay also be useful (see below)

30.3.2.1 Sensory cues for freezing

Several techniques have been used to alleviate freezing

episodes through external visual input Visual markers

can be placed in the home in areas where freezing

epi-sodes are common such as doorways and narrow

hall-ways These may include horizontal markers on the

floor over which the individual is instructed to step, or

a dot on the wall on which the patient is instructed to

focus in the event of freezing If the patient is

accompa-nied, the other person may place a foot in front of the

patient, which the patient then steps over (Morris

et al., 1995) Inverted walking sticks, with the handle

used as a horizontal visual cue at the level of the foot,

have also been investigated as a potential means of

improving freezing (Kompoliti et al., 2000) Results

have been inconsistent, with some subjects showing

worsening of freezing while using such a walking stick

and others showing improvement (Dietz et al., 1990;

Kompoliti et al., 2000) Additionally, caution must be

used with inverted sticks in PD patients, as these sticks

may cause tripping and increase the risk of fall

Acous-tic cues can also be used to decrease freezing PD

patients may carry a metronome, which can be switched

on during a freezing episode emitting an auditory

beat Such external cues may be sufficient to initiate

movement

30.3.2.2 Attentional strategies for freezing

A number of adjustments of motor behavior have been

suggested to alleviate freezing episodes when they occur

These include:

 Focusing on swaying from side to side,

transfer-ring body weight from one leg to the other (Morris

et al., 1995)

 Singing, whistling, loudly saying ‘go’ or ‘left,

right, left, right’, clapping or saying a rhyme and

stepping off at the last word are behavioral

strate-gies that have the additional advantage of

generat-ing acoustic cues (Morris et al., 1995)

 Cue cards posted on the walls of freezing-prone

areas, with instructions such as ‘go’ or ‘large step’

(Morris et al., 1995)

 The one-step-only technique – strategy of

distrac-tion from the funcdistrac-tional or social meaning of the

action to be accomplished Success with a method

using a deep-breathing relaxation technique has

been noted in a patient who had failed several

other techniques to reduce freezing episodes

(Macht and Ellgring, 1999) It is often noted that

during an episode of freezing, the more the patient

worries about the functional end-goal of walking

(freeing the elevator entry for other people to

come out, moving out of a crowded store through

a narrow exit, entering the doctor’s office), themore difficult the task becomes, particularly asothers look on The emotional stress associatedwith the social function of walking in these situa-tions makes the freezing episode worse At theMount Sinai Movement Disorders Clinic weattempt to have the patient disconnect for a shortwhile from the social and functional implications

of walking forward again, and instead to focusanalytically on the walking technique Walking isnormally a smooth succession of steps The patient

is asked to focus only on achieving one tary unit of walking, i.e one step only One singlestep should have minimal social role (since onestep is usually not sufficient to enter or exit acrowded place) and thus minimal emotionalcharge In practice, the first stage is tostop trying

elemen-to walk The patient may then take a deep breath

to mark a pause in the effort and achieve betterrelaxation and spread the feet Then the patientshould concentrate on taking one big step onlyand specifically on the power of the hip, kneeand foot flexor movements required to achieve thisone step Clinical experience shows that when astrong first step is achieved the second and thirdsteps naturally follow

 Movement planning and attention – switching backfrom automatic movements to consciously con-trolled movements To enhance movement inadvanced PD, patients can be taught – or repeatedlyreminded – to rehearse mentally each movementbefore it is executed and to pay close attention tothe movement while it is being performed Forexample, in crowded environments where the risk

of freezing episodes or tripping increases, thepatient should think ahead and plan the most directroute through the obstacles Turning around isanother difficult task in advanced PD, which may

be the most common circumstance causing falls

in the home setting Before turning, the patientshould rehearse the individual leg movements thatare required to turn the body around effectively.Also, it is recommended to accomplish the turnover a wide arc instead of swiveling (Morris et al.,

1995)

30.3.3 Strategies to minimize postural instability

In general, advanced PD patients have difficulty taining balance secondary to slow righting reactions(recruitment of the appropriate axial muscles) in response

main-to a challenge main-to equilibrium Therefore, patients shouldtry to apply the above principle of conscious control of

previously automatic tasks to postural balance Patients

may be taught actively to focus their attention on balance

whenever they perform an activity involving standing,

similar to what healthy subjects must do when they stand

on a small boat in a turbulent sea The purpose is to be

in a state of alertness and readiness to respond to threats

of balance and thus promptly implement the necessary

actions to restore equilibrium (Morris and Iansek,

1996) A recent open-label study suggested that 14-day

repetitive training of compensatory steps might enhance

protective postural responses and shorten the period of

double support during gait in PD In addition, significant

increases in cadence, step length and gait velocity were

observed after such training These effects were stable

for 2 months without additional training (Jobges et al.,

2004)

30.3.4 Motor subunits

It is beneficial for the PD patient to treat long

move-ment sequences not as a whole, but to break them

down as a series of component parts or subunits With

this strategy, each subunit is considered and performed

as if it were itself a whole movement This strategy

is partly used in the one-step-only technique to

allevi-ate freezing Focusing on each subunit of a motor

sequence may be particularly effective for multijoint

actions such as reaching and grasping, thus facilitating

activities such as feeding and dressing, or whole-body

activities such as standing up from a bed or a chair

(Morris and Iansek, 1996) For example, to stand up

from a bed, the patient should first mentally rehearse

the entire movement and then break the motor

sequence down into a series of subunits, including

bending the knees, turning the head, reaching both

arms in the desired direction, turning the body,

swing-ing the legs over the bed and then finally sittswing-ing up

(Morris et al., 1995)

A similar strategy can be used for rising from a

chair The patient is encouraged to rehearse the

sequence mentally, then to wriggle forward to the front

of the seat, make sure the feet are placed back

under-neath the chair, lean forward, push on the legs and

straighten up the back to stand up In an open study,

PD patients trained with these techniques as part of a

6-week physical therapy home regimen showed

signif-icant improvement in their ability to transfer in and out

of chairs and beds (Nieuwboer et al., 2001)

30.3.5 Avoidance of dual-task performance

It has been hypothesized that PD patients may

mini-mize their balance or walking difficulties by using

conscious cortically mediated control to overcome

defective automatic basal ganglia activation (Morris

et al., 2000) When conscious attention is divertedfrom the task of maintaining equilibrium, the balan-cing deficits may be accentuated The set-shifting dif-ficulties commonly seen in advanced PD preventefficient and rapid switches in concentration betweentwo motor tasks that must be achieved simultaneously(Gracies and Olanow, 2003)

