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Current Concepts and Perspectives in Parkinson’s Disease

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1 Current Concepts and Perspectives in Parkinson’s Disease
Section I Current Concepts and Perspectives in Parkinson’s Disease Anthony H.V. Schapira, DSc, MD, FRCP, FMedSci Professor of Neurology University Department of Clinical Neurosciences Royal Free and University College Medical School, and Institute of Neurology University College London London, UK Matthias R. Lemke, MD Professor of Psychiatry Centre of Psychiatry and Neurology Rhine Clinic Bonn Bonn, Germany

2 Section I Contents Section I – Epidemiology, Pathophysiology and Diagnosis of Parkinson’s Disease Introduction and Historical Perspectives Definition Epidemiology Pathophysiology and Genetics Diagnosis and Symptoms Differential Diagnosis Clinical Evaluation – Scales and Scores Disease Burden Section II – Treatment of Parkinson’s Disease General Principles Drug Therapy in Parkinson’s Disease Surgery Management of Non-Motor Symptoms Disease Modification (Neuroprotection) Physical Therapy Future Treatments Section III – Depression in Parkinson’s Disease Overview Epidemiology and Pathophysiology Burden Diagnosis and Evaluation Treatment

3 Section I Section I Epidemiology, Pathophysiology and Diagnosis of Parkinson’s Disease

4 Section I – Summary Introduction and Historical Perspectives
Definition Epidemiology Pathophysiology and Genetics Diagnosis and Symptoms Differential Diagnosis Clinical Evaluation – Scales and Scores Disease Burden

5 Introduction and Historical Perspectives
Section I Introduction and Historical Perspectives

6 Parkinson’s Disease – Introduction
Section I Parkinson’s Disease – Introduction Parkinson’s disease: a progressive neurodegenerative disease Early clinical features: Typical motor symptoms result from the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain Other dopaminergic structures (e.g. the limbic system) may be affected, resulting in early symptoms such as depression As the disease progresses, additional brain areas degenerate, resulting in non-dopaminergic, non-motor features Introduction of levodopa treatment has resulted in significant improvements in both quality of life (QoL) and life expectancy Current challenges: Prevention of motor complications Treatment of non-motor features Slowing of disease progression Parkinson’s disease (PD) is a neurodegenerative disease whose initial clinical features result from the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. However, other structures—the limbic dopaminergic system for instance—may be affected, resulting in symptoms such as depression years before the occurrence of typical PD motor symptoms. As the disease progresses, the involvement of additional brain areas in the degenerative process produces predominantly non-dopaminergic, non-motor features. The discovery of dopamine deficiency in PD and the introduction of levodopa treatment have provided patients with significant improvements in both quality of life (QoL) and life expectancy. Indeed, PD remains the neurodegenerative disease that is most amenable to treatment and for which there are currently multiple therapeutic options that benefit patients. However, treatment of non-motor features and slowing of disease progression are currently two of the most important challenges for the management of PD.1 This educational resource aims at providing clinical neurologists with updated information on current approaches and perspectives in the management of PD. The development of successful disease-modifying therapies will depend upon an exact understanding of the pathogenesis of PD. Effective “neuroprotective” therapies will hopefully delay or prevent degeneration of dopaminergic and non-dopaminergic pathways. These approaches are examined in the section dedicated to treatment. In addition, the clinician is faced with the challenge of managing the variety of motor and non-motor features that emerge in Parkinson’s disease patients as the disease progresses. Among non-motor symptoms, depression appears to be a feature that is both frequent and, to a significant extent, treatable. Therefore, another focus of this series will be the recognition and management of non-motor symptoms, particularly depression. Reference 1. Schapira AHV and Olanow WC, eds. Principles of Treatment in Parkinson’s Disease. 7th ed. Philadelphia, PA: Butterworth Heinemann; 2005. Schapira AHV, Olanow WC. In: Principles of Treatment in Parkinson’s Disease; 2005.

7 Section I First Description of the “Shaking Palsy” as a Clinical Syndrome by James Parkinson in 1817 1500s: Leonardo da Vinci identifies a “paralytic” condition involving trembling limbs. 1700s: John Hunter, a British surgeon, describes patients with ‘severe tremor on awakening who do not complain from tiredness in the muscles.’ 1817: James Parkinson publishes the Essay on the Shaking Palsy, the first and definitive clinical description of paralysis agitans, the condition that subsequently comes to bear his name. The first known recognition of what we now call “Parkinson’s disease” was by one of the greatest original minds of all time, Leonardo da Vinci. Fascinated by the structure and functioning of the human body, Leonardo noted in about 1500 that some people experienced abnormal, involuntary movements and, simultaneously, difficulty in performing the movements they did wish to make. “This appears clearly in paralytics—whose trembling limbs move ... without permission of the soul; which soul with all its power cannot prevent these limbs from trembling.” Some two centuries later, the famous British surgeon John Hunter was probably referring to PD when he commented on an odd phenomenon: Patients with severe tremor did not complain about tiredness in the muscles that produced the incessant shaking. “For instance,” said Hunter, “Lord L’s hands are almost perpetually in motion, and he never feels the sensation of them being tired. When he is asleep his hands, etc., are perfectly at rest; but when he wakes, in a little while they begin to move.”1 When Hunter made this point in a London lecture in 1776, his audience may have included a bright, 21-year-old student named James Parkinson—born in 1755 in what was then the village of Hoxton near London—who later published his classic An Essay on the Shaking Palsy. James Parkinson is credited with providing the first and definitive clinical description of the disease known as paralysis agitans, the disease that was subsequently to bear his name.2 References Hunter J. In: Parkinson JWK, ed. Hunterian Reminiscences. London: Sherwood, Gilbert and Piper; 1833: Parkinson J. An Essay on the Shaking Palsy. London: Whittingham & Rowland, 1817 (reprinted in Medical Classics 1938;2:946-97; facsimile editions printed by the American Medical Association in 1917; facsimile edition, with biography of Parkinson by Macdonald Critchley, London, 1955; facsimile reproduction by Dawson in London, 1959). Parkinson J. An Essay on the Shaking Palsy; 1817.

8 Parkinson’s Disease – Historical Perspective
Section I Parkinson’s Disease – Historical Perspective James Parkinson, 1817 Shaking Palsy Detailed analyses of the clinical effects Jean-Martin Charcot, 1867 Clinical classification and differential diagnosis Proposes the eponymous label “Parkinson’s disease” First effective treatment: belladonna alkaloids Friedrich Heinrich Lewy, 1912 Intracytoplasmic inclusions: the hallmark of Parkinson's disease Constantin Trétiakoff, 1919 Cell degeneration in the substantia nigra Herbert Ehringer and Oleh Hornykiewicz, 1960 Dopamine deficiency in the striatum James Parkinson was born in 1755 in what was then the village of Hoxton near London. His Essay on the Shaking Palsy was published in 1817 and was based on six cases, three of which were based only on observations as opposed to an examination of the patients.1 His description remains one of the best detailed analyses ever published of the clinical effects of PD that also makes comment on the aetiology and pathogenesis of the disease. What he observed was shaking, bending forward, slowness of movement, poor balance, and a curious telltale feature that is almost diagnostic: freezing as if rooted to the ground for a few seconds, followed by a tendency to shuffle in steps that get progressively shorter and quicker until walking is no longer under control. His observations on pathology were naturally limited; he did suggest that the disease had its origins in the medulla, ‘although that part contained within the cervical vertebrae’ (sic). Suggestions for the relief of symptoms included the letting of blood from the upper cervical area and the production of a purulent discharge with the use of the Sabine Liniment. Several physicians published case reports based on Parkinson’s description. However, it was Jean-Martin Charcot, the nineteenth-century French neurologist, who confirmed the common occurrence of the condition and made significant advances in the clinical classification and differential diagnosis of PD. Charcot paid tribute to Parkinson’s salient contribution and was the first to propose the eponymous label of the disease. Charcot also introduced the first effective treatment for PD: belladonna alkaloids. While the motor and non-motor features of PD are well described in these early works, the pathological definition of PD evolved rather slowly. Friedrich Heinrich Lewy described the intracytoplasmic inclusions that are a hallmark of the disease in and Constantin Trétiakoff is credited with the discovery of cell degeneration in the substantia nigra.3 In 1960, Herbert Ehringer and Oleh Hornykiewicz identified dopamine deficiency in the striatum of patients with PD.4 Studies on the replacement of dopamine with levodopa produced equivocal results until used in sufficient quantity. Thus began the era of symptomatic treatment for PD, which has remained focused on the dopaminergic system for almost the last 40 years. References 1. Parkinson J. An Essay on the Shaking Palsy. London: Whittingham & Rowland, 1817. 2. Lewy FH. Paralysis agitans. In: Lewandowsky M, ed. Pathologische Anatomie. Handbuch der Neurologie. Berlin: Springer Verlag;1912:920–33. 3. Trétiakoff C. Contribution à l’étude de l’anatomie pathologique du locus niger de soemmering avec quelques déductions relatives à la pathogénie des troubles de tonus musculaire et de la maladie de Parkinson. PhD Thesis, University of Paris; 1919. 4. Ehringer H, Hornykiewicz O. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Klin Wochenschr 1960;38: Parkinson J. An Essay on the Shaking Palsy; 1817. Lewy FH. In: Handbuch der Neurologie; 1912: Trétiakoff C. PhD Thesis, University of Paris; 1919. Ehringer H, Hornykiewicz O. Klin Wochenschr 1960;38:

9 Section I Definition

10 Parkinson’s Disease – Definition
Section I Parkinson’s Disease – Definition Parkinson’s disease: A clinical and neuropathological entity characterised by: Bradykinesia Rigidity Tremor Onset usually asymmetric and responsive to dopaminergic treatment No historical or examination clues to indicate secondary parkinsonism (e.g. Wilson’s disease, multiple system atrophy) The brunt of the early pathology falls on the dopaminergic nigrostriatal pathway Parkinsonism: Any bradykinetic-rigid syndrome that is not Parkinson’s disease The definition of PD is rather difficult. Diagnosing PD first requires identifying parkinsonism. Parkinsonism describes a syndrome characterised by rigidity, tremor and bradykinesia, of which idiopathic PD is the main cause.1 PD is a clinical and neuropathological entity that includes parkinsonism and additional specific features that confirm the diagnosis, and loss of pigmented dopaminergic neurons in the brain stem, particularly in the pars compacta region of the substantia nigra, along with the presence of neuronal intracytoplasmic inclusions called Lewy bodies.2 In theory, therefore, diagnosis of PD requires a post-mortem neuropathological examination. However, patient history and examination by skilled clinicians can predict the pathological findings with fairly high certainty.3 PD is usually asymmetric and responsive to dopaminergic treatment, with no historical or examination factors suggesting an alternative cause for symptoms.4 This educational resource addresses idiopathic PD, including genetic forms where a positive family history can be elicited. Parkinsonism, i.e. akinetic-rigid syndromes that are not part of PD (e.g. multiple system atrophy, progressive supranuclear palsy), is excluded. References 1. Rajput AH, Offord KP, Beard CM, Kurland LT. Epidemiology of parkinsonism: incidence, classification, and mortality. Ann Neurol 1984;16: 2. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004;363: 3. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002;125: 4. Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med 2005;353: Samii A, et al. Lancet 2004;363: Nutt JG, Wooten GF. N Engl J Med 2005;353:

11 Section I Epidemiology

12 Epidemiology of Parkinson’s Disease – Prevalence
Section I Epidemiology of Parkinson’s Disease – Prevalence Population-based prevalence studies of Parkinson’s disease Idiopathic Parkinson’s disease is a common age-related condition 5 10 15 20 25 30 35 40 45 50 60 70 80 90 100 Rotterdam, the Netherlands Central Spain Copiah County, USA France Sicily Aragon, Spain Europe China Taiwan, China Prevalence (%) Age (years) Defining the epidemiology of PD is confounded by several variables, including the difficulty of diagnosis and the age-dependence of the disease. The prevalence of PD in industrialised countries is generally estimated at 0–3% in the global population and at about 1% in individuals over 60 years of age.1 The age-adjusted prevalence is approximately 115 per 100,000; it is estimated to be 1.3 per 100,000 in persons under 45 years of age and per 100,000 in individuals aged 75–85.2 A prevalence study in the Netherlands found 3100 cases per 100,000 in individuals aged 75–85 and 4300 per 100,000 in persons over 85 years old.3 The geographic distribution of the disease appears similar across the US and Japan, but failure to adjust population figures for age can lead to widely discrepant results, e.g. a prevalence of 10 per 100,000 in Nigeria.4 The graph summarises age-specific prevalence rates obtained from population-based surveys. It appears that PD is clearly an age-related condition; it is rare before the age of 50, with increasing prevalence with age—up to 4% in the highest age group.5 References 1. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med 2003; 348: 2. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157: 3. de Rijk MC, Breteler MM, Graveland GA, et al. Prevalence of Parkinson’s disease in the elderly: the Rotterdam Study. Neurology 1995;45: 4. Zhang ZX, Roman GC. Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepidemiology 1993;12: 5. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol 2006;5: References for the graph: de Rijk MC, et al. Neurology 1995;45:2143-6; Benito-Leon J, et al. Mov Disord 2003;18:267-74; Schoenberg BS, et al. Neurology 1988;38:645-6; Tison F, et al. Acta Neurol Scand 1994;90:111-15; Morgante L, et al. Neurology 1992;42:1901-7; Claveria LE, et al. Mov Disord 2002;17:242-9; de Rijk MC, et al. Neurology 2000;54 (11 Suppl 5):S21-3; Li SC, et al. Arch Neurol 1985;42:655-7; Chen RC, et al. Neurology 2001;57: de Lau LM, Breteler MM. Lancet Neurol 2006;5: © 2006, with permission from Elsevier.