Not surprisingly, studies have shown that it is eficial in PD to avoid performing two tasks simulta-neously In a study comparing PD patients to age-matched healthy controls, subjects performed twowalking trials, one freely and one while carrying a traywith four glasses on it Whereas the gait performancechanged only minimally across conditions in controls,the PD patients showed decreased walking speed andstride length while carrying the tray with glasses(Bond and Morris, 2000) In another study, single setinstructions to increase walking speed, arm swing orstride length (all contributors to efficient walking)resulted in improvement not only of the specific vari-able upon which the patient had focused, but in theother gait variables as well However, when subjectswere instructed to count aloud while walking (anactivity that is not a direct component of the walkingmovement), these gait improvements did not occur(Behrman et al., 1998) In this particular paradigm,the acoustic cue provided by the loud counting – thatcould have been expected to help walking – may havebeen counteracted by the distraction from the walkingmovements caused by the additional cognitive task

ben-A more recent study confirms that dual-task mance worsens gait in PD with an equal impairmentwhether the secondary task is motor or cognitive innature (O’Shea et al., 2002)

perfor-Dual-task performance appears to affect standingbalance as well, particularly in PD patients with a pre-vious history of falls (Morris et al., 2000; Marchese

et al., 2003) In a study comparing PD patients andage-matched controls there were no differences in pos-tural stability between groups when subjects simplystood on a platform, but PD patients showed signifi-cantly greater postural instability compared to controlswhen given additional tasks, either cognitive or motor(Marchese et al., 2003)

Therefore PD patients should be instructed to avoidcarrying out dual tasks and focus on one task at a time.For example, while walking, patients should be encour-aged to avoid carrying objects (the use of backpacksmay be recommended), talking or thinking about othermatters and instead, focus attention towards eachindividual step and on increasing the stride length(Morris et al., 1995) To prevent loss of balance and falls,

PD patients should avoid standing while performing

complex motor or cognitive tasks such as showering,

dressing or conversing (Morris, 2000)

30.3.6 Modification of the home environment

In advanced PD, attention should be paid to the home

environment, with the goal of maintaining

indepen-dence and ensuring safety from falls The ability to

transfer self from bed to chair, chair to toilet and to

stand up is of primary importance in remaining

inde-pendent To assist with difficulties in transferring from

a lying or sitting to a standing position, higher chairs,

toilet seats and beds can be beneficial as they reduce

the energy requirements to raise the center of gravity

In addition, because narrow constricted spaces and

obstacles can induce freezing episodes and place

indi-viduals at risk for tripping and falling, care should be

taken to create clear, wide spaces with a minimum of

low-lying obstacles (such as carpets and stools) in

the home setting Finally, to assist with difficulties

with turning in bed, sheets made of satin in the upper

part (to allow the body to slide) and of cotton in the

lower part (to allow the heels to grip on it and initiate

the turning movement) may be used

30.3.7 Ambulation assistive devices

Although walkers are meant to improve walking

sta-bility and prevent falls in general and particularly in

orthopedic conditions, the impact of chronic walker

use in PD needs to be critically examined The

argu-ments for or against a walker should be weighed on a

case-by-case basis, as the use of walkers may worsen

gait and increase the risk of tripping or falling

(Morris et al., 1995; Kompoliti et al., 2000) A recent

study evaluated the acute effects of standard walkers

and wheeled walkers as compared to unassisted

walk-ing in PD (Cubo et al., 2003) Both wheeled and

stan-dard walkers significantly slowed gait compared to

unassisted walking, and the standard walker also

increased freezing In addition to potentially

exacer-bating posture and balance difficulties, walkers may

also become deleterious in individuals whose steps

have become faster and shorter: when the frame

advances too far in front of the feet, the person may

bend over too far and possibly fall (Morris et al.,

1995)

However, the main issue with walkers may not be

their acute effects on freezing, gait-slowing or the

possibility of forward falls, but the possibility of

long-standing posture and balance impairment caused

by chronic use of these devices By chronically

providing passive forward support, walkers may

decondition the forward-righting reactions required

during inadvertent backward sways (i.e appropriatelytimed rectus femoris and tibialis anterior contractions)and aggravate or even generate a clinical syndrome ofretropulsion This risk has not been measured in a pro-spective study, but anecdotal evidence has been suffi-ciently prevalent in our center and others (Morris

et al., 1995), that leads us to limit the chronic use ofwalkers in PD to a minimum in our clinics

The use of a cane without objectively verifying

a positive effect on gait parameters and without ing specific training to the patient is also questionable.Patients with PD often handle canes improperly, carry-ing them around instead of using them as a support.This is particularly problematic in this condition, asthe use of a cane becomes a form of dual task perfor-mance, involving the simultaneous activities of walkingand carrying an object As described above, performingadditional tasks while walking can result in gait dete-rioration However, it should be recognized that patientsmay sometimes feel more comfortable using a cane forwalking outdoors or in public places, not for the sup-posed increase in stability that the cane may provide,but as a social signal helping to be recognized by others

provid-as someone walking slowly or with a handicap.Whether a cane or a walker is considered, theindication should be determined objectively andaccurately: psychological reassurance, social signal,objective improvement in stability, reduction inenergy consumption during gait Whichever indica-tions are assumed, patients should be tested withand without the assistive device at the clinic to obtain

a rigorous assessment of the acute impact of the device

on freezing episodes, walking speed and stride length.Finally, regardless of the acute effects observed at theclinic, the potential effects of chronic use of thesedevices should also be considered, particularly withthe use of walkers An assistive device must not neces-sarily be used indefinitely One may consider thetemporary use of an assistive device in acute periodssuch as after deep brain stimulation surgery, during aperiod of intensive medication adjustments with risks

of walking instability due to excess levodopa and kinesias, or after an orthopedic injury such as a hipfracture

dys-30.4 Conclusions

Interest in physical therapy for patients with PD hasgrown over recent years It should intensify furtherwith the recent evidence of neuroprotective effects ofphysical exercises in animal models of PD Although

a number of studies have explored specific treatmentoptions, they are complicated by heterogeneous treat-ment methods, different outcome measures and varying

timeframes of analysis (Deane et al., 2002) Many studies

have also been limited by inadequate randomization

methods and lack of convincing sham treatments The

latter two are a particular problem in physical therapy

research, since neither the therapist nor the patient can

be blinded to the arm of the trial (Deane et al., 2002)

In the future, larger, randomized, sham-controlled studies

with staged follow-up will be necessary to determine for

each program the benefits, the duration and the

appropri-ate frequency of training

However, the limitations of the current literature

should not lead neurologists to underestimate the

fun-damental role of daily physical exercise in PD To

optimize motor function, we provide personal

recom-mendations consisting of strict programs of daily

home exercises in the mild to moderate stages of

the disease and the teaching – to the patient and then

to the care-giver – of compensation strategies in the

late stages

Acknowledgments

We are grateful to Jerri Chen and Jonathan Alis for

their excellent work in illustrating some of the

exer-cises recommended in this chapter We also thank

Sheree Loftus Fader, MSN, APRN, BC, CRRN for her

expert comments

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Chapter 31Neuroprotection in Parkinson’s disease: clinical trials

FABRIZIO STOCCHI*

Department of Neurology, IRCCS San Raffaele Pisana, Roma, Italy

31.1 Introduction

Parkinson’s disease (PD) is an age-related

neurodegen-erative disorder characterized clinically by resting

tremor, rigidity, bradykinesia and a gait disorder

Pathologically, there is degeneration of nigrostriatal

neurons in the substantia nigra pars compacta (SNpc)

and the presence of intracytoplasmic inclusions known

as Lewy bodies Biochemically, degeneration of

nigrostriatal neurons is associated with a decline in

striatal dopamine and this finding is the basis for the

symptomatic treatment of the disorder with the

dopa-mine precursor levodopa However, in the majority

of patients, levodopa treatment is complicated by

motor fluctuations, dyskinesia and the development

of features that do not respond to the drug (e.g

freez-ing, dementia, autonomic disturbances and postural

instability) Further, levodopa does not stop disease

progression Consequently, despite the major benefits

associated with levodopa therapy, the majority of

patients with advanced disease suffer unacceptable

levels of functional disability that cannot be controlled

with existing therapies

Because of these limitations, there has been a

con-certed effort aimed at designing a neuroprotective

therapy for PD (Marsden and Olanow, 1998) Such a

treatment can be defined as a treatment or intervention

that slows or stops disease progression by protecting,

rescuing or restoring the nerve cells that degenerate

in PD Toward this end, an understanding of the

etiolo-gic and pathogenetic factors responsible for cell death

is of critical importance Both autosomal-dominant

and -recessive gene mutations have been reported to

cause PD (see Ch 9), but these account for only a

small number of cases There is also evidence that

environmental factors contribute to the etiology of

PD, as suggested by the association of parkinsoniansyndromes with exposure to neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

or hydrocarbons (Langston et al., 1983; Pezzoli et al.,

1996) Further, epidemiological studies indicate thatrural living, well-water consumption and exposure topesticides increase the risk of developing PD, whereasthere is a decreased risk of PD associated with smok-ing and coffee consumption (Koller et al., 1990) None

of these factors, however, explain the large majority ofcases who appear to have a sporadic form of the dis-ease Indeed, twin studies suggest that genetic factorsprobably play a dominant role in young-onset caseswhere environmental factors are likely to be the moreimportant in most older sporadic cases (Tanner et al.,

1999) It is likely that sporadic PD is related to a plex interaction between a variety of genetic andenvironmental factors that may be different in differ-ent individuals This implies that there are many dif-ferent causes of PD and makes it unlikely that asingle neuroprotective treatment aimed at interferingwith a single etiologic factor will be effective in themajority of PD patients

com-Other opportunities for neuroprotection in PDderive from studies on the pathogenesis and mechan-ism of cell death Current information suggests thatneurodegeneration in PD is associated with a cascade

of events including oxidant stress, mitochondrialabnormalities, excitotoxicity and inflammation (Jennerand Olanow, 1998) Based on this evidence, a number

of theoretical neuroprotective strategies can bedesigned What is not clear, however, is whether theseprocesses are primary or secondary, which if any is thedriving force that initiates neurodegeneration and whatrole each plays in the neurodegenerative process thatoccurs in an individual patient In addition, recent

*Correspondence to: Dr Fabrizio Stocchi, Department of Neurology, IRCCS San Raffaele, Via della Pisana 285, 00165 Rome,Italy E-mail: fabrizio.stocchi@fastwebnet.it, Tel: þ 39-33-690-9255, Fax: þ 39-06-678-9158

Parkinson’s disease and related disorders, Part II

W C Koller, E Melamed, Editors

# 2007 Elsevier B V All rights reserved

studies suggest that protein aggregation due to failure

of the ubiquitin-proteasome system to clear unwanted

proteins may be a common theme in PD

neurodegen-eration, but how to prevent or deal with this problem

is presently not known (McNaught et al., 2001; see

Ch 28) Further, considerable evidence supports the

notion that cell death in PD, regardless of etiology,

occurs by way of signal-mediated apoptosis (Hirsch

et al., 1999) The importance of defining a common

factor that contributes to neurodegeneration in PD is

that it provides an opportunity to develop a single

roprotective therapy that might interfere with the

neu-rodegenerative process that ensues as a result of many

different etiologies and therefore may be of value to a

large population of PD patients This chapter addresses

a clinical relevant question regarding the management

of PD: are there any therapies that can slow down the

progression of PD?

31.2 Trials with antioxidants and monoamine

oxidase-B inhibitors

Considerable evidence supports the notion that

oxida-tive stress plays a role in the pathogenesis of cell death

in PD (see Ch 24) Postmortem studies in the

substan-tia nigra of PD patients demonstrate increased levels

of iron (which promotes oxidative stress) and

decreased levels of glutathione (the major brain

anti-oxidant) (Jenner and Olanow, 1998) Further, there is

evidence of oxidative damage to carbohydrates, lipids,

proteins and DNA in the SNpc of PD patients

Addi-tionally, the oxidative metabolism of levodopa and/or

dopamine can generate reactive oxygen species that

can induce or aggravate underlying oxidative stress

These considerations formed the basis for initiating

clinical trials aimed at obtaining a neuroprotective

effect in PD with antioxidant agents The initial drugs

chosen for study were a-tocopherol (vitamin E) and

deprenyl (selegiline, eldepryl) a-Tocopherol was

selected because it is the most potent lipid-soluble

anti-oxidant in plasma and plasma levels can be increased

by dietary augmentation (Ingold et al., 1987) Deprenyl

was selected because in doses of 10 mg/day it is a

rela-tively selective inhibitor of monoamine oxidase type B

(MAO-B) that avoids the risk of a sympathomimetic

cri-sis (the ‘cheese effect’) associated with non-selective

MAO inhibition (Elsworth et al., 1978) Interest in

depre-nyl as a possible neuroprotective agent in PD was

fos-tered by the observation that MPTP can induce

parkinsonism in humans (Langston, 1983) and that

MPTP-induced parkinsonism in monkeys can be

pre-vented by deprenyl (Cohen et al., 1985) In this model,

deprenyl inhibits the MAO-B oxidation of MPTP to the

pyridinium ion 1-methyl-4-phenylpyridinium ion

(MPPþ) which is responsible for MPTP toxicity (Chiba

et al., 1984) It was reasoned that if PD were related to

an MPTP-like protoxin, MAO-B inhibition with deprenylmight similarly prevent the oxidation of other toxins thatcontribute to neuronal degeneration In addition, it wasalso postulated that deprenyl could block the MAO-B-dependent oxidative metabolism of dopamine andthereby limit free radical damage to SNpc neurons(Cohen and Spina, 1989)

A prospective, randomized, double-blind, cebo-controlled study involving 800 patients known

pla-as the DATATOP study (Deprenyl And TocopherolAntioxidant Therapy Of PD) was performed toevaluate deprenyl 10 mg/day and tocopherol 2000

IU (Parkinson Study Group, 1989a, b, 1993).Untreated PD patients were randomly assigned in a

2
2 factorial design to treatment with deprenyl(10 mg/day), tocopherol (2000 IU), the combination

of both, or placebo Patients were followed with noother treatment until they deteriorated to a point thatblinded investigators felt that symptomatic therapy

in the form of levodopa needed to be introduced(the primary endpoint) In this study, no effect onthe primary endpoint was detected witha-tocopheroltreatment In contrast, treatment with selegiline sig-nificantly delayed the emergence of disability neces-sitating treatment with levodopa (P < 0.0001).After 12 months, levodopa treatment was required

in 26% of selegiline recipients compared with 47%

of those who received placebo Onset of disabilitynecessitating levodopa therapy occurred after amean of 26 months in the 375 selegiline recipientscompared to 15 months in 377 placebo recipients(with or without tocopherol) Similar results wereobserved with selegiline in a smaller study involving

54 patients that served as a pilot for the DATATOPstudy (Tetrud and Langston, 1989) Although theseresults were impressive and suggested that deprenylmight have a neuroprotective effect, a careful post-hoc analysis demonstrated that selegiline was asso-ciated with both wash-in and wash-out effects indi-cative of a symptomatic effect in addition to anyputative neuroprotective effect Thus, although therewas no doubt that selegiline delayed the emergence

of disability in otherwise untreated PD patients, itwas unclear as to the responsible mechanism(Olanow and Calne, 1991) Namely, was the delay

in requiring levodopa in selegiline-treated patientsdue to the drug having a neuroprotective effect onremaining dopamine neurons or was it due to thesymptomatic effect of the drug masking ongoingneurodegeneration?