13 Epidemiology of Parkinson’s Disease – Incidence
Section I Epidemiology of Parkinson’s Disease – Incidence Idiopathic Parkinson’s disease is uncommon before the age of 50 There is a sharp increase in incidence after the age of 60 200 300 400 500 600 700 30 40 50 60 70 80 90 100 Spain Rotterdam, the Netherlands Hawaii, USA Manhattan, USA Taiwan, China London, UK Rochester, USA Italy China Incidence Rate (cases per 100,000 person-years) Prospective population-based incidence studies of Parkinson’s disease Age (years) Several studies have sought to define the incidence of PD.1 Reported standardised incidence rates of PD are 8–18 per 100,000 person-years. In the United States, the age-adjusted figure is 13.5–13.9 per 100,000 person-years.2,3 The graph displays age-specific incidence rates from prospective population-based studies with either record-based or in-person case-finding. PD rarely occurs before the age of 50 and a sharp increase in incidence is seen after the age of 60. References 1. de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol 2006;5: 2. Mayeux R, Marder K, Cote LJ, et al. The frequency of idiopathic Parkinson’s disease by age, ethnic group, and sex in northern Manhattan, Am J Epidemiol 1995;142:820-7. 3. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, Neurology 1999;52: References for the graph: Benito-Leon J, et al. Neurology 2004;62:734-41; de Lau LM, et al. Neurology 2004;63:1240-4; Morens DM, et al. Neurology 1996;46: ; Mayeux R, et al. Am J Epidemiol 1995;142:820-7; Chen RC, et al. Neurology 2001;57: ; MacDonald BK, et al. Brain 2000;123:665-76; Rajput AH, et al. Ann Neurol 1984;16:278-82; Baldereschi M, et al. Neurology 2000;55: ; Wang YS, et al. Chin Med J (Engl) 1991;104:960-4. de Lau LM, Breteler MM. Lancet Neurol 2006;5: © 2006, with permission from Elsevier.

14 Mortality in Parkinson’s Disease
Section I Mortality in Parkinson’s Disease Location (country) Type of study Source of study Cases Type of cases Follow-up (years) HR (95% CI) Morens (1996) Honolulu (USA) Cohort study Population 92 Incident 29.0 2.50* Louis (1997) New York (USA) Case-control Hospital 180 Prevalent 3.0 2.70 ( ) Hely (1999) Sydney (Australia) Case series Hospital 130 Prevalent 10.0 1.58 ( )** Berger (2000) Europe (5 countries) 5 cohort studies Population 252 Prevalent Variable 2.30 ( ) Morgante (2000) Sicily (Italy) Case-control Population 59 Prevalent 8.0 2.30 ( ) Guttman (2001) Ontario (Canada) Case-control Register 15,304 Prevalent 6.0 2.50 ( ) Elbaz (2003) Olmsted (USA) Case-control Register 196 Incident 7.2 1.60 ( ) Fall (2003) Ostergotland (Sweden) Case-control Population 170 Prevalent 9.4 2.40 ( ) Herlofson (2004) Rogaland (Norway) Case series Population 245 Prevalent 8.7 1.52 ( )* Hughes (2004) Leeds (UK) Case-control Hospital 90 Prevalent 11.0 1.64 ( ) de Lau (2005) Rotterdam (Netherlands) Cohort study Population 166 Both 6.9 1.83 ( ) * In people aged years (95% CI not provided); ** standardised mortality ratio; HR, mortality hazard ratio. Studies of mortality hazard ratios in patients with Parkinson’s disease Although PD per se is not a direct cause of death, death may occur as a secondary result of severe motor dysfunction, e.g. falls in advanced PD. Despite the differences in methodology, the results of most epidemiological studies consistently suggest that PD reduces life expectancy. In more recent years, there seems to be a reduced mortality from PD owing to the use of more effective therapies.1 Available studies show that mortality hazard ratios vary from 1.5 to 2.7.2 References 1. Poewe W. The Sydney multicentre study of Parkinson's disease. J Neurol Neurosurg Psychiatry 1999;67:280-1. 2. de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol 2006;5: References for the table Morens DM, et al. Neurology 1996;46: ; Louis ED, et al. Arch Neurol 1997;54:260-4; Hely MA, et al. J Neurol Neurosurg Psychiatry 1999;67:300-7; Berger K, et al. Neurology 2000; 54 (11 Suppl 5):S24-7; Morgante L, et al. Arch Neurol 2000; 57:507-12; Guttman M, et al. Neurology 2001;57: ; Elbaz A, et al. Arch Neurol 2003;60:91-6; Fall PA, et al. Mov Disord 2003;18:1312-6; Herlofson K, et al. Neurology 2004;62:937-42; Hughes T, et al. Acta Neurol Scand cta 2004;110:118-23; de Lau LM, et al. Arch Neurol 2005; 62: de Lau LM, Breteler MM. Lancet Neurol 2006;5:

15 Pathophysiology and Genetics
Section I Pathophysiology and Genetics

16 Pathology of Parkinson’s Disease – Macroscopy
Section I Pathology of Parkinson’s Disease – Macroscopy A: Rostral (R), intermediate (I) and caudal (C) transverse planes of the mesencephalon on a sagittal MRI of the brainstem. B: MRI of the intermediate transverse plane. Arrows show the emergence of the third cranial nerve fibres. Normal Parkinson’s disease Normal substantia nigra Depigmentation of substantia nigra This MRI view of the brainstem illustrates the location of the mesencepahlon and macroscopic findings after sectioning of the brain. Gross examination of the external aspects of the brain in PD does not reveal any specific features, whereas macroscopic examination of the sectioned PD brain shows decreased pigmentation of the substantia nigra (Figure) and locus ceruleus. The globus pallidus, putamen and caudate nucleus appear normal on gross examination.1,2 References 1. Jellinger KA. The pathology of Parkinson’s disease. Adv Neurol 2001;86:55-72. 2. Braak H, Braak E. Pathoanatomy of Parkinson’s disease. J Neurol 2000;247(Suppl 2):II3-10. Damier P, Brain 1999;122: Images courtesy of JJ Hauw, Department of Neuropathology, Hôpital de la Pitié-Salpêtrière, Paris, France.

17 Pathology of Parkinson’s Disease – Microscopy
Section I Pathology of Parkinson’s Disease – Microscopy Loss of pigmented dopaminergic neurons Normal Parkinson’s disease Normal substantia nigra Degeneration of nigral cells Images courtesy of É tienne Hirsch, MD, INSERM U679, Hôpital de la Pitié-Salpêtrière, Paris, France. Histopathological hallmark: Lewy bodies The characteristic pathological changes in PD are the loss of pigmented dopaminergic neurons, particularly in the ventral tier of the substantia nigra pars compacta, and the presence of intracytoplasmic eosinophilic inclusions known as Lewy bodies in a proportion of the surviving neurons. Lewy bodies have attracted considerable attention over the years, as they may hold important clues to the pathogenesis of the disease. They are 5–30 microns in diameter and often have a dense hyaline eosinophilic core composed of concentric lamellae and a pale halo surrounding the core. Under electron microscopy, they are shown to have intermediate filaments that measure 7–20 nanometers. The Lewy body is composed of a number of different proteins that exhibit staining for ubiquitin, -synuclein and proteasomal components. It is not known whether these inclusions represent a protective response to abnormal or toxic protein aggregates or whether their formation is part of a toxic process that damages the cell. As seen on the upper right figure, surviving dopamine neurons seen at autopsy are shrunken (approximately 15% no longer express tyrosine hydroxylase [TH]). If on close examination of several sections of the midbrain no Lewy bodies are found in the substantia nigra, a diagnosis of PD can usually be excluded and other causes of parkinsonism considered.1 Reference 1. Gibb WR, Lees AJ. The significance of the Lewy body in the diagnosis of idiopathic Parkinson’s disease. Neuropathol Appl Neurobiol 1989;15:27-44. Images courtesy of JJ Hauw, Department of Neuropathology Hôpital de la Pitié-Salpêtrière, Paris, France. Gibb WR, Lees AJ. Neuropathol Appl Neurobiol 1989;15:27-44.

18 Neuronal Cell Death and Motor Symptoms
Section I Neuronal Cell Death and Motor Symptoms Staining for tyrosine hydroxylase on a section of human post-mortem mesencephalon Control Parkinson’s disease SNpc SNpl rn A8 cp PGS CGS These images show tyrosine hydroxylase-labelled dopaminergic neurons on a section of human post-mortem mesencephalon from a control subject (on the left) and a PD subject (on the right). The relatively selective loss of dopaminergic neurons in the nigrostriatal pathway is responsible for the dopamine deficiency in the striatum, resulting in the typical symptoms of PD. Although most dopaminergic systems are affected, the severity of the lesions varies in the different systems.1 There are massive lesions (70–80%) in the substantia nigra pars compacta (SNpc), whereas the lesions are moderate (40–50%) in the substantia nigra pars lateralis (SNpl) and dopaminergic group A8. Reference 1. Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson’s disease. Nature 1988;334:345-8. Abbreviations: SNpc, substantia nigra pars compacta; SNpl, substantia nigra pars lateralis; A8, dopamingergic group A8; rn, red nucleus; PGS, periaqueductal gray substance; cp, cerebellus peduncule; CGS, central gray substance Hirsch E, et al. Nature 1988;334:345-8.

19 Multicentric Neurodegeneration
Section I Multicentric Neurodegeneration STN subthalamic nucleus GPi globus pallidus interna Gpe globus pallidus externa SNpc substantia nigra pars compacta VTA ventral tegmental area Dopamine Parkinson’s disease brain Serotonin Noradrenaline GPi GPe Putamen STN Amygdala Thalamus Substantia innominata Caudate SNpc VTA Locus coeruleus Raphe nuclei Pedunculopontine nucleus Not all PD symptoms are caused by degeneration of the dopaminergic systems. This figure is a schematic representation of the neurodegenerative changes in the central nervous system in PD. The pathways of the affected monoamine neurotransmitters are shown. Acetylcholine pathways, which are also severely affected in PD, are not included. The excellent control of parkinsonian motor symptoms afforded by dopaminergic therapies and surgery mean that it is now common to see patients with disease progression over a period of 15–20 years or even longer. Problems such as gait dysfunction, disequilibrium, swallowing and speech difficulties, urinary dysfunction, severe constipation and nocturnal sleep disorders have become increasingly prevalent. At the same time, depression, daytime somnolence and dementia are also more prevalent, occurring in 40–50% of patients. These so-called “non-dopaminergic” clinical manifestations are probably caused by the loss of neurons in the cortex, subcortex, brainstem and other peripheral autonomic sites subject to the same neurodegenerative process affecting the nigrostriatal system.1 Reference 1. Lang AE, Obeso JA. Challenges in Parkinson’s disease: restoration of the nigrostriatal dopamine system is not enough. Lancet Neurol 2004;3: Lang AE, Obeso JA. Lancet Neurol 2004;3: © 2004, with permission from Elsevier.