This confound remains unresolved, although sequent clinical trials provide some support for the

possibility that the drug may have neuroprotective

effects in addition to its established symptomatic

effects The SELEDO (selegiline-levodopa) study

evaluated 120 early-stage PD patients who received

treatment with either levodopa monotherapy or

levo-dopa plus selegiline (Przuntek et al., 1999) The

pri-mary endpoint was the need for a50% increase in

baseline levodopa dosage Selegiline-treated patients

were less likely to require this additional increase in

levodopa, suggesting the possibility that the disease

was progressing at a slower rate Further, the

levo-dopa plus selegiline group had a lower incidence of

motor fluctuations despite comparable clinical

con-trol, again suggesting that selegiline influences the

natural course of levodopa-treated PD

The SINDEPAR (Sinemet-Deprenyl-Parlodel) was

a prospective double-blind study that attempted to

define the putative neuroprotective effects of selegiline

in a trial that controlled for the drug’s symptomatic

effects (Olanow et al., 1995) Patients with untreated

PD (n ¼ 100) were randomized to receive treatment

with selegiline versus placebo in addition to treatment

with either Sinemet or bromocriptine Thus, patients

were randomized to one of four treatment groups;

Sinemet plus selegiline, Sinemet plus placebo,

bromo-criptine plus selegiline, or bromobromo-criptine plus placebo

The primary endpoint of the study was the change in

Unified Parkinson’s Disease Rating Scale (UPDRS)

motor score between original untreated baseline

and final visit performed 2 months after washout of

selegiline and 7 days after washout of either the

bromocriptine or the Sinemet This study showed that

deterioration in UPDRS score over the course of the

study was significantly less in patients randomized to

receive selegiline than in those receiving placebo

regardless of whether they received symptomatic

treatment with levodopa/carbidopa (Sinemet) or

bromocriptine (P< 0.0001) To insure adequate drug

washout, a subgroup of 23 patients underwent a

14-day washout of their Sinemet or bromocriptine

Even with this small sample size, deprenyl-treated

patients had significantly less deterioration from

origi-nal baseline than did placebo controls The authors

interpreted these findings as being consistent with the

hypothesis that selegiline has a neuroprotective effect

that could not be accounted for by the symptomatic

effect of the drug in view of the fact that patients were

washed out of selegiline for a relatively long period of

time while receiving powerful symptomatic agents in

addition to the study drugs However, even in this

circumstance some doubt remains as it is not possible

to state with any certainty that washout was sufficient

to rid patients of a long-duration symptomatic effect

associated with either selegiline or the symptomatic

agents employed Indeed, Hauser et al (2000)suggestthat even 2 weeks of withdrawal from levodopa orbromocriptine may not be sufficient to eliminate thesymptomatic effects associated with their use

Although the debate continues as to whether or notthe drug has protective effects, it is clear that selegilinetreatment does not stop disease progression (Elizan

et al., 1989) and several reports suggest that aftermany years of treatment patients receiving deprenylare no less impaired than patients who have notreceived the drug (Parkinson Disease Research Group

in the United Kingdom, 1993; Brannan and Yahr,1995; Parkinson Study Group, 1996a, b) A long-termfollow-up of the DATATOP patients similarly noted nomajor difference between those originally on selegiline

or placebo, but it is perhaps noteworthy that line-treated patients had a reduced frequency of freez-ing and ‘off’ episodes which are thought to be related

selegi-to degeneration of non-dopaminergic systems (Shoulson

et al., 2002) The problem has been further confused bythe report of an open-label long-term study suggestingthat selegiline increases the risk of early death in levo-dopa-treated PD patients (Lees et al., 1995) Therewere, however, statistical concerns about how this studywas performed and analyzed (Olanow et al., 1996a) andsimilar findings were not observed in an assessment ofmortality in the DATATOP cohort (Parkinson StudyGroup, 1998) or in a large meta-analysis that includedall prospective long-term double-blind controlled trialscomparing selegiline to placebo (Olanow et al., 1998b).Based on the results of the DATATOP study, trials

of other MAO-B inhibitors were initiated as putativeneuroprotective agents Lazabemide is a relativelyshort-acting, reversible and selective MAO-B inhibitorthat is not metabolized to amphetamines or activecompounds (Cesura et al., 1989) The ability of lazabe-mide to influence the progression of disability inuntreated PD was assessed in a randomized, multicen-ter, placebo-controlled, double-blind clinical trial (Par-kinson Study Group, 1996c) A group of 321 untreated

PD patients were assigned to one of five treatmentgroups (placebo or lazabemide at a dose of 25, 50,

100 or 200 mg/day) and followed for up to 1 year.The risk of reaching the primary endpoint (the onset

of disability sufficient to require levodopa therapy)was reduced by 51% for the patients who receivedlazabemide compared with placebo-treated subjects(P<0.001) This effect was consistent among alldosages and the magnitude and pattern of benefits seenwith lazabemide were similar to those observed withselegiline treatment in the DATATOP clinical trial.However, as with selegiline, lazabemide also hassymptomatic effects and there were similar concerns

as to whether or not benefits seen with this drug

8 terminated

5 terminated

6 mo

Double-blind, placebo-controlled

Double-blind, rasagiline early vs delayed

Ongoing extension

Up to 6.5 y from TEMPO start

Open-label Rasagiline 1 mg/d

N = 306/360 completers elected to continue

Fig 31.1 TEMPO trial study design

were due to neuroprotective or symptomatic effects

(Le Witt et al., 1993) This uncertainty caused the

sponsor to discontinue further trials in PD with this

agent (Youdim and Weinstock, 2001)

31.2.1 Rasagiline

Rasagiline is an irreversible and selective MAO-B

inhibitor which does not generate amphetamine

meta-bolites The drug proved to be effective in the

sympto-matic treatment of early and advanced parkinsonian

patients However, there are some indications that the

drug may have disease modification effects A total of

380 patients from the TEMPO trial (Tvp-1012

(rasagi-line) in early monotherapy for Parkinson’s disease

out-patients – a randomized, double-blind study versus

placebo including 404 patients with early PD

placebo-controlled phase) entered a 6-month phase of active

treatment, where patients previously receiving placebo

were switched to rasagiline 2 mg/day (Fig 31.1) The

aim of this phase of the study was a comparison between

those patients who received 12 months’ treatment with

rasagiline and those patients, previously on placebo,

who had a delayed start and received only 6 months’

treatment with rasagiline This delayed-start technique

is one of several study designs that have been employed

to evaluate the disease-modifying potential of

antipar-kinsonian agents The theory behind this particular

design is that by the end of the full 12 months of study,

the symptomatic effects of treatment will be balanced in

all groups, leaving any observed differences attributed

to disease-modifying effects

Results showed that patients receiving 2 mg/day

rasagiline for a 12-month period had a significant

benefit over patients who had their treatment delayed

by 6 months, as measured by UPDRS-Total score(–2.29 unit difference, P ¼ 0.01) and UPDRS-ADL(activities of daily living) score (–0.96 unit difference,

P< 0.01) Once again, this was supported by a ior responder rate in the 12-month treatment group(P< 0.05) Comparisons of other subscales (UPDRS-Motor and -Mental) were not significant Patientswho received 1 mg/day rasagiline for 12 months alsoshowed significant benefits over the 2 mg/day delayed-treatment group in UPDRS-Total score (–1.82 unitdifference;P¼ 0.05)

super-One potential disadvantage of this method of suring disease modification is that symptomatic effectsmay be enhanced if treatment is started earlier in the dis-ease course However, taken as a preliminary indication,this delayed-start study provides promising indications

mea-of disease modification that certainly warrant furtherinvestigation To this end, a new controlled study ofrasagiline, with disease modification as a primaryendpoint, is ongoing ADAGIO-study (Attenuation ofdisease progression with azilect given once-daily).31.2.2 Antiexcitotoxic agents

There is substantial evidence suggesting that excess tamatergic stimulation with consequent excitotoxicitycontributes to the neurodegenerative process in PD, rais-ing the possibility that antiexcitotoxic drugs might beneuroprotective (Lipton and Rosenberg, 1994).Physiologic and metabolic studies demonstrate thatneuronal activity in the subthalamic nucleus (STN)

glu-is increased in parkinsonian animals and humans(Obeso et al., 2000) As the STN uses the excitatory

neurotransmitter glutamate as a neurotransmitter and

projects to the internal segment of globus pallidus, the

pedunculopontine nucleus and the SNpc, it is reasonable

to consider that these targets might be subject

to excitotoxic damage (Rodriguez et al., 1998)

N-methyl-D-aspartate (NMDA) receptor antagonists have

been reported to protect dopamine neurons from

gluta-mate-mediated toxicity in tissue culture and in rodent

and primate models of PD (Turski et al., 1991;

Greena-myre et al., 1994; Doble, 1999) Further, there is a

retro-spective report suggesting that early use of the NMDA

receptor antagonist amantadine might slow the rate of

PD progression (Uitti et al., 1996) A double-blind

pla-cebo-controlled dosing study was performed testing the

safety and tolerability of remacemide hydrochloride, a

low-affinity NMDA channel blocker (Parkinson Study

Group, 2000a) Total daily doses of 150, 300 and 600

mg were not as well tolerated as placebo, but were not

associated with serious side-effects and, importantly,

symptomatic effects were not detected, although only

small numbers of patients were studied However, the

drug failed to provide evidence of a neuroprotective

benefit in patients with Huntington’s disease even when

combined with coenzyme Q10and formal tests of

neuro-protection in PD have not been carried out (Huntington’s

Disease Study Group, 2000)

Riluzole is another antiglutamate agent that acts

by inhibiting sodium channels and thereby prevents

the release of glutamate in overactive glutamatergic

neurons The drug is approved for use in the

treat-ment of amyotrophic lateral sclerosis (Bensimon

et al., 1994; Lacomblez et al., 1996) and preclinical

studies have demonstrated the capacity of riluzole to

protect dopamine neurons in rodent and primate

mod-els of PD (Araki et al., 2001; Obinu et al., 2002) A

small open-label pilot study in PD patients

demon-strated that riluzole is well tolerated at doses of 100

mg/day and does not provide symptomatic benefits

(Jankovic and Hunter, 2002) Morover, despite the

short duration of the trial and the small sample size

(20 patients), there was a trend toward benefit for

patients in the riluzole group with riluzole patients

remaining unchanged over the course of the study

whereas those randomized to placebo seemed to

deteriorate A randomized, double-blind,

placebo-controlled trial evaluated riluzole 50 mg b.i.d

com-pared to placebo with a primary outcome of change

in UPDRS No significant difference was found

(Jankovic and Hunter, 2002)

31.2.3 Bioenergetics

A body of information suggests that mitochondrial

dysfunction plays a role in the pathogenesis of PD

(see Ch 22) Decreased levels of complex I activityand reduced staining are observed in the substantianigra of PD patients and the selective complex I inhi-bitor MPTP induces a levodopa-responsive PD syn-drome in both animal models and human patients.More recently chronic administration of rotenone, awidely available pesticide which selectively inhibitscomplex I, has been shown to be capable of inducing

a parkinsonian syndrome with selective degeneration

of nigral dopaminergic neurons, a reduction in striataldopamine and intracellular inclusions resemblingLewy bodies (Betarbet et al., 2000) The precisemechanism whereby inhibition of complex I activityleads to a parkinsonian syndrome is not known andreduced adenosine triphosphate formation, free radicalgeneration and reduction in mitochondrial membranepotential have all been implicated These findings do,however, raise the possibility that bioenergetic agentssuch as creatine, coenzyme Q10, ginkgo biloba, nicoti-namide, riboflavin, acetyl-carnitine or lipoic acidmight be neuroprotective in PD Indeed, creatine andcoenzyme Q have been shown to protect dopamineneurons in MPTP-treated rodents (Beal et al., 1998;Matthews et al., 1999)

The Parkinson Study Group recently completed aphase II clinical study of coenzyme Q10 in de novo

PD patients The study was double-blind and thepatients were randomized to treatment with placebo,

300, 600 or 1200 mg of coenzyme Q10for 16 months

or until disability required levodopa The primary come measure was the change from baseline in theUPDRS In addition, levels of complex I activity

out-of the mitochondrial electron transport chain andcoenzyme Q10levels were obtained The study demon-strated a dose-dependent reduction in disease progres-sion as assessed by the UPDRS which correlated withincreases in plasma coenzyme Q10 levels Althoughthe results were not statistically significant, a positivetrend was observed The study was designed to deter-mine safety and tolerability and only a relatively smallnumber of patients were included; therefore a largerphase III study is required Nonetheless, this studysupports the notion that bioenergetic agents such ascoenzyme Q10might offer promise as neuroprotectiveagents for PD and studies of other such agents arelikely to be performed in the near future

31.2.4 Antiapoptotic agentsAlthough the issue of neuroprotection with deprenyland other MAO-B inhibitors remains unresolved at theclinical level, in the laboratory the situation has becomemuch clearer An increasing body of evidence has nowaccumulated supporting the capacity of deprenyl to

provide neuroprotection for dopaminergic and other

motoneurons in a variety of in vitro and in vivo studies

(Mytilineou and Cohen, 1985; Tatton and Greenwood,

1991; Ansari et al., 1993; Roy and Bedard, 1993; Wu

et al., 1993, and reviewed in Olanow et al., 1998c)