20 Basal Ganglia Circuit Normal Parkinsonism Levodopa dyskinesia Cortex
Section I Basal Ganglia Circuit Cortex GPe STN GPi SNpr PPN VL Putamen SNpc (a) (b) (c) Normal Parkinsonism Levodopa dyskinesia DA Excitatory Neuronal Firing Inhibitory Neuronal Firing The basal ganglia consist of the caudate nucleus, the putamen, the globus pallidus and the subthalalmus. In addition, the substantia nigra, a midbrain structure, is reciprocally connected with the basal ganglia of the forebrain. The caudate and putamen together are called the striatum, which is the target of cortical input to the basal ganglia. The globus pallidus is the source of output to the thalamus. The basic circuit of the basal ganglia is ostensibly a loop where information cycles from the cerebral cortex through the basal ganglia and thalamus, and then back to the cortex, particularly the supplementary motor area (SMA). One of the functions of this loop appears to be the selection and initiation of voluntary movement. Cortex  Striatum  Globus pallidus  Ventral lateral nucleus (VL)  Cortex (SMA). This slide represents the classic model of the basal ganglia circuit in (a) normal, (b) parkinsonian, and (c) levodopa-induced dyskinesia states.1 This model proposes that the striatum, the major input region of the basal ganglia, is connected to the major output region, the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNpr), by a direct pathway and by an indirect pathway that has synaptic connections in the external globus pallidus (GPe) and subthalamic nucleus (STN). (a) In normal subjects, dopamine neurons in the substantia nigra pars compacta (SNpc) act to excite inhibitory neurons in the direct pathway and inhibit the excitatory influence of the indirect pathway. (b) In PD, the model proposes that dopamine depletion leads to overactivity in the GPi and SNpr with excess inhibition of the thalamus, reduced activation of cortical motor regions, and the development of parkinsonian features. (c) In contrast, the model proposes that dyskinesia results from excess levels of dopaminergic activation causing suppression of firing in GPi and SNpr with disinhibition of the thalamus and overexcitation of cortical motor regions. Reference 1. Olanow CW. The scientific basis for the current treatment of Parkinson’s disease. Annu Rev Med 2004;55:41-60. Olanow CW. Annu Rev Med 2004;55: Copyright © 2004 by Annual Reviews. All rights reserved

21 Cell Death in Parkinson’s Disease
Section I Cell Death in Parkinson’s Disease Genetics  Environment Activation signal Cell death program Free radicals Iron Nitric oxide Excitotoxicity Complex I deficiency Proteasomal inhibition Glial factors Inflammation Healthy DA neuron Damaged DA neuron Apoptotic DA neuron The aetiology of PD is thought to involve either a genetic predisposition or exposure to an environmental factor, or a combination of both.1-4 There is still no clear explanation for the exact mechanism of dopamine cell death in PD. Evidence suggests that dopamine neuronal death in the substantia nigra pars compacta (SNpc) can occur either through necrosis or apoptosis.5 Necrosis, an uncontrolled form of cell death, results from excessive ionic flux across the cell membrane, which in turn results in protease activation, catastrophic destruction of cell organelles and cell disintegration, and their subsequent removal by phagocytosis through an inflammatory response. It was recently demonstrated that apoptosis, a controlled or programmed form of cell death, is for the most part implicated in dopamine cell death in PD.6 Apoptosis is characterised by chromatin condensation, DNA fragmentation, cell shrinkage, relative sparing of organelles, and lack of an inflammatory response. Several biochemical abnormalities have been identified in PD substantia nigra. They include abnormal iron accumulation, alterations in the concentrations of iron-binding proteins, evidence for increased oxidative stress and oxidative damage, mitochondrial complex I deficiency, increased nitric oxide formation, and generation of nitrotyrosine residues. The exact chronology of the steps that result in neuronal death remains to be established. In theory, the aetiological factors, be they genetic and/or environmental, would cause mitochondrial dysfunction and increased production of free oxygen radicals, resulting in a process that activates the release of microglial factors and the subsequent production of tumor necrosis factor alpha, which, in turn, would initiate the apoptosis program. The monogenic forms of PD appear to involve pathogenetic pathways similar to those seen in idiopathic PD. References 1. Warner TT, Schapira AH. Genetic and environmental factors in the cause of Parkinson’s disease. Ann Neurol 2003;53(Suppl 3):S16-23; discussion S23-5. 2. Huang Z, de la Fuente-Fernandez R, Stoessl AJ. Etiology of Parkinson’s disease. Can J Neurol Sci 2003;30(Suppl 1):S10-8. 3. Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson’s disease. Annu Rev Neurosci 1999;22: 4. Di Monte DA, Lavasani M, Manning-Bog AB. Environmental factors in Parkinson’s disease. Neurotoxicology 2002;23: 5. Faherty CJ, Smeyne RJ. Cell death in Parkinson’s disease. In: Ebadi M, Pfeiffer RF, eds. Parkinson’s Disease. Boca Raton: CRC Press; 2005. 6. Anglade P, Vyas S, Javoy-Agid F, et al. Apoptosis and autophagy in nigral neurons of patients with Parkinson’s disease. Histol Histopathol 1997;12:25-31. ? Abbreviation: DA, dopamine Courtesy of Andreas Hartmann, MD, INSERM U679, Hôpital de la Pitié-Salpêtrière, Paris, France

22 Potential Neuroprotective Approaches
Section I Potential Neuroprotective Approaches Pathways involved in MPTP toxicity and potential neuroprotective drugs or strategies NMDA receptor Ca2+ Na+/Ca2+ NMDA antagonists AMPA AMPA receptor MAO-B inhibitors DAT inhibitors MPTP MPP+ DA transporter MAO-B H Complex I ROS, ONOO- ROS scavengers Energy mimetics Coenzyme Q10 Metal chelators nNOS inhibitors PARP inhibitors Iron Heavy metals? Necrotic Death Pathways nNOS activation DNA damage PARP activation Apoptotic Death Pathways Generation of the apoptosome Caspase activation p53 activation ER stress Cell death Inhibitors of -syn toxicity Caspase inhibitors Inhibitors of ER stress response p53 inhibitors MLK inhibitors GAPDH translocation inhibitors Minocycline iNOS inhibitors PPAR inhibitors Microglial activation ROS –syn Altered -syn Conformation oligomer/fibrils Abbreviations: AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionate; DAT, dopamine transporter; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; iNOS, inducible nitric oxide synthase; MAO-B, monoamine oxidase B; MLK, mixed lineage kinase; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NMDA, N-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase; PARP, poly (ADP-ribose) polymerase; ROS, reactive oxygen species; PPAR, peroxisome proliferator-activated receptors-gamma The absolute determination of neuronal cell death in PD has far-reaching therapeutic consequences even in the absence of a clear aetiological factor. This knowledge would allow for the development of drugs that could exert their effects on the various steps in the neuronal death cascade. Examples might include anti-apoptotic agents, antioxidants to reduce free radicals, or inhibitors of microglial cytokine release. Recent studies have highlighted the key role of reactive oxygen species (ROS) and decrements in mitochondrial complex I activity in the pathogenesis of sporadic PD. The discovery of complex I deficiency and the role of mitochondria in PD have been enhanced by the subsequent identification of mutations in genes encoding mitochondrial proteins (e.g. PINK1 and DJ1) as causes of autosomal recessive PD, as well as by the mitochondrial abnormalities associated with alpha-synuclein and parkin expression. Furthermore, the environmental toxins causing parkinsonism identified so far are all mitochondrial inhibitors of complex I, e.g. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone and annonacin. Many potential pathways of dopamine neuronal death—and therapeutic agents—have been suggested or identified.1 As the figure shows, toxicity requires conversion of MPTP, the prototypical mitochondrial complex I inhibitor, to 1-methyl-4-phenyl-pyridinium (MPP+) by monoamine oxidase B (MAO-B); MPP+ is captured via the dopamine transporter by dopamine neurons, where inhibition of mitochondrial complex I occurs. Most pathways implicated in neuronal cell death, if not all, involve this MPTP model and PD pathogenesis, including excitotoxicity, oxygen species toxicity (superoxide anion, nitric oxide, hydroxyl radical), apoptosis (caspase-dependent and -independent pathways), necrosis, and glial-induced inflammatory injury. Reference 1. Dawson TM, Dawson VL. Neuroprotective and neurorestorative strategies for Parkinson’s disease. Nat Neurosci 2002;(5 Suppl): Reprinted by permission from Macmillan Publishers Ltd: Dawson TM, Dawson VL. Nat Neurosci 2002;(5 Suppl): , © 2002.

23 Genetic Factors in Parkinson’s Disease
Section I Genetic Factors in Parkinson’s Disease Gene Locus (Chromosomal position) Age of onset Inheritance Clinical phenotype -synuclein PARK1 (4q21-q23) Young AD Similar to IPD, rapid progression Parkin PARK2 (6q25.2-q27) AR Symptomatic improvement following sleep, mild dystonia, good response to levodopa, slow progression UCHL1 PARK5 (4p14) Similar to IPD PINK1 PARK6 (1p35-p36) Benign course, levodopa-responsive DJ1 PARK7 (1p36) Levodopa-responsive LRRK2 PARK8 (12q12) Similar to IPD (LRRK2 mutations are the commonest cause of either familial or ‘sporadic’ PD) PARK9, 10, and 11 (1p36, 1p32, and 2q36-q37, respectively ) AR (PARK9) PARK9: spasticity, dementia and supranuclear palsy PARK10: similar to IPD PD is a complex, multifactorial neurodegenerative disease. Although hereditary factors were originally thought unlikely, recent studies have identified several genes in its pathogenesis. This table lists the genes currently known to cause PD. However, only a minority of PD cases have a clear family pedigree. Some of the single-gene mutations listed, e.g. LRRK2, may account for a proportion of the remaining majority of patients. The current understanding is that such single-gene causes of PD will remain in the minority. Therefore, the large majority of PD patients may develop the disease either as a result of environmental factors, polygenic influences, or a combination of the two. Genetic insights provide the rationale for new strategies in prevention and therapy. They have led to animal models of PD in which these strategies, for example neuroprotection in affected patients and in asymptomatic carriers, can be evaluated.1,2 References 1. Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet 2006;7: 2. de Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol 2006;5: Abbreviations: AD, autosomal dominant; AR, autosomal recessive; IPD, idiopathic Parkinson’s disease; LRRK2, leucine-rich repeat kinase 2; PARK2, parkin-encoding gene; PINK1, PTEN induced putative kinase 1; UCHL1, ubiquitin carboxyl-terminal esterase L1; UPS, ubiquitin-proteasome system. Farrer MJ. Nat Rev Genet 2006;7: de Lau LM, Breteler MM. Lancet Neurol 2006;5:

24 Diagnosis and Symptoms
Section I Diagnosis and Symptoms

25 Clinical diagnostic criteria for idiopathic Parkinson’s disease
Section I Diagnostic Criteria Clinical diagnostic criteria for idiopathic Parkinson’s disease Clinically possible One of: Asymmetric resting tremor Asymmetric rigidity Asymmetric bradykinesia Clinically probable Any two of: Clinically definite Criteria for clinically probable, plus Definitive response to antiparkinson drugs Exclusion criteria Exposure to drugs that can cause parkinsonism, such as neuroleptics, some anti-emetic drugs, tetrabenazine, reserpine, flunarizine and cinnarizine Cerebellar signs Corticospinal tract signs Eye-movement abnormalities other than slight limitation of upward gaze Severe dysautonomia Early moderate to severe gait disturbance or dementia History of encephalitis, recurrent head injury (such as seen in boxers) Evidence of severe subcortical white-matter disease, hydrocephalus or other structural lesions on MRI that may account for parkinsonism Definite diagnosis of PD requires a post-mortem neuropathological examination.1,2 However, the development of rigorous criteria for disease recognition allows for a clinical diagnosis with a high degree of accuracy. In the absence of reliable and readily available laboratory tests for the diagnosis of PD, the diagnosis currently relies on the clinical manifestations of the disease. There is general agreement that the three cardinal signs of PD are bradykinesia, resting tremor and rigidity. A resting tremor with a frequency of 3–5 Hz (classically resembling pill-rolling) is the first symptom in 70% of PD patients. However, 30% of patients will never display tremor, the main symptom of PD being bradykinesia. Tremor is usually asymmetric at disease onset and worsens with anxiety, contralateral motor activity and during ambulation. Postural instability, sometimes considered a cardinal sign, is non-specific and usually absent in early disease, particularly in younger patients. An excellent levodopa response lasting at least five years is generally a feature of clinically definite disease. Other features are severe levodopa-induced dyskinesia and the absence of features suggesting an alternate parkinsonian process. Based on these criteria, a gradation of diagnostic certainty for idiopathic PD is possible:3,4 Clinically possible, with the presence of one of the three cardinal features; Clinically probable, with any two of the cardinal features; Clinically definite, criteria for clinically probable and definitive response to antiparkinson drugs. The presence of exclusion criteria suggests an alternative diagnosis to idiopathic PD.3,5 References 1. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004;363: 2. Tarsy D. Diagnostic criteria for Parkinson’s disease. In: Ebadi M, Pfeiffer RF, eds. Parkinson’s Disease. Boca Raton: CRC Press; 2005. 3. Calne DB, Snow BJ, Lee C. Criteria for diagnosing Parkinson’s disease. Ann Neurol 1992;32(Suppl):S125-7. 4. Ward CD, Gibb WR. Research diagnostic criteria for Parkinson’s disease. Adv Neurol 1990;53:245-9. 5. Gelb DJ, Oliver E, Gilman S. Diagnostic criteria for Parkinson disease. Arch Neurol 1999;56:33-9. Samii A, et al. Lancet 2004;363: Calne DB, et al. Ann Neurol 1992;32(Suppl):S125-7. Ward CD, Gibb WR. Adv Neurol 1990;53:245-9.