Further, it has now become clear that MAO-B

inhibi-tion is not a prerequisite for these benefits (Mytilineou

and Cohen, 1985; Mytilineou et al., 1997a) Indeed,

there is evidence indicating that the neuroprotective

effect s seen with deprenyl are du e to its metabo lite,

desmet hyl depren yl (Myt ilineou et al., 1997b, 1 998 )

These benefits are attribut ed to the propa rgyl

com-ponent of the depre nyl molecu le and indeed some

othe r drugs that are propa rgylam ines show a similar

effect on glycera ldehyde- 3-phosphat e dehydr ogenase

(GAPD H) and simi lar neuro protectiv e effects

( Boulton, 1999; Waldm eir et al., 2000; Youd im and

Weinst ock, 2001 ) Data now indicat e that neuro

protec-tion assoc iated with deprenyl is due to an antiapo ptotic

effect rel ated to drug-ind uced transcrip tional events

with the synt hesis of new proteins (Tatt on et al., 1994,

2002 ) Sp ecifically , depre nyl has been show n to induc e

alter ed expre ssion of a numb er of genes involved in

apopt osis, includi ng SOD1 and SOD2 , glutat hione

perox idase , c-JUN , GAP DH, BCL-2 and BAX Th ese

finding s sugges t that the antiapo ptotic prope rties o f

depre nyl rel ate to their potential to p rotect the

mito-chondr ial membr ane po tential and to exer t antioxi dant

effect s More recent fin dings indicate that GAPD H

may be central to these effects GAP DH is an intermed

i-ate in glycogen metabo lism and plays an important rol e

in protein translation and synt hesis Howeve r, under

certain adver se conditions, GAPD H in its tetra meric

form transl ocates to the nucl eus whe re it interf eres with

BCL- 2 upreg ulation and prom otes apopt osis Desmethy l

depre nyl b inds to GAPD H and maintai ns it as a dimm er,

in whi ch form it does not translocate to the n ucleus and

allow s the norm al antiapo ptotic neuro protectiv e

pro-grams to b e initiat ed (Carl ile et al., 2000 ) Other propa

r-gyla mines can also provide neuroprot ective effects in

mode l system s of parkinso nism (Tatton et al., 2000;

Waldm eir et al., 2000; Youd im and Wei nstock, 2001 )

Two curr ently under going testing for putative

neuro-protect ive effects in PD are rasagili ne (see above) and

CGP3466 or TCH346 TCH346 is a more potent neuro

-protectant than deprenyl in laboratory models and does

not inhibit MAO-B, which may eliminate a

sympto-matic confound and make detection of a neuroprotective

effect easier to detect In MPTP monkeys, TCH346

pre-vented neuronal degeneration and led to functional

improvement (Waldmeir et al., 2000) Prospective

dou-ble-blind trials comparing TCH346 with placebo were

stopped after an interim analysis for lack of efficacy

(Olan ow, 2006)

There are several different signaling pathways thatcan lead to apoptosis depending on the model andtoxin that are tested, providing different opportunitiesfor introducing antiapoptotic strategies (Reed, 2002),but none has yet been adequately tested in clinicaltrials or established to be neuroprotective in PD.31.3 Restorative therapies

Whereas most studies have focused on attempts toalter the natural course of PD through manipulation

of factors thought to be involved in the pathogenesis

of cell death, other approaches have attempted torestore dopaminergic neuronal function This has beenattempted with transplantation strategies designed toprovide new cells to replace those that have under-gone neurodegeneration or trophic factors that mightrestore or enhance function in remaining dopamineneurons

Transplanted fetal nigral cells implanted into thedenervated striatum have been demonstrated to sur-vive, manufacture dopamine and provide behavioraleffects in rodent and primate models of PD (reviewed

by Olanow et al., 1996b) Open-label studies inadvanced PD patients have reported clinical benefits,increased fluorodopa uptake on positron emissiontomography (PET) and robust survival of implanteddopamine neurons with organotypic reinnervation ofthe stria tum (revie wed by Olanow et al., 1996b) How-ever, these benefits have not yet been reproduced indouble-blind, placebo-controlled trials Freed et al.(2001)randomized 40 advanced PD patients to receivetransplantation with embryonic ventromesencephaliccells or sham surgery The study failed to meet itsprimary endpoint (a quality-of-life measure) Improve-ment was observed in UPDRS motor scores, particu-larly in patients younger than 60 years, but benefitswere not of the magnitude reported in open-labelstudies Further, some of the patients developed severeoff-medication dyskinesia which persisted for daysafter withdrawal of levodopa A similar type of dyski-nesia has now been reported by the Swedish group(Hagell et al., 2002) The mechani sm resp onsible forthis unanticipated side-effect is not known, but it isnoteworthy that this type of dyskinesia has not beendetected in patients with advanced PD who have notundergone transplantation (Cubo et al., 2001) Thisstudy illustrates the importance of placebo-controlledtrials (Freeman et al., 1999) and the need to addressclinically relevant issues in the laboratory beforebeginning trials in PD patients in order to minimizethe risk of running into unanticipated side-effects Inthis regard it should be noted that transplantation hasnot yet been tested in levodopa-treated parkinsonian

monkeys to see if they have been primed to develop

off-medication dyskinesia A second double-blind

pla-cebo-controlled trial of fetal nigral transplantation has

just been completed in which different concentrations

of donor tissue were tested, immunosuppression was

employed and patients were followed for 2 years

(Freeman et al., 1999), but final results are not yet

published

The use of human embryonic neural tissue creates

logistical and societal problems such as acquiring

enough tissue for grafting in a predictable and

large-scale manner and ethical problems inherent in the use

of aborted human fetal tissue For these reason

alterna-tive sources of fetal dopaminergic neurons have been

sought One such approach involves the use of porcine

fetal nigral cells Implanted porcine fetal nigral cells

have been shown to survive and to provide some

beha-vioral effects However, open-label trials showed no

benefit for patients with Huntington’s disease and only

minimal benefit in PD patients with no increase in

striatal fluorodopa uptake on PET and only minimal

survival at postmortem (Deacon et al., 1997; Fink

et al., 2000; Schumacher et al., 2000) A

double-blind, placebo-controlled study has been performed

in patients with advanced PD and demonstrated no

benefit in comparison to patients receiving a placebo

procedure (unpublished information) In this study

the magnitude of the placebo effect was extensive

and sustained, emphasizing again the importance of

placebo-controlled trials in evaluating new

interven-tions (Freeman et al., 1999) A small open-label trial

reported some clinical benefits following

transplanta-tion of retinal pigmented epithelial cells (Watts,

2002) and a prospective double-blind

placebo-con-trolled trial has been initiated

Although these studies are not encouraging, it is

possible that better results can be obtained with

differ-ent transplant variables such as increased numbers of

cells, continued use of immunosuppression, combined

use of antiapoptotic factors and different transplant

tar-gets (Barker, 2002) It is also possible that better

results can be obtained with stem cells (see Ch 44)

Stem cells are capable of self-renewal and expand

after implantation Neural stem cells are found in the

developing brain (embryonic neural stem cells), but

also in certain sites within the adult brain (Armstrong

and Svendsen, 2000; Gage, 2000) Embryonic neural

stem cells can be isolated and grown in culture and

made to differentiate into all of the major cell types

of the central nervous system, including dopaminergic

neurons (Kawasaki et al., 2002) Indeed, initial studies

demonstrate that embryonic stem cells can

sponta-neously differentiate into neurons, with a small

percen-tage being dopaminergic neurons Further, following

transplantation, they can survive and induce behavioraleffects in the dopamine-lesioned rodents (Bjorklund

et al., 2002) However, these experiments are not withouttheir own problems and, in one study, 5 of 19 transplantedanimals developed tumors (Kim et al., 2002) Stem cellshave not yet been implanted into PD patients and,although they offer considerable promise, many clinicalissues remain to be resolved at the preclinical level beforeclinical trials in PD patients can be considered

A second restorative approach involves the use oftrophic factors Numerous studies have demonstratedthe capacity of a variety of trophic factors to protectdopamine neurons in tissue culture and to restorenigrostriatal function in dopamine-lesioned animals(Collier and Sortwell, 1999) Among these, glial-derived neurotrophic factor (GDNF) appears to bethe most effective in laboratory models (see Ch 45).GDNF treatment has been shown to protect cultureddopamine neurons from a variety of toxins (Lin

et al., 1993) and to restore function to the nigrostriatalsystem of the MPTP-lesioned monkey even whentreatment is delayed for up to several weeks (reviewed

byHebert et al., 1999) One of the major limitations oftrophic factors relates to delivery of the protein to thetarget site An open-label trial of intraventricularGDNF did not provide meaningful benefit to advanced

PD patients, probably because the protein was not able

to gain entry from the cerebrospinal fluid into the brain(Kordower et al., 1999) Side-effects of GDNF deliv-ered in this way were troublesome and included consi-titutional complaints, pain and Lhermitte’s sign,probably reflecting meningeal irritation Anotheropen-label study was subsequently performed inadvanced PD patients in which GDNF was directlyinjected into the striatum (Bark er, 2006) Theseresearchers claimed to observe antiparkinsonian bene-fits and direct infusion of GDNF was better toleratedthan with the intraventricular approach, although 4 of

5 patients still experienced Lhermitte’s sign A spective double-blind placebo-controlled trial testingcontinuous infusion of GDNF into the striatum ofparkinsonian patients, recently conducted, failed todemonstrat e efficacy vers us placebo (Lang, 2006) Analternate approach utilizes gene therapy to deliverGDNF Using a modified lentivirus vector to deliverGDNF to the striatum and nigra of MPTP-lesioned mon-keys, dramatic histologic and behavioral improvementwas observed (Kordower et al., 2000) Further, the pro-tein was well tolerated Long-term safety studies in non-human primates are currently underway and a clinicaltrial of lentivirus GDNF in PD patients is ongoing.Numerous other preclinical studies have been per-formed testing different vectors (e.g adeno-associatedvirus), different proteins (e.g AADC or GAD) and

different targets (e.g SNpc or STN) and it is anticipated

that favorable behavioral results and safety profiles will

lead to clinical trials in PD in the not too distant future

Based on the unanticipated off-medication dyskinesia

observed in some patients following transplantation, it

remains necessary to demonstrate that GDNF does not

induce dyskinesias and debate continues with regard to

whether or not to use a regulatable gene therapy system

Nevertheless, based on laboratory studies available to

date and the preliminary results with direct infusion in

PD patients, GDNF therapy appears to be very promising

for PD patients

Immunophilins are partial ligands for the

ciclos-porin-binding site that, independent of their

immuno-suppressant properties, provide trophic-like effects

for dopamine neurons in tissue culture and animal

models (Steiner et al., 1997) Two immunophilin

agents have been tested in PD patients, but the results

have been disappointing and no evidence of a

neuro-protective or restorative effect has been observed

(Gold and Nutt, 2002)

31.4 Dopamine agonists

There has been considerable interest for more than a

decade in the potential of dopamine agonists to provide

neuroprotective effects and to alter the natural course

of the levodopa-treated PD patient (Olanow, 1992;

Stocc hi, 2000) In the laboratory , dopam ine agoni sts

have been shown to protect dopamine neurons from a

variety of toxins in both in vitro and in vivo models

(Olan ow et al., 1998; see Ch 22) Var ious theo ries have

emerged to account for these effects, including

levo-dopa-sparing, stimulation of dopamine autoreceptors,

direct free radical scavenging, inhibition of

STN-mediated excitotoxicity and activation of dopamine

receptors with signal-mediated antiapoptotic effects

Two prospective randomized clinical trials have

recently been performed in early PD patients to test

the putative neuroprotective effects of dopamine

ago-nists In one study (the Comparison of the agonist

pra-mipexole with levodopa on motor complications of

Parkinson’s disease, CALM-PD, study), patients with

untreated PD were randomized to initiate therapy with

either the dopamine agonist pramipexole or levodopa

(Marek et al., 2002) In the second (the Requip as an

early therapy versus levodopa PET, REAL-PET, study),

patients were randomized to initiate therapy with the

agonist ropinirole or levodopa (Whone et al., 2002)

Open-label levodopa could be added to the blinded

ther-apy if deemed necessary for patients in both studies In an

attempt to circumvent the problems of detecting a

neuro-protective effect with symptomatic agents, both trials

uti-lized a neuroimaging surrogate marker of nigrostriatal

function as a primary endpoint The REAL-PET studyused striatal fluorodopa uptake on PET whereas theCALM-PD study used striatal beta-carbomethoxy-3beta-(4-iodophenyl)tropane (b-CIT) uptake on single-photon emission computed tomography (SPECT) Theresults of two trials have recently been released

In the CALM PD-SPECT study, an estimate of therate of dopamine neuronal degeneration was assessed

by measuring the rate of decline in b-CIT, a marker

of the dopamine transporter This study was performed

in a subsection of patients participating in the

CALM-PD trial (Olanow et al., 1998) A total of 82 patientswith early PD requiring dopaminergic therapy to treatemerging disability were enrolled in the study Patientswere randomly assigned to receive pramipexole in adose of 0.5 mg t.i.d (n¼ 42), or carbidopa/levodopa25/100 mg t.i.d (n¼ 40) The primary outcome vari-able was the percentage change from baseline in stria-tal b-CIT uptake after 46 months The mean ( SD)percentage loss in striatalb-CIT uptake between base-line and 46 months was significantly reduced in thepramipexole group compared with the levodopa group(16.0 13.3% versus 25.5  14.1%; P < 0.05) Theauthors concluded that patients initially treated withpramipexole demonstrated a reduced rate of PD pro-gression, as determined by rate of decline in striatalb-CIT uptake if treatment was initiated with the dopa-mine agonist As there was no placebo control group, nocomment could be made as to whether the agonist groupdeteriorated at a slower rate or the levodopa group at afaster rate Interestingly, there was no clinical correlate