26 Non-Motor Symptoms of Parkinson’s Disease (1)
Section I Non-Motor Symptoms of Parkinson’s Disease (1) Neuropsychiatric symptoms Depression, apathy, anxiety Anhedonia Attention deficit Hallucinations, illusions, delusions Dementia Obsessional behaviour (can be drug-induced) and repetitive behaviour Confusion Delirium (could be drug-induced) Panic attacks Sleep disorders Restless legs and periodic limb movements Rapid eye movement (REM) sleep behaviour disorder and REM loss of atonia Non-REM sleep-related movement disorders Excessive daytime somnolence Vivid dreaming Insomnia Sleep-disordered breathing Autonomic symptoms Bladder disturbances Urgency Nocturia Frequency Sweating Orthostatic hypotension Falls related to orthostatic hypotension Coat-hanger pain Sexual dysfunction Hypersexuality (likely to be drug-induced) Erectile impotence Dry eyes Although motor symptoms define PD, the widespread and progressive neurodegeneration in the PD brain leads to the emergence of a variety of features that are collectively grouped under the title of non-motor symptoms. These are predominantly, but not exclusively, the consequence of loss of non-dopaminergic pathways. The non-motor symptoms of PD range from neuropsychiatric disturbances, such as apathy, depression, anxiety disorders and hallucinations, to fatigue, gait and balance disturbances, hypophonia, sleep disorders, sexual dysfunction, bowel problems, drenching sweats, sialorrhoea and pain.1 These symptoms are often the most troubling for patients and contribute significantly to morbidity and impaired quality of life.2 References 1. Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006;5: 2. Hely MA, Morris JG, Reid WG, Trafficante R. Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 2005;20:190-9. Adapted from Chaudhuri KR, et al. Lancet Neurol 2006;5:

27 Non-Motor Symptoms of Parkinson’s Disease (2)
Section I Non-Motor Symptoms of Parkinson’s Disease (2) Gastrointestinal symptoms (overlap with autonomic symptoms) Drooling Ageusia Dysphagia and choking Reflux, vomiting Nausea Constipation Unsatisfactory voiding of bowel Faecal incontinence Sensory Symptoms Pain Paraesthesia Olfactory disturbance Other symptoms Fatigue Diplopia Blurred vision Seborrhoea Weight loss Weight gain (possibly drug-induced) Adapted from Chaudhuri KR, et al. Lancet Neurol 2006;5:

28 Neuroimaging in Parkinson’s Disease
Section I Neuroimaging in Parkinson’s Disease Diagnosis of Parkinson’s disease (PD) is mainly clinical MRI can be helpful in detecting other causes of parkinsonism such as vascular parkinsonism Neuroimaging of the nigrostriatal dopaminergic pathway: Single photon emission computed tomography (SPECT) with [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) and positron emission tomography (PET) with 6-[18F]fluoro-L-dopa (F-DOPA) Mostly used in therapeutic trials measuring disease progression SPECT may be helpful to distinguish PD from essential tremor (ET) The diagnosis of PD is mainly clinical and in typical cases no neuroimaging is necessary. However, many patients still present a diagnostic challenge, especially those who have no tremor or who have a marked asymmetric tremor but limited bradykinesia or rigidity.1 When the patient’s history or clinical presentation is atypical, MRI can help in detecting other causes such as vascular parkinsonism. Neuroimaging of the nigrostriatal dopaminergic pathway quantifies functional dopaminergic terminals in the striatum.2 PD is characterised by decreased striatal uptake of 6-[18F]fluoro-L-dopa (F-DOPA) measured by positron emission tomography (PET). There is also a reduction of binding to the monoamine vesicular transporter with tetrabenazine, to the dopamine transporter with methylphenidate by PET, and to this transporter, as assessed by single photon emission computed tomography (SPECT) with [123I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT). Functional neuroimaging is mainly used in pharmaceutical trials evaluating therapies aimed at slowing disease progression. SPECT is also used as a diagnostic test in patients in whom the clinical diagnosis is unclear. References 1. Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinson’s disease. Lancet Neurol 2006;5:75-86. 2. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004;363: Tolosa E, et al. Lancet Neurol 2006;5:75-86. Samii A, et al. Lancet 2004;363:

29 Differential Diagnosis
Section I Differential Diagnosis

30 Classification – Differential Diagnosis of Parkinsonism
Section I Classification – Differential Diagnosis of Parkinsonism Hereditary disorders Frontotemporal dementias Dystonias Huntington’s disease Wilson’s disease Inherited ataxias Parkinson-plus syndromes Dementia with Lewy bodies Multiple system atrophy (olivopontocerebellar atrophy, Shy-Drager syndrome, striatonigral degeneration) Progressive supranuclear palsy Corticobasal degeneration Idiopathic Parkinson’s disease: approximately 75% of cases Symptomatic Drug-induced: up to 20% of cases Dopamine blockers: major neuroleptics, metoclopramide Hydrocephalus Metabolic (hepatocerebral) degeneration, parathyroid disorders Structural lesions of the brain: tumour, infarct or haemorrhage Toxins (carbon monoxide, MPTP) Infections The combination of any of the parkinsonian cardinal features, namely bradykinesia, rigidity and resting tremor, constitutes a cluster of symptoms that define parkinsonism. Parkinsonism has multiple possible causes. PD is the most common cause of parkinsonism and represents approximately 75% of cases.1 The diagnosis of PD is best predicted by the presence of an asymmetric bradykinetic rigid syndrome with a resting tremor and a good response to levodopa (see Diagnostic Criteria).2 The diagnostic specificity of these criteria is estimated at 98.6% and sensitivity, at 91.1%.3 Parkinsonism disorders that are not PD include drug-induced parkinsonism, Parkinson-plus syndromes—that is to say diseases that include parkinsonism combined with other clinical signs (e.g. dementia with Lewy bodies, multiple system atrophy [MSA], progressive supranuclear palsy and corticobasal degeneration)—toxin-induced parkinsonism, infections of the central nervous system, structural lesions of the brain, metabolic disorders, normal pressure hydrocephalus, and some hereditary disorders. Most of these causes are rare and are generally suggested by atypical features in the history or examination. In practice, clinicians routinely need to consider two main differential diagnoses: drug-induced parkinsonism and Parkinson-plus syndromes. Any dopamine receptor blocker has the potential to induce parkinsonism. Drug-induced parkinsonism accounted for 20% of parkinsonism cases in a population-based study.4 The most common agents to be considered are the major neuroleptics, but drugs such as metoclopramide can also induce symptoms that may be confused with PD. Approximately 25% of patients who have received an initial clinical diagnosis of PD are found to have Parkinson-plus syndromes.2 However, the accuracy of the diagnosis depends on whether it is made by a general practitioner, a neurologist or a movement disorder specialist. References 1. Colcher A, Simuni T. Clinical manifestations of Parkinson’s disease. Med Clin North Am 1999;83: 2. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181-4. 3. Hughes AJ, Daniel SE, Ben Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002;125: 4. Bower JH, Maraganore DM, McDonnell SK, Rocca WA. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, Neurology 1999;52: Colcher A, Simuni T. Med Clin North Am 1999;83: Hughes AJ, et al. J Neurol Neurosurg Psychiatry 1992;55:181-4. Hughes AJ, et al. Brain 2002;125: Bower JH, et al. Neurology 1999;52:

31 Parkinson’s Disease and Essential Tremor
Section I Parkinson’s Disease and Essential Tremor Differential criteria Essential tremor (ET): Tremor with no other sign of parkinsonism Presence of a head or voice tremor Strong and usually autosomal dominant family history Improvement with alcohol Parkinson’s disease (PD): Resting tremor Clear asymmetry Presence of bradykinesia or rigidity Leg tremor Improvement with dopaminergic treatment Both PD and ET have a kinetic and rest component Kinetic tremor can interfere with rapid alternating movements Cogwheel rigidity is rare in ET Typical essential tremor (ET) comprises a bilateral, usually symmetrical, visible and persistent upper limb postural or kinetic tremor.1 Bradykinesia, rigidity and postural abnormalities are not present. The tremor of ET is present at rest in only 10% of cases.2 When present or asymmetric, this can cause difficulty in distinguishing it from PD although such patients usually evolve to PD.3 The presence of a head or voice tremor, a strong and usually autosomal dominant family history and improvement with alcohol all favor a diagnosis of ET. In contrast, clear asymmetry, the presence of bradykinesia or rigidity, and leg tremor support a diagnosis of PD. References 1. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998;13 Suppl 3:2-23. 2. Cohen O, Pullman S, Jurewicz E, Watner D, Louis ED. Rest tremor in patients with essential tremor: prevalence, clinical correlates, and electrophysiologic characteristics. Arch Neurol 2003;60: 3. Chaudhuri KR, Buxton-Thomas M, Dhawan V, Peng R, Meilak C, Brooks DJ. Long duration asymmetrical postural tremor is likely to predict development of Parkinson’s disease and not essential tremor: clinical follow up study of 13 cases. J Neurol Neurosurg Psychiatry 2005;76:115-7. Deuschl G, et al. Mov Disord 1998;13(Suppl 3):2-23. Chaudhuri KR, et al. J Neurol Neurosurg Psychiatry 2005;76:115-7.

32 Clinical Evaluation – Scales and Scores
Section I Clinical Evaluation – Scales and Scores

33 Section I Parkinson’s Disease Scales and Scores – Hoehn and Yahr Staging of Parkinson’s Disease Stage One 1.  Signs and symptoms on one side only 2.  Symptoms mild 3.  Symptoms inconvenient but not disabling 4.  Usually presents with tremor of one limb 5.  Friends have noticed changes in posture, locomotion and facial expression Stage Two 1.  Symptoms are bilateral 2.  Minimal disability 3.  Posture and gait affected Stage Three  1. Significant slowing of body movements  2. Early impairment of equilibrium on walking or standing  3. Generalised dysfunction that is moderately severe  Stage Four  1.  Severe symptoms   2.  Can still walk to a limited extent   3.  Rigidity and bradykinesia  4.  No longer able to live alone 5.  Tremor may be less than earlier stages Stage Five  1.  Cachectic stage  2.  Invalidism complete 3.  Cannot stand or walk  4.  Requires constant nursing care There are three “major” scales to evaluate PD: the Hoehn and Yahr (HY) staging scale and the Schwab and England Activities of Daily Living scale which rank PD severity, and the Unified Parkinson’s Disease Rating Scale (UPDRS) which is a rating tool to follow the longitudinal course of PD. The HY scale has been largely supplanted by the UPDRS. Nevertheless, it remains useful for demographic presentation of patient groups. In research settings, the HY scale is primarily useful for defining inclusion/exclusion criteria. Although a modified HY scale is widely used, this adaptation has not undergone clinimetric testing. The original five-point scale should, therefore, be maintained.1,2 References 1. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967;17: 2. Goetz CG, Poewe W, Rascol O, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 2004;19: Hoehn MM, Yahr MD. Neurology 1967;17:

34 Section I Parkinson’s Disease Scales and Scores – Schwab and England Activities of Daily Living 100% – Completely independent. Able to do all chores without slowness, difficulty or impairment. 90% – Completely independent. Able to do all chores with some slowness, difficulty or impairment. May take twice as long. 80% – Independent in most chores. Takes twice as long. Conscious of difficulty and slowing. 70% – Not completely independent. More difficulty with chores. Three to four times as long on chores for some. May take large part of day for chores. 60% – Some dependency. Can do most chores, but very slowly and with much effort. Errors. Some chores impossible. 50% – More dependent. Help with 1/2 of chores. Difficulty with everything. 40% – Very dependent. Can assist with all chores, but do few alone. 30% – With effort, now and then does a few chores alone or begins alone. Much help needed. 20% – Nothing alone. Can do some slight chores with some help. Severe invalidity. 10% – Totally dependent, helpless. 0% – Vegetative functions such as swallowing, bladder and bowel function are not functioning. Bedridden. The Schwab and England scale reflects the patient’s ability to perform daily activities in terms of speed and independence. Rating can be assigned by rater or by patient.1 Reference 1. Gillingham FJ, Donaldson MC, eds. Third Symposium of Parkinson's Disease. Edinburgh, Scotland: E&S Livingstone; 1969:152-7. Gillingham FJ, Donaldson MC, eds. Third Symposium of Parkinson’s Disease. Edinburgh, Scotland: E&S Livingstone; 1969:152-7.

35 Section I Parkinson’s Disease Scales and Scores – Unified Parkinson’s Disease Rating Scale (UPDRS) Mentation, Behaviour, Mood Non-motor symptoms with one question on intellect, one on thought disorders, one on depression, and one on motivation Activities of Daily Living (ADL) 13 questions, almost all about motor symptoms Two questions on salivation (autonomic function) and sensory complaints Motor Examination Motor symptoms Treatment Complications Yes/no questions on anorexia, nausea, vomiting and sleep The Unified Parkinson’s Disease Rating Scale (UPDRS) is a rating tool devised to follow the longitudinal course of PD. It is the most widely used scale. The UPDRS was introduced in 1987 as an overall assessment scale to quantify all motor and behavioural aspects of the disease as a single number, thereby easily enabling physicians to assess the worsening or improvement of PD with treatment and time. This scale is, therefore, widely used in clinical research and drug trials. The UPDRS includes an evaluation of self-reported disability (activities of daily living [ADL]) as well as clinical scoring by a physician (motor examination). However, the UPDRS focuses mostly on motor features. The UPDRS is made up of four sections: 1) mentation, behaviour and mood; 2) activities of daily living; 3) motor examination; and 4) treatment complications. These are evaluated by interview. Some sections require multiple grades assigned to each extremity.1 Reference 1. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 2003;18: A total of 199 points are possible, with 199 representing total disability and 0 meaning no disability Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. Mov Disord 2003;18:

36 Section I Disease Burden

37 Burden of Parkinson’s Disease
Section I Burden of Parkinson’s Disease Reduced quality of life1 Higher susceptibility to depression and cognitive impairment2 Increased risk for comorbidities such as pneumonia2 Increased medical expenses (physician visits and emergency care)2 Caregiver burden and risk of early nursing home placement2,3 Both generic and disease-specific quality-of-life instruments show that the motor symptoms of PD have a very strong impact on patient quality of life. PD can severely limit the activities of daily living, especially in the later stages of the disease.1 In addition to the physical challenges of the disease, many patients experience cognitive difficulties and other neuropsychiatric conditions, such as depression and, in advanced disease, dementia.2 Patients with PD are subject to comorbidities secondary to the disease, such as aspiration pneumonia, which may contribute to increased mortality.3 Because PD progresses slowly, patients often live with the disease for an extended period of time. This can mean large accumulated medical expenses incurred as a result of medication costs, increased physician visits and emergency care. One estimate for total direct costs in the US is $10,168 per patient per year.1 This estimate does not include the indirect costs, such as caregiver loss of work. The burden on the caregiver can be great, especially for an elderly spouse, and result in early nursing home placement.3 In a study of 380 spouse caregivers of patients with PD, it was found that depression was significantly increased in the caregiver by the time the patient reached Stage 4/5. Indeed, all aspects of caregiver strain (e.g. worry, tension, lack of resources) significantly increased with the patient’s increased disease severity.4 References 1. Dodel RC, Berger K, Oertel WH. Health-related quality of life and healthcare utilization in patients with Parkinson’s disease. Pharmacoeconomics 2001;19: 2. Siderowf A. Parkinson’s disease: clinical features, epidemiology, and genetics. Neurol Clin 2001;19: 3. Parashos SA, Maraganore DM, O’Brien PC, et al. Medical services utilization and prognosis in Parkinson disease: a population-based study. Mayo Clin Proc 2002;77: 4. Carter JH, Stewart BJ, Archbold PG, et al. Living with a person who has Parkinson’s disease: the spouse’s perspective by stage of disease. Parkinson’s Study Group. Mov Disord 1998;13:20-8. 1. Dodel RC, et al. Pharmacoeconomics 2001;19: 2. Parashos SA, et al. Mayo Clin Proc 2002;77: 3. Carter JH, et al. Mov Disord 1998;13:20-8.

38 Section I Section I – Conclusion Parkinson’s disease affects about 1% of adults over the age of 60. Clinical features: Motor symptoms define the disorder: bradykinesia, rigidity and rest tremor. Non-motor symptoms: autonomic dysfunction, cognitive and other psychiatric changes, sensory symptoms and sleep disturbances. Therapeutic challenge The diagnosis of Parkinson’s disease is clinical but can be supported in certain circumstances with SPECT imaging. Parkinson’s disease is a complex, multifactorial disease. Several genetic causes have been characterised and appear to result in downstream effects that include abnormal free radical metabolism, defective mitochondrial function, and dysfunction of the ubiquitin proteasomal system. The determination of mechanisms of dopamine neurons has major consequences on the development of drugs slowing cell degeneration and improving symptomatology. PD is the most common neurodegenerative disorder in the world after Alzheimer’s disease, affecting about 1% of the population over the age of 60. The initial clinical features of PD result from the loss of dopaminergic neurons in the substantia nigra pars compacta of the midbrain. As the disease progresses, the involvement of additional brain areas in the degenerative process produces predominantly non-dopaminergic, non-motor features. The management of non-motor symptoms usually represents a major therapeutic challenge to clinicians. The diagnosis of PD is mainly clinical but can be established in certain circumstances with the help of SPECT imaging. PD is a complex, multifactorial and aetiologically heterogeneous disorder. Several genetic causes have been characterised and appear to result in downstream effects that include abnormal free radical metabolism, defective mitochondrial function, and dysfunction of the ubiquitin proteasomal system. Insights into understanding the exact mechanisms of neuronal death are key to the development of drugs aimed at slowing disease progression and improving patient symptoms, outcome and quality of life.

39 Section II Treatment of Parkinson’s Disease

40 Section II – Summary General Principles
Drug Therapy in Parkinson’s Disease Surgery Management of Non-Motor Symptoms Disease Modification (Neuroprotection) Physical Therapy Future Treatments

41 Section I General Principles

42 General Principles for the Treatment of Parkinson’s Disease
Section I General Principles for the Treatment of Parkinson’s Disease Accurate and early diagnosis: an opportunity for coherent long-term treatment strategy Diagnostic accuracy as high as 98.5% based on clinical criteria alone Single photon emission computed tomography (SPECT) useful to differentiate PD from essential tremor Purpose of treatment: Symptomatic treatment of motor features Prevention of motor complications Symptomatic control of motor complications Symptomatic treatment of non-motor features Prevention of disease progression: disease modification (neuroprotection) The treatment of PD comprises several stages and different treatment modalities, namely drugs, surgical interventions and physical therapy, to address the following needs: prevention of disease progression (rationale for early drug therapy1), symptomatic treatment of motor features (parkinsonism), prevention and symptomatic control of motor complications, and symptomatic treatment of non-motor features.1,2 The treatment strategy is conditional upon the natural progression of the disease, the array of symptoms (motor and non-motor), and the early and late side effects associated with therapeutic interventions. At present, it is not possible to identify individuals with presymptomatic PD with any degree of certainty. Positron emission tomography (PET) scans, single photon emission computed tomography (SPECT), and detection through defective olfactory sense cannot yet be considered screening tools.2 Therefore, PD can currently be diagnosed only when the patient first manifests clinical features. The diagnostic accuracy of PD can reach 98.5% based on clinical criteria alone.3 This diagnosis can be supported, when necessary, by SPECT or PET scans. Accurate and early diagnosis of PD offers the patient and physician an opportunity to develop the foundations for a coherent long-term treatment strategy. References 1. Schapira AHV, Olanow CW. The medical management of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 2002;359: 3. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002;125: Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005. Hughes AJ, et al. Brain 2002;125:

43 Evidence on Efficacy of Treatment Interventions
Section I Evidence on Efficacy of Treatment Interventions Category evaluated Levodopa COMT inhibitors MAO-B inhibitors Anticholinergics & amantadine Dopamine agonists (details on slide 70) Monotherapy in early PD NA √ (pramipexole, ropinirole, pergolide) Combination with levodopa in advanced PD √(MF) ? √ (pramipexole, bromocriptine, cabergoline, pergolide) Treatment of motor complications - √ (D; amantadine) - (MF) Prevention of motor complications - (D) ? (MF) √ (pramipexole, ropinirole, cabergoline) Imaging indicates slowed loss of dopamine neurons -(?) √ (pramipexole, ropinirole) This table summarises the evidence on the efficacy of therapeutic intervention in the management of PD on the basis of the evidence-based review1 and update2 of the Movement Disorder Society and the 2006 European Federation of Neurological Societies guidelines.3,4 The findings of the Later Levodopa Therapy in Parkinson’s Disease (ELLDOPA) study5 were also reviewed with regard to levodopa and disease modification. This study shows conflicting data when neuroimaging and clinical outcome measures are examined. Clinical data suggest that levodopa either slows the progression of PD or has a prolonged effect on PD symptoms, whereas neuroimaging supports either the acceleration of nigrostriatal dopamine neuronal loss or the modification of dopamine transporter. Consequently, until more evidence is available, physicians are encouraged to customise levodopa doses to the needs of the individual patient based on clinical response and adverse events. This strategy also constitutes part of the rationale for initiating treatment in younger PD patients with dopamine agonists having potential neuroprotective activity (e.g. pramipexole and ropinirole), although the clinical beneficial effect remains to be confirmed. (Detailed results for dopamine agonists are displayed on slide 70.) References 1. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 2002;359: 2. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to Mov Disord 2005;20: 3. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006;13: 4. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES). Part II: late (complicated) Parkinson’s disease. Eur J Neurol 2006;13: 5. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351: √ efficacious (maximum strength of evidence) ± probably efficacious - not efficacious ? insufficient data 0 no studies D dsykinesias MF motor fluctuations COMT catechol-O-methyltransferase MAO-B monoamine oxidase B DAs dopamine agonists Rascol O, et al. Lancet 2002;359: Goetz CG, et al. Mov Disord 2005;20: Fahn S, et al. N Engl J Med 2004;351: Horstink M, et al. Eur J Neurol 2006;13: Horstink M, et al. Eur J Neurol 2006;13: 43

44 Drug Therapy in Parkinson’s Disease
Section I Drug Therapy in Parkinson’s Disease

45 Drug Therapy in Parkinson’s Disease – Summary
Section I Drug Therapy in Parkinson’s Disease – Summary Therapeutic Approaches and Strategies Levodopa Efficacy Management of motor complications Dopamine Agonists Clinical pharmacology Tolerability Other Drug Therapies for Parkinson’s Disease MAO-B* inhibitors Anticholinergics Amantadine * Monoamine oxidase B

46 Drug Therapy in Parkinson’s Disease
Section I Drug Therapy in Parkinson’s Disease Therapeutic Approaches and Strategies

47 Drug Therapy in Parkinson’s Disease – Initiation
Section I Drug Therapy in Parkinson’s Disease – Initiation Traditionally When symptoms interfere with social, domestic or professional life Patient judgment Physician advice to prevent: Unnecessary prolongation of disability Impaired quality of life Alternative approach Consider advantages of early treatment Symptomatic relief of motor symptoms Improvement of quality of life Avoidance of irreversible motor programme loss Potential disease modification (neuroprotection) with some agents Delay levodopa therapy and use alternatives to avoid or delay motor complications Traditionally, drugs for PD have been considered only for symptomatic relief. Their initiation has, therefore, been conditional upon PD symptom interference with social, domestic or occupational activities.1 In this approach, the patient best judges when to initiate medical treatment, although physician evaluation of inappropriate reluctance to start medication—reluctance that may result in the unnecessary prolongation of the disability and impaired quality of life—is a must. However, a gradual understanding of the exact mechanisms of neurodegeneration in PD and the perspective of slowing disease progression have prompted a re-evaluation of this traditional approach with respect to whether treatment should be offered at diagnosis and, if so, which agent should be used initially. Indeed, the potential advantages of early pharmacological therapy are symptomatic relief and disease modification (neuroprotection).2 In addition, regardless of any neuroprotective effect, delaying symptomatic therapy may result in an irreversible loss of motor programmes.3 References 1. Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med 2005;353: 2. Schapira AHV, Olanow CW. The medical management of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 3. Schapira AH, Obeso J. Timing of treatment initiation in Parkinson’s disease: a need for reappraisal? Ann Neurol 2006;59: Nutt JG, Wooten GF. N Engl J Med 2005;353: Schapira AH, Obeso J. Ann Neurol 2006;59:

48 Drug Therapy – Symptomatic Treatment of Motor Symptoms
Section I Drug Therapy – Symptomatic Treatment of Motor Symptoms Dopaminergic agents Levodopa Levodopa + carbidopa Levodopa + benserazide COMT inhibitors* (entacapone, tolcapone) Dopamine agonists Non-ergot† Pramipexole Ropinirole Rotigotine Piribedil Ergot Bromocriptine Pergolide Cabergoline Dihydroergocryptine Lisuride Selective MAO-B‡ inhibitors Selegiline Rasagiline Non-dopaminergic agents Anticholinergic agents: Trihexyphenidyl Benztropine NMDA§ antagonists Amantadine * catechol-O-methyltransferase inhibitors; always used in conjunction with levodopa † apomorphine is available for subcutaneous injections and may be useful in patients with levodopa-related motor fluctuations ‡ monoamine oxidase type-B § N-methyl-D-aspartate Pharmacological agents available for the symptomatic relief of the motor features of PD include levodopa, dopamine agonists, selective monoamine oxidase B (MAO-B) inhibitors, as well as anticholinergics and amantadine. Patient characteristics are the most important factors in the selection of initial drug therapy. The drug’s benefits should be weighed against potential short- and long-term side effects and complications. Anticholinergics can be used in young patients in whom tremor is the major symptom; however, the frequent side effects of these agents limit their usage, particularly in older patients. Amantadine has weak antiparkinsonian actions; nevertheless, it is sometimes considered for initial therapy.1 Consequently, although direct head-to-head comparisons of efficacy among these agents are lacking, clinical experience suggests that dopaminergic agents are more potent than the anticholinergics, amantadine and selective MAO-B inhibitors.2 American Academy of Neurology guidelines3 and the evidence-based review of the Movement Disorder Society4 suggest that initial therapy with levodopa or a dopamine agonist is a reasonable option. Dopamine agonists have the advantage of delaying the introduction of levodopa, allowing for a lower dose of levodopa when necessary (and thus preventing motor complications) and, in the case of pramipexole and ropinirole in particular, having a potential disease-modifying effect.5 In patients treated with levodopa, the routine adjuvant use of a dopa-decarboxylase inhibitor such as carbidopa or benserazide improves absorption. However, levodopa is still primarily metabolised in the gut by COMT which produces 3-O-methyldopa. Two selective COMT inhibitors are available for clinical use in the treatment of PD. These drugs exert a profound influence on levodopa kinetics by increasing its bioavailability and elimination half-life. This allows for more stable levodopa plasma levels to be obtained via the oral route and, conceivably, for more sustained brain dopaminergic stimulation to be attained.6 References 1. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004;363: 2. Nutt JG, Wooten GF. Clinical practice. Diagnosis and initial management of Parkinson’s disease. N Engl J Med 2005;353: 3. Miyasaki JM, Martin W, Suchowersky O, Weiner WJ, Lang AE. Practice parameter: initiation of treatment for Parkinson’s disease: an evidence-based review: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2002;58:11-7. 4. Management of Parkinson’s disease: an evidence-based review. Mov Disord 2002;17(Suppl 4):S1-166. 5. Schapira AHV, Olanow CW. The medical management of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 6. Nirenberg MJ and Fahn S. The role of levodopa and catechol-O-methyltransferase inhibitors. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.