of this finding, with patients randomized to initial ment with levodopa doing as well as or better than ago-nist-treated patients on the UPDRS scale

treat-The REAL-PET study was designed to compare therate of PD progression using striatal fluorodopa uptake

on PET as a marker of nigrostriatal function A total

of 186 patients with early untreated PD were mized in a 1:1 ratio to initiate treatment with eitherthe dopamine agonist ropinirole or levodopa The pri-mary outcome variable was the percentage reduction

rando-in putamenal 18F-dopa influx constant (Ki) over the2-year study in patients with both clinical and PET evi-dence of PD Data were collected from six PET centersand centrally transformed at the Hammersmith Hospital(London, UK) so as to standardize brain position andshape and the placement of the regions of interest(ROIs) for calculation of putamen Ki Parametricimages were also interrogated with statistical para-metric mapping (SPM) to localize regions of significantwithin-group and between-group differences in rates ofloss of dopaminergic function Secondary endpointsincluded the incidence of dyskinesias and clinical effi-cacy evaluations The central ROI analysis of putamen

Ki showed that, over the course of the 2-yea r study,

there was a sign ificantly slower rate of deteri oration in

the ropinirol e group as compared to the levodopa group

(–13% versus –20 %; P < 0.05) Using the SPM anal

y-tic tec hnique, a significa ntly slower rate of progress ion

for agonist -treated patient s was detected in both

puta-men and nigra ( P < 0.05 for both) The authors

con-clud ed that the progress ion of PD, as reflecte d by loss

of puta menal 18F-dopa uptake, was slower in PD

patients when treatment was initiat ed with the

dopa-mine agoni st ropinirol e as compare d to levod opa

Inter-estingly, this study also found no clinical correlate for

the imagi ng finding , with UPD RS scor es bein g

compar-able or superior in the levodo pa group

Both studies clearly demonstrate a reduced rate of loss

of nigrostriatal function, as determined by imaging

surro-gate markers in patients treated with dopamine agonists

compared to levodopa As previously (Parkinson Study

Group, 2000b;Rascol et al., 2000), patients initiated on

agonists also had a significantly reduced risk of

develop-ing motor complications than did those started on

levo-dopa Interestingly, neither study demonstrated a

clinical correlate to go along with the improvement

detected in the imaging studies In both studies clinical

efficacy, as measured by the UPDRS rating scale, favored

patients in the levodopa group This, too, is similar to

what was described in other trials comparing initial

ther-a py w it h d op ther-am in e ther-a go ni s ts v er su s l ev od op ther-a ( Pa rk i n so n

Study Group, 2000b;Rascol et al., 2000) Although the

clinical significance of this difference can be debated,

as patients in the agonist groups could receive levodopa

supplement whenever either the patient or physician

deemed it was necessary, it is evident that there is no clear

clinical indication of slower disease progression in the

agonist groups

These represe nt the first stud ies in PD to demo

n-strat e positive results uti lizing im aging tec hniques to

seek evidence of neuro protectio n There remain

sev-eral issues Firs tly, if benefit s seen on imaging reflec t

a change in the rate of disease progress ion, is this a

functi on of a neuro protectiv e effect of the agoni st or

acce lerated d isease progress ion due to levodopa?

Furt her stud ies with a plac ebo control will be required

to address this issue Secondly , are there pharmac

olo-gic effect s that interf ere with the comparison of

levo-dopa versus a levo-dopamin e agoni st that give the false

impre ssion that agoni sts have a slower rate of reduc

-tion in imagi ng marker s of nigrost riatal functi on than

does levo dopa? Here too, further stud ies shoul d clari fy

this issue Prelimi nary stud ies have not show n a speci

-fic levodopa or dop amine agonist effect on flu orodopa

upta ke on PET or ß-CIT uptake on SPECT Finall y, if

the imaging studies do reflec t a neurop rotective effect

of agoni sts, why is there no clinical correl ate? Is the

benefit so slight at this early time point that it ismasked by the sym ptomatic effects of the drugs and

is longer follow-u p require d?

Th ese results are mos t exciting and, independe nt ofwhether or not dopam ine agonist s prove to be neuro -protectiv e in the long run, neuroimagi ng offers thepotential of establ ishing a surr ogate mar ker of nigros-triatal function that will enable the asse ssment of themany putativ e neuro protectiv e drugs that are currently

or will event ually b ecome available Toward this end,

it is im portant to perf orm careful studies to est ablishthat thes e imagi ng surr ogates do in fact repr esent accu-rate marker s of the numb er of dopamin e terminal s and/

or neurons and to dete rmine the inf luence on thes emarkers of time, drug therapy and dise ase progr ession

A delayed sta rt desi gn trial with prami pexole in early

PD patient s is ongoi ng

31.5 Levodopa

A double-bli nd cont rolled randomized trial levo dopa(150, 300, 600 mg/day) versus plac ebo including 361patients was recently conduc ted Th e pri mary outcomewas masked assignm ent of change in UPDR S frombaseline after 40 weeks of treatme nt and a 2-w eek wash-out In additi on SPECT ß-CIT was perf ormed at base-line and week 40 in a subgr oup of 116 p atients.Patients randomized to all levo dopa doses had signifi-cantly better UPDR S scor es than patients on plac ebo,with the g reatest improv ement seen on the highe st dose,showing a clear dose–resp onse rel ationship Af ter thewashout period none o f the three tre ated groups matche dthe disease sever ity scored in the placebo group Thesedata sugges ted that patient s on levodopa had a sustai nedfunctional improvement and this was more evident inthe higher-dose group However, it is possible that thewashout period was not sufficient to exclude a persistentsymptomatic effect (long-duration response) Patients

on the highest dose of levodopa developed more nesias and motor complications This may be due tothe dose of levodopa but also to the way levodopa wasadministered (t.i.d.) There was no significant difference

dyski-in ß-CIT uptake across the groups However a greaterreduction in ß-CIT uptake was observed in patientstaking the higher levodopa dose

31.6 Conclusion

In establishing that an intervention has a neuroprotectiveeffect, it is necessary to choose outcome measures of dis-ease progression that are satisfactory to both cliniciansand regulatory authorities To date, no drug has beenestablished to be neuroprotective in PD (Morrish, 2002)and regulatory agencies have not yet confirmed that any

of the outcome measures that have been used are

acceptable for purposes of drug approval and labeling

Several clinical trials aimed at detecting a

neuropro-tective effect have shown positive results, but

interpre-tation has been confounded by the symptomatic effects

of the drugs being tested As a consequence, positive

results cannot be interpreted as representing

neuropro-tection More recently, clinical trials have attempted to

detect neuroprotection by utilizing neuroimaging

surrogate markers of nigrostriatal function However,

even though results have been positive, it is not

estab-lished that these imaging surrogate markers do in fact

accurately represent the number of dopamine neurons or

terminals and no clinical correlate has been observed in

these studies In the final analysis, it will probably be

necessary to provide evidence of improvement in both

imaging and clinical markers of disease progression

before it can be declared that an intervention is

neuropro-tective and has a disease-modifying effect

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