49 Algorithm for the Management of Early Parkinson’s Disease
Section I Algorithm for the Management of Early Parkinson’s Disease Diagnosis Decision to treat YES Evaluate degree of disability Moderate motor disability No cognitive disability Begin dopamine agonist Treat to maximum response or tolerance of dopamine agonist Consider MAO-B inhibitor Disability requiring additional therapy NO Review Mild motor disability or MAO-B inhibitor * Additional symptomatic benefit required Begin dopamine agonist if not already started Titrate to maximum response or tolerance of dopamine agonist Begin levodopa 1, 2 3 1 2 4 Dopamine agonists are not recommended in patients with cognitive disturbance. Gradual dose escalation is important for patient compliance and maintaining motor control. Dopamine agonist dosage should be gradually increased over time in order to maintain motor control. Levodopa introduction is necessary in the majority of patients to maintain and optimise motor control. This algorithm provides clinicians with a practical approach to the management of early PD.1 The decision as to when to treat is considered in slide 47. Reference 1. Schapira AHV, Olanow CW. The medical management of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. Adapted from Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005:127. © 2005, with permission from Elsevier. * Monoamine oxidase B

50 Section I The Basis for Symptomatic Drug Therapy of Motor Symptoms in Parkinson’s Disease Abbreviations: DDC, dopa decarboxylase; TH, tyrosine hydroxylase; L-DOPA, levodopa; MAO-A, monoamine oxidase A; MAO-B, monoamine oxidase B; COMT, catechol-O-methyltransferase; D, dopamine receptors; 3-OMD, 3-O-methyldopa Dopamine transporter Postsynaptic terminal in the striatum Synaptic vesicle Dopamine L-DOPA Tyrosine MAO-A TH DDC Presynaptic terminal from the substantia nigra D Blood-brain barrier 3-OMD Entacapone Benzerazide Carbidopa COMT Moclobemide Selegiline Rasagiline Lazabemide Safinamide MAO-B Glial cell Astrocyte Schematically, motor features in PD are explained by a model in which the striatum plays a key role in the cerebral motor pathways. The degeneration of dopaminergic nigrostriatal neurons results in the disruption of dopamine striatal modulation and abnormal motor functions.1 Based on this model, increasing dopamine stimulation or reducing cholinergic or glutamatergic stimulation improves symptoms. This figure illustrates dopamine synthesis and catabolism and provides the rationale for drug therapies aimed at the symptomatic treatment of motor symptoms.2 Dopamine synthesis proceeds as follows: catalysis of tyrosine via tyrosine hydroxylase to levodopa and the subsequent decarboxylation of levodopa via dopa decarboxylase to produce dopamine. Dopamine is metabolised by intraneuronal monoamine oxidase A (MAO-A) and by glial and astrocyte MAO-A and MAO-B. Because dopamine cannot cross the digestive barrier, its levogyral precursor, levodopa, is used in therapy. After oral administration and intestinal absorption, levodopa, unlike dopamine, crosses the blood-brain barrier. Levodopa is then captured by the terminals of the surviving nigrostriatal neurons and also probably by the microglia and serotoninergic neurons. Levopoda is decarboxylated to dopamine. Released dopamine binds to the dopaminergic receptors after reuptake into the presynaptic nigrostriatal terminals. Finally, dopamine is metabolised via auto-oxidation by MAO-B and by catechol-O-methyltransferase. References 1. DeLong MR. Primate models of movement disorders of basal ganglia origin. Trends Neurosci 1990;13:281-5. 2. Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 2006;7: Adapted by permission from Macmillan Publishers Ltd: Youdim MB, et al. Nat Rev Neurosci 2006;7: © 2006.

51 Section I Main Mechanisms of Action of Therapeutic Interventions in Parkinson’s Disease Action Drugs Promote dopamine synthesis Activate specific receptors Prolong dopamine availability Prolong levodopa bioavailability Dopaminergic Levodopa DAs MAO-B inhibitors COMT inhibitors Antiglutamatergic Amantadine* Anticholinergic† Trihexyphenidyl Benztropine Surgery Lesion Thalamotomy Pallidotomy Subthalamic nucleotomy DBS Thalamus Pallidum Subthalamic nucleus Transplantation‡ Foetal mesencephalic cells Rehabilitation procedures Physical therapy Occupational therapy Speech therapy As this table shows, there are three main therapeutic options available for the management of patients with PD: pharmacological therapy, surgery and rehabilitation techniques.1,2 The available pharmacological agents in each category are listed below. DDIs (dopa decarboxylase inhibitors): benserazide, carbidopa DAs: non-ergot: pramipexole, ropinirole, rotigotine, apomorphine, piribedil ergot: bromocriptine, cabergoline, pergolide, lisuride MAO-B inhibitors: selegiline, rasagiline COMT inhibitors: entacapone, tolcapone Anticholinergics: benztropine, biperiden, orphenadrine, procyclidine, trihexyphenidyl References 1. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 2002;359: 2. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to Mov Disord 2005;20: Abbreviations: DAs, dopamine agonists; MAO-B, monoamine oxidase B; COMT, catechol-O-methyltransferase; DBS, deep brain stimulation * mechanism of action not fully known, the antiglutamatergic action being only part of the drug's effect † only drugs commonly used are listed ‡ experimental Rascol O, et al. Lancet 2002;359: Goetz CG, et al. Mov Disord 2005;20:

52 Drug Therapy in Parkinson’s Disease
Section I Drug Therapy in Parkinson’s Disease Levodopa

53 Levodopa in the Management of Parkinson’s Disease (1)
Section I Levodopa in the Management of Parkinson’s Disease (1) First of the dopaminergic drugs Used since late 1960s1 Highly effective drug Relatively rapid relief2 of bradykinesia, rigidity and associated pain Reduces tremor in many patients Levodopa improves quality of life3 and life expectancy4 in patients with PD Levodopa was the first dopaminergic drug to be introduced and remains the "gold standard" against which the efficacy of other drugs is evaluated. Levodopa is a highly effective drug for controlling the symptoms of Parkinson’s disease. It and the other dopaminergic agents improve the quality of life1 and life expectancy2 of PD patients. Levodopa has been used since the late 1960s, when it was established as the single most effective agent for the control of symptoms in PD.3 Levodopa has a relatively rapid onset of action: after absorption in the duodenum, it is transported across the gut wall by a saturable facilitated carrier system.4 References 1. Rajput AH. Levodopa prolongs life expectancy and is non-toxic to substantia nigra. Parkinsonism Relat Disord 2001;8: 2. Karlsen KH, Tandberg E, Arsland D, Larsen JP. Health related quality of life in Parkinson’s disease: a prospective longitudinal study. J Neurol Neurosurg Psychiatry 2000;69:584-9. 3. Tolosa E, Martí MJ, Valldeoriola F, Molinuevo JL. History of levodopa and dopamine agonists in Parkinson’s disease treatment. Neurology 1998:50(Suppl 6):S2-S10. 4. Stacy M. Pharmacotherapy for advanced Parkinson’s disease. Pharmacotherapy 2000;20(Suppl):8S-16S. 1. Tolosa E, et al. Neurology 1998;50(Suppl 6):S2-10. 2. Stacy M. Pharmacotherapy 2000;20(Suppl):8S-16S. 3. Rajput AH. Parkinsonism Relat Disord 2001;8: 4. Karlsen KH, et al. J Neurol Neurosurg Psychiatry 2000;69:584-9.

54 Levodopa in the Management of Parkinson’s Disease (2)
Section I Levodopa in the Management of Parkinson’s Disease (2) Must be metabolised to dopamine to be effective1 Addition of dopa decarboxylase inhibitors (DDIs) (benserazide, carbidopa) is required to limit additional peripheral side effects1 Absorption delayed or diminished by large neutral amino acids or agents that slow transit time, antacids and anticholinergics1,2 Short half-life causes pulsatile stimulation of dopamine receptors3 To be effective in controlling the symptoms of PD, levodopa must first be converted to dopamine.1 Dopa decarboxylase and catechol-O-methyltransferase (COMT), the primary enzymes responsible for the metabolism of levodopa, are distributed widely throughout the body.1,2 Effective therapy with levodopa requires the addition of peripheral dopa decarboxylase inhibitors that do not cross the blood-brain barrier such as benserazide and carbidopa; these agents block the conversion of levodopa to dopamine. Benserazide and carbidopa allow for a four- to fivefold levodopa dose reduction and, therefore, for a decrease in levodopa-related peripheral side effects, i.e. anorexia, nausea and vomiting.1 Absorption of levodopa can be delayed or diminished by amino acids in protein meals.1 Because levodopa has such a short half-life, patients may experience a pulsatile, rather than continuous, stimulation of dopamine receptors.3 References 1. Jankovic J. Levodopa strengths and weaknesses. Neurology 2002;58(Suppl 1):S19-32. 2. Deleu D, Northway MG, Hanssens Y. Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson’s disease. Clin Pharmacokinet 2000;41: 3. Olanow CW, Stocchi F. Why delaying levodopa is a good treatment strategy in early Parkinson’s disease. Eur J Neurol 2000;7(Suppl 1):3-8. 1. Jankovic J. Neurology 2002;58(Suppl 1):S19-32. 2. Deleu D. Clin Pharmacokinet 2002;41: 3. Olanow CW, Stocchi F. Eur J Neurol 2000;7(Suppl 1):3-8.

55 Levodopa in the Management of Parkinson’s Disease (3)
Section I Levodopa in the Management of Parkinson’s Disease (3) Levodopa induces motor complications Up to 80% of PD patients suffer from motor fluctuations and dyskinesias after approximately 5 to 10 years of treatment with levodopa1 50 to 75% of patients develop motor fluctuations 3 to 6 years after initiating therapy2-4 70% of young-onset PD patients develop motor complications after 3 years5 There is some controversy regarding what constitutes optimal early pharmacological management of PD and when levodopa should be introduced. The potential contribution of dopamine to the acceleration of disease progression through the formation of toxic free radicals and the later development of drug-related motor complications are issues of concern.1 Over time, increasing amounts of levodopa are administered in order to minimise the progression of functional disability. The duration of levodopa response becomes increasingly shorter, with patients experiencing motor fluctuations and dyskinesia as the therapeutic window narrows.1-7 Dyskinesias develop at a rate of approximately 10% per annum although this rate is much greater in young-onset PD patients, 70% of whom will develop dyskinesias within three years of levodopa initiation.8 References 1. Fahn S. Controversies in the therapy of Parkinson’s disease. Adv Neurol 1996;69: 2. Stacy M. Pharmacotherapy for advanced Parkinson’s disease. Pharmacotherapy 2000;20:S8-16. 3. Lang AE, Lozano AM. Parkinson’s disease. Second of two parts. N Engl J Med 1998;339: 4. Obeso JA, Olanow W, Nutt JG. Levodopa motor complications in Parkinson’s disease. Trends Neurosci 2000;23(Suppl):S2-7. 5. Poewe WH, Wenning GK. The natural history of Parkinson’s disease. Neurology 1996;47(Suppl 3):S 6. Parkinson’s Study Group. Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP patients requiring levodopa. Ann Neurol 1996;39:37-45. 7. Olanow CW, Stocchi F. Why delaying levodopa is a good treatment strategy in early Parkinson’s disease. Eur J Neurol 2000;7(Suppl 1):3-8. 8. Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson's disease. Neurology 1991; 41(2 [Pt 1]):202-5. 1. Olanow CW, Stocchi F. Eur J Neurol 2000;7(Suppl 1):3-8. 2. Fahn S. Adv Neurol 1996;69: 3. Poewe WH, Wenning GK. Neurology 1996;47(Suppl 3):S 4. Parkinson Study Group. Ann Neurol 1996;39:37-45. 5. Kostic V, et al. Neurology 1991;41:202-5.

56 Causes of Treatment-Related Motor Complications in Parkinson’s Disease
Section I Causes of Treatment-Related Motor Complications in Parkinson’s Disease Pulsatile stimulation of dopamine receptors with short half-life drugs Progressive dopaminergic neuronal degeneration The mechanisms by which these motor complications develop are not completely understood. Pulsatile stimulation of dopamine receptors by short-acting agents, including levodopa, and the degree of striatal denervation have, however, been implicated.1 Reference 1. Obeso JA, Rodriguez-Oroz C, Chana P, Lera G, Rodriguez M, Olanow CW. The evolution and origin of motor complications in Parkinson's disease. Neurology 2000; 55(Suppl 4):S13-20. Obeso JA, et al. Neurology 2000;55(Suppl 4):S13-20.

57 Response to Levodopa and Progression of Parkinson’s Disease
Section I Response to Levodopa and Progression of Parkinson’s Disease Response Threshold Dyskinesia Threshold Time (h) Early PD Levodopa Clinical Effect 2 4 6 Response Threshold Time (h) 4 Dyskinesia Threshold 2 Moderate PD Clinical Effect Levodopa 6 Advanced PD Time (h) Clinical Effect Levodopa 2 4 6 Dyskinesia Threshold Response Threshold Long duration motor response Low incidence of dyskinesias Shorter duration motor response Increased incidence of dyskinesias Short duration motor response “On” time consistently associated with dyskinesias This slide depicts the induction of levodopa-related motor fluctuations over time. The development of motor fluctuations and dyskinesias appears to reflect a gradual narrowing of the therapeutic window for levodopa as the disease and treatment progress:1 The threshold level of levodopa exposure that is required to achieve a therapeutic response progressively increases. At the same time, the threshold level above which levodopa causes dyskinesias decreases. In patients with advanced PD, it may, therefore, become impossible to find a levodopa dose that has an antiparkinsonian effect without causing dyskinesias. Reference 1. Obeso JA, Olanow W, Nutt JG. Levodopa motor complications in Parkinson’s disease. Trends Neurosci 2000;23(Suppl):S2-7. Obeso JA, et al. Trends Neurosci 2000;23(Suppl):S2-7.

58 Management of Motor Fluctuations
Section I Management of Motor Fluctuations Treatment options Increase the frequency of dose administration (e.g. change from t.i.d. levodopa to q.i.d. levodopa, with the last dose during the day rather than at bedtime) Useful in short but not long term Maintain levodopa and Add a dopamine agonist Add a COMT inhibitor Add a MAO-B inhibitor Levodopa dose may need modification depending on patient response Surgery Continuous infusion of carbidopa-levodopa for rescue therapy Motor fluctuations (“wearing-off” or “on-off” phenomenon) are due to a) the loss of effectiveness of a given dose of a dopaminergic agent and b) the emergence of the primary motor features of PD (bradykinesia and rigidity) that still remain responsive to dopaminergic treatment. The mechanisms by which motor fluctuations (and dyskinesia, the other motor complication of dopaminergic therapy) develop are not completely understood. However, pulsatile stimulation of dopamine receptors by short-acting agents, particularly levodopa, and the degree of striatal denervation have been implicated.1 Motor fluctuations are markedly reduced by continuous administration of either levodopa or a dopamine agonist. However, this approach is not practical for the majority of patients. This slide shows the therapeutic approaches to motor fluctuations. Wearing-off effects frequently require an adjustment of the dose and/or dose frequency, or the introduction of additional or alternative therapies. Controlled-release levodopa formulations have proved disappointing with often little improvement in the duration of response and unpredictable absorption and motor response. The simplest strategy is to increase the frequency of administration of levodopa; however, dosage regimens may require six or more administrations per day, a difficult dosing schedule for most patients. Therefore, the introduction of a dopamine agonist should be considered in levodopa-treated patients who experience motor fluctuations and in whom this treatment remains an option, i.e. patients with no significant cognitive disturbance. The adjuvant use of a dopamine agonist may also allow for a reduction in levodopa doses.2 Other options are adjunctive treatment with a COMT inhibitor or a MAO-B inhibitor. Surgery may be considered in patients refractory to medical treatment.3,4 In those patients in whom surgery is not an option, rescue therapy entails the administration of a liquefied carbidopa-levodopa solution prepared by dissolution of four 25/250 mg tablets into a litre of fluid; 1 mL of the solution yields 1 mg of levodopa, allowing patients to sip small doses at regular intervals.5 References 1. Obeso JA, Rodriguez-Oroz C, Chana P, Lera G, Rodriguez M, Olanow CW. The evolution and origin of motor complications in Parkinson’s disease. Neuroogy 2000:55(Suppl 4):S13-20. 2. Schapira AHV, Olanow CW. The medical management of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 3. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 2002;359: 4. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to Mov Disord 2005;20: 5. Djaldetti R, Melamed E. Management of response fluctuations: practical guidelines. Neurology 1998;51(2 Suppl 2):S36-40. Abbreviations: COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase B; t.i.d., ter in die; q.i.d., quater in die Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005. Rascol O, et al. Lancet 2002;359: Goetz CG, et al. Mov Disord 2005;20:

59 Management of Dyskinesias
Section I Management of Dyskinesias Treatment options for the management of peak-dose dyskinesias Administer fractionated levodopa doses (with or without increased total daily doses) in order to avoid peak plasma levodopa concentrations Useful in short but not long term Or, reduce levodopa dose and Increase dopamine agonist dose Add a dopamine agonist if not already used Surgery As for motor fluctuations, the mechanisms by which dyskinesias develop are not completely understood. However, pulsatile stimulation of dopamine receptors by short-acting agents, including levodopa, and the degree of striatal denervation seem to be implicated.1 Dyskinesias, including chorea and dystonia, are involuntary movements predominantly induced by exposure to levodopa. Motor complications can be an important source of disability for some patients who alternate between “on” periods complicated by dyskinesias and “off” periods in which they suffer from severe parkinsonism.2 The practical management of dyskinesias depends on the severity of the involuntary movements and their relationship to the medication dosage schedule. Dyskinesias may occur at the time of maximal clinical benefit and peak levodopa concentration (peak-dose dyskinesias), at the onset and wearing-off of the levodopa effect (diphasic dyskinesias), or randomly. Peak-dose dsykinesias can be managed by fractionating levodopa doses to avoid peak concentrations. This practice may or may not require increased total daily doses.3 Alternative strategies include the adjunctive use of a dopamine agonist if the patient is not already taking such an agent and if the indication for a dopamine agonist is still valid. Long-acting dopamine agonists such as pramipexole are particularly useful in the management of dyskinesias, presumably because of their ability to provide more continuous dopaminergic stimulation, while avoiding rapid fluctuations in receptor stimulation.4 Amantadine may improve peak-dose dyskinesias. Diphasic dyskinesias are more difficult to manage. They are usually associated with lower plasma levodopa concentrations and may respond to higher levodopa doses for maintaining plasma concentrations above a critical level. When medical therapy fails in controlling dyskinesias, surgery may be an option. References 1. Obeso JA, Rodriguez-Oroz C, Chana P, Lera G, Rodriguez M, Olanow CW. The evolution and origin of motor complications in Parkinson’s disease. Neuroogy 2000:55(Suppl 4):S13-20. 2. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 2005;20: 3. Schapira AHV, Olanow CW. The medical management of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 4. Marco AD, Appiah-Kubi LS, Chaudhuri KR. Use of the dopamine agonist cabergoline in the treatment of movement disorders. Expert Opin Pharmacother 2002;3: Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005.

60 Drug Therapy in Parkinson’s Disease
Section I Drug Therapy in Parkinson’s Disease Dopamine Agonists

61 Dopamine Agonists in the Treatment of Parkinson’s Disease
Section I Dopamine Agonists in the Treatment of Parkinson’s Disease First-line therapy in early PD in younger patients Rare motor complications Delay the use of levodopa and related motor complications Good side-effect tolerance Avoid ergot dopamine agonists: rare but serious fibrotic reactions1,2 Agonist monotherapy can provide control of motor symptoms for several years in some patients2 Adjunctive treatment in more advanced PD4 Putative neuroprotection with some agents, particularly pramipexole3 and ropinirole4 Because dopamine agonists rarely cause dyskinesia and motor fluctuations,1,2 they are the preferred first-line initial treatment in younger PD patients.3-5 They are also indicated as adjunctive treatment in more advanced PD patients. In addition, there are impressive laboratory data demonstrating neuroprotective effects that might be capable of intervening independently of the dopamine receptor. The results from two clinical trials on pramipexole6 and ropinirole7 that assessed imaging endpoints suggest, but do not prove, a disease-modifying ability in PD patients. Although no direct comparison between the various dopamine agonists has been performed, their side-effect profiles seem to be similar. Non-ergot compounds such as pramipexole, ropinirole and rotigotine should be preferred over ergot-derived agonists. Long-term therapy with ergot-derived agonists is associated with rare but serious retroperitoneal, pulmonary and cardiac-valve fibrosis.8 References 1. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 2000;284: 2. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342: 3. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006;13: 4. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004;363: 5. Schapira AHV, Olanow CW. The medical management of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 6. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287: 7. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003;54: 8. Pritchett AM, Morrison JF, Edwards WD, Schaff HV, Connolly HM, Espinosa RE. Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2002;77: 1. Pritchett AM, et al. Mayo Clin Proc 2002;77: 2. Horstink M, et al. Eur J Neurol 2006;13: 3. Parkinson Study Group. JAMA 2002;287: 4. Whone AL, et al. Ann Neurol 2003;54:

62 Chemical Structures of Dopamine Agonists
Section I Chemical Structures of Dopamine Agonists Bromocriptine a-Dihydroergocryptine Cabergoline Lisuride Pergolide OH O HN CH3 Br H Non-ergot dopamine agonists N S Rotigotine Pramipexole Ropinirole NH2 H3CH2CH2CHN CH2CH2N(CH2CH2CH3)2 H N CH2CH2CH3 CH2SCH3 CON(CH2CH3)2 CONHCH2CH3 CH2CHCH2 CH2CH2CH2N(CH3)2 CH2CH(CH3)2 (CH3)2CH N H (CH3)2HC

63 Dopamine Receptor Nomenclature
Section I Dopamine Receptor Nomenclature D1 family receptor subtypes D1 D5 D2 family receptor subtypes D2 D3 D4 Localisation D1, D2 striatum and substantial nigra D3, D4 limbic brain areas D5 hippocampus, hypothalamus, parafascicular nucleus of the thalamus Dopamine agonists were introduced in clinical practice in the 1970s.1 Since then, progress in understanding the pharmacology of dopamine receptors has allowed for the development of these agents in clinical practice. Dopamine receptors were originally characterised by ligand specificity and coupling to adenylate cyclase (D1 and D2); the D1 class stimulates the adenylate cyclase pathway while the D2 class inhibits it.2 Currently, five human dopamine receptors have been identified and are classified into two main receptor families: D1 (receptor subtypes D1 and D5) and D2 (receptor subtypes D2, D3, and D4). D1 and D2 receptor activation produces synergistic effects.3,4 The selective D1 and D2 agonists are clinically effective because of the availability of endogenous dopamine in the neuron terminals. D1 and D2 receptors are mainly found in the striatum and the substantia nigra. The antiparkinsonian effects of most dopamine agonists are related to the stimulation of D2 receptors, whereas mixed D1/D2 agonist activity may be important for a full reversal of PD motor deficits.5 D3 and D4 receptors are more selectively associated with the limbic brain areas, which receive their dopamine input from the ventral tegmental area and is known to be associated with cognitive, emotional and endocrine functions.2 D5 receptors are expressed in the hippocampus, the hypothalamus and the parafascicular nucleus of the thalamus6 and thus might be involved in affective, neuroendocrine or pain-related aspects of dopaminergic functions. References 1. Calne DB, Teychenne PF, Claveria LE, Eastman R, Greenacre JK, Petrie A. Bromocriptine in Parkinsonism. Br Med J 1974;4:442-4. 2. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev 1998;78: 3. Smith LA, Jackson MJ, Al-Barghouthy G, Jenner P. The actions of a D-1 agonist in MPTP treated primates show dependence on both D-1 and D-2 receptor function and tolerance on repeated administration. J Neural Transm 2002;109: 4. Blanchet P, Bedard PJ, Britton DR, Kebabian JW. Differential effect of selective D-1 and D-2 dopamine receptor agonists on levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- exposed monkeys. J Pharmacol Exp Ther 1993;267:275-9. 5. Poewe W. Drug therapy: dopamine agonists. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 6. Ciliax BJ, Nash N, Heilman C, et al. Dopamine D(5) receptor immunolocalization in rat and monkey brain. Synapse 2000;37: Missale C, et al. Physiol Rev 1998;78: Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.

64 Dopaminergic Pathways
Section I Dopaminergic Pathways Caudate nucleus Putamen Nucleus accumbens Ventral tegmental area Amygdala Substantia nigra Dopamine is the principal neurotransmitter in three major neuronal systems in the midbrain: the nigrostriatal pathway, the mesolimbic system and the mesocortical pathway. Two of these pathways are of particular interest in PD with regard to pathology and therapeutic effects of dopaminergic medications. 1. The nigrostriatal pathway. Dopaminergic neurons originating in the substantia nigra send axons to the striatum (caudate + putamen). The striatum is involved in the control of motor function. D2 receptors are highly expressed postsynaptically in this region.1,2 2. The mesolimbic pathway. This pathway originates from the ventral tegmental area and projects to the limbic brain areas which encompass the nucleus accumbens and the amygdala. Limbic areas are associated with cognition and emotions. D3 receptors are preferentially localised in limbic brain areas where, perhaps, they affect reinforcement and reward.3 References 1. Mengod G, Martinez-Mir MI, Vilaro MT, Palacios JM. Localization of the mRNA for the dopamine D2 receptor in the rat brain by in situ hybridization histochemistry. Proc Natl Acad Sci USA 1989;86: 2. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev 1998;78: 3. Shafer RA, Levant B. The D3 dopamine receptor in cellular and organismal function. Psychopharmacology (Berl) 1998;135:1-16. mesolimbic pathway nigrostriatal pathway D3 receptor D2 receptor Missale C, et al. Physiol Rev 1998;78: Shafer RA, et al. Psychopharmacology (Berl) 1998;135:1-16.

65 Dopamine Agonists – Pharmacological Advantages
Section I Dopamine Agonists – Pharmacological Advantages Pharmacological profile of dopamine agonists Advantages over levodopa Direct dopamine-receptor stimulation No need for conversion to dopamine No interference with food for absorption Longer half-life compared with levodopa (pramipexole, ropinirole, rotigotine, pergolide, cabergoline) Putative neuroprotective action (pramipexole, ropinirole) Unlike levodopa, dopamine agonists act directly on postsynaptic dopamine receptors without the need for metabolic conversion to dopamine, storage and release in degenerating nigrostriatal nerve terminals. In addition, dopamine agonists decrease endogenous dopamine turnover, which is enhanced by levodopa, and is a potential source of increased neurotoxic free radials attributable to oxidation of accumulating dopamine.1 In vivo and clinical trials show conflicting results with regard to levodopa toxicity, however.2,3 Another advantage of dopamine agonists over levodopa in the treatment of PD is a significantly higher half-life. In primate PD models, long-acting dopamine agonists did not induce dyskinesias whereas drug-induced dyskinesia developed after exposure to levodopa or short-acting dopamine agonists.4 These findings suggest a reduced risk for the development of motor complications with the long-term treatment of long-acting dopamine agonists because of more continuous striatal dopamine receptor stimulation. In addition, in vitro and in vivo studies, including clinical studies on neuroimaging outcomes, suggest potential neuroprotective action of dopamine agonists, particularly pramipexole and ropinirole.5-7 References 1. Olanow CW. A radical hypothesis for neurodegeneration. Trends Neurosci 1993;16: 2. Agid Y, Olanow CW, Mizuno Y. Levodopa: why the controversy? Lancet 2002;360:575. 3. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351: 4. Bedard PJ, Gomez-Mancilla B, Blanchette P, Gagnon C, Falardeau P, DiPaolo T. Role of selective D1 and D2 agonists in inducing dyskinesia in drug-naive MPTP monkeys. Adv Neurol 1993;60:113-8. 5. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 2000;284: 6. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342: 7. Poewe W. Drug therapy: dopamine agonists. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.

66 Clinical Pharmacology of Dopamine Agonists
Section I Clinical Pharmacology of Dopamine Agonists Drug Dopamine receptor interaction Interaction with other receptors Half-life (h) NA 5-HTP Non-ergot Pramipexole D2 - 10 Ropinirole 6 Rotigotine D2 > D1 + 5-7 (td) Apomorphine D2/D1 0.5 (sc) Ergot Bromocriptine 3-6 Pergolide 15 Cabergoline 65 Dopamine agonists include ergot derivatives and non-ergot agents. The main clinical pharmacological properties of the compounds most commonly used are listed in the table.1-3 References 1. Poewe W. Drug therapy: dopamine agonists. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. Kyniyoshi S, Jankovic J. Dopamine agonists in Parkinson’s disease. In: Ebadi M, Pfeiffer RF, eds. Parkinson’s Disease. Boca Raton: CRC Press; 2005. 3. Jenner P. A novel dopamine agonist for the transdermal treatment of Parkinson’s disease. Neurology 2005; 65(2 Suppl 1):S3-5. All mentioned D2-family agonists have D3/D2 subtype affinity ratio > 1 except for bromocriptine. Abbreviations: NA, noradrenaline; 5-HT, 5-hydroxytryptophan; td, transdermal; sc, subcutaneous Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005. Kyniyoshi S and Jankovic J. In: Parkinson’s Disease; 2005. Jenner P. Neurology 2005;65(2 Suppl 1):S3-5.

67 Adjunct to levodopa (mg)
Section I Dopamine Agonists in the Treatment of Parkinson’s Disease – Mean Daily Dosage Drug Monotherapy (mg) Adjunct to levodopa (mg) Non-ergot Pramipexole Ropinirole 6-18 6-12 Rotigotine 4-8 - Apomorphine 1.5-6 (sc* bolus) Ergot Bromocriptine 25-45 15-25 Pergolide 0.75-5 Cabergoline 2-6 2-4 The average daily dose of dopamine agonists most commonly used in the treatment of PD are listed.1 Reference 1. Poewe W. Drug therapy: dopamine agonists. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. * subcutaneous Poewe W. In: Principles of Treatment in Parkinson’s Disease; 2005.

68 Clinical Importance of D2 Selectivity
Section I Clinical Importance of D2 Selectivity All dopamine agonists stimulate D2 receptors stimulation of D2 receptors is thought to mediate improvement of cardinal motor symptoms1 Stimulation of D1 receptors results in dyskinesias in experimental animal models2 Histological, electrophysiological and pharmacological studies support a dichotomy in D1 and D2 dopamine receptor function. D1 receptors preferentially seem to function on spiny neurons projecting directly into the pars reticulata of the substantia nigra and internal globus pallidus. D2 receptors mainly function on neurons that project indirectly into the internal globus via the external globus pallidus and subthalamic nucleus.1-6 All dopamine agonists stimulate D2 receptors, which are thought to mediate cardinal motor symptoms.7 Although D1 dopamine receptors also positively regulate motor symptoms, in animal models, D1 receptor stimulation results in dyskinesias.8 The exact impact of drug-specific interference with dopamine receptor subtype deserves, therefore, further study in terms of therapeutic benefits versus risk of motor complications. References 1. Gerfen CR, Engber TM, Mahan LC, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 1990;250: 2. Gerfen CR. The neostriatal mosaic: multiple levels of compartmental organization. Trends Neurosci 1992;15:133-9. 3. Robertson GS, Vincent SR, Fibiger HC. D1 and D2 dopamine receptors differentially regulate c-fos expression in striatonigral and striatopallidal neurons. Neuroscience 1992;49: 4. Anderson JJ, Chase TN, Engber TM. Differential effect of subthalamic nucleus ablation on dopamine D1 and D2 agonist-induced rotation in 6-hydroxydopamine-lesioned rats. Brain Res 1992;588: 5. Bergson C, Mrzljak L, Smiley JF, Pappy M, Levenson R, Goldman-Rakic PS. Regional, cellular, and subcellular variations in the distribution of D1 and D5 dopamine receptors in primate brain. J Neurosci 1995;15: 6. Wooten GF. Functional anatomical and behavioral consequences of dopamine receptor stimulation. Ann N Y Acad Sci 1997;835:153-6. 7. Guttman M, Jaskolka J. The use of pramipexole in Parkinson's disease: are its actions D(3) mediated? Parkinsonism Relat Disord 2001;7:231-4. 8. Fici GJ, Wu H, VonVoigtlander PF, Sethy VH. D1 dopamine receptor activity of anti-parkinsonian drugs. Life Sci 1997;60: 1. Guttman M, Jaskolka J. Parkinsonism Relat Disord 2001;7:231-4. 2. Fici GJ, et al. Life Sci 1997; 60:

69 Clinical Implications of D3 Preference
Section I Clinical Implications of D3 Preference D3 receptors in the mesolimbic dopamine system may be involved in cognition, mood and behaviour1,2 Preferential stimulation of D3 receptors (D3 preference) may explain the antidepressive and anti-anhedonic properties of dopamine agonists such as pramipexole3,4 D3 dopamine receptors have a different distribution than D1 and D2 receptors, preferentially existing in the limbic brain areas that include the nucleus accumbens and the amygdala. Limbic regions are associated with cognition and emotion, making D3 (and D4) receptors an attractive and promising target for new antidepressant and antipsychotic drugs with a low incidence of extrapyramidal side effects.1,2 Interestingly, pramipexole, a dopamine agonist with preferential D3 receptor stimulation activity, has been shown to possess significant antidepressant and anti-anhedonic properties, thus suggesting an important possible use in patients with PD who suffer from depression.2-4 References 1. Missale C, Nash SR, Robinson SW, Jaber M, Caron MG. Dopamine receptors: from structure to function. Physiol Rev 1998;78: 2. Willner P. The mesolimbic dopamine system as a target for rapid antidepressant action. Int Clin Psychopharmacol 1997;12 (Suppl 3):S7-14. 3. Guttman M, Jaskolka J. The use of pramipexole in Parkinson’s disease: are its actions D(3) mediated? Parkinsonism Relat Disord 2001;7:231-4. 4. Piercey MF. Pharmacology of pramipexole, a dopamine D3-preferring agonist useful in treating Parkinson’s disease. Clin Neuropharmacol 1998;21: 1. Guttman M, Jaskolka J. Parkinsonism Relat Disord 2001;7:231-4. 2. Missale C, et al. Physiol Rev 1998;78: 3. Piercey FM. Clin Neuropharmacol 1998;21: 4. Willner P. Int Clin Psychopharm 1997;12(Suppl 3):S7-14.

70 Section I Evidence on Efficacy of Dopamine Agonists in Patients With Parkinson’s Disease Evaluation of published studies according to evidence-based medicine criteria Category evaluated Bromocriptine Cabergoline Lisuride Pergolide Pramipexole Ropinirole Monotherapy in early PD ? Combination with L-Dopa in advanced PD Treatment of motor fluctuations Prevention of motor complications and dyskinesias Imaging indicates slowed loss of dopamine neurons This table summarises the results of a systematic review in which the available evidence concerning the indications for dopamine agonists in the management of PD was uniformly assessed.1-4 Monotherapy in early PD for symptomatic treatment of motor symptoms. Symptomatic control of motor symptoms in conjunction with levodopa. Symptomatic treatment of levodopa-induced motor complications (motor fluctuations and dyskinesias). Prevention of motor complications in terms of reducing the probability of developing motor complications for up to five years in previously untreated patients who received the evaluated drug versus levodopa-treated controls. Since the incidence of motor complications is 10% per year of levodopa therapy, this preventive ability is of the utmost importance. References 1. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 2002;359: 2. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to Mov Disord 2005;20: 3. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006;13: 4. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies (EFNS) and the Movement Disorder Society-European Section (MDS-ES). Part II: late (complicated) Parkinson’s disease. Eur J Neurol 2006;13: √ efficacious (maximum strength of evidence) ± probably efficacious ? insufficient data 0 no studies Rascol O, et al. Lancet 2002;359: Goetz CG, et al. Mov Disord 2005;2:523-39 Horstink M, et al. Eur J Neurol 2006;13: Horstink M, et al. Eur J Neurol 2006;13:

71 Section I Tolerability of Dopamine Agonists in Early Parkinson’s Disease – Main Adverse Events Adverse events (%) Nausea Somnolence Hallucinations CALM-PD1 Pramipexole 36.4 32.4 9.3 Levodopa 36.7 17.3 3.3 RQP 0562 Ropinirole 48.6 27.4 17 49.4 19.1 6 CBS 093 Cabergoline 37.4 26.5* 4.3 32.2 28.4* 4.8 * includes sleep problems and insomnia Currently available dopamine agonists share a variety of side effects with levodopa as a result of peripheral and central dopaminergic stimulation. Common peripheral dopaminergic sides effects of all dopamine agonists include nausea, vomiting, postural hypotension, dizziness, bradycardia and other effects related to stimulation of the peripheral autonomic system. Co-administration of the peripheral dopamine-receptor blocker domperidone (off-label use in the USA) can be used to counteract these symptoms. Daytime sedation is a side effect common to all dopaminergic agents, including levodopa. Patients must, therefore, be warned about driving. The table lists the frequency of the main side effects of dopamine agonists administered as monotherapy versus levodopa in randomised controlled trials. Since no direct comparison studies between the various agents have been performed, the data cannot be considered in a comparative approach.1-3 References 1. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 2000;284: 2. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342: 3. Rinne UK, Bracco F, Chouza C, et al. Early treatment of Parkinson’s disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group. Drugs 1998;55 (Suppl) 1:23-30. There are no head-to-head studies comparing the various agents: these data do not allow for direct comparisons of dopamine agonists. 1. Parkinson Study Group. JAMA 2000;284: 2. Rascol O, et al. N Engl J Med 2000;342: 3. Rinne UK, et al. Drugs 1998;55 (Suppl 1):23-30.

72 Valvular Regurgitation (%)
Section I Drug-Induced Valvular Heart Disease – Ergot versus Non-Ergot Dopamine Agonists 80 69** Peralta et al.1 Yamamoto et al.2 60 43* ** P < vs. controls Valvular Regurgitation (%) * P < vs. controls 40 31* 29 25 18 20 14 10 Ergot dopamine agonists have been associated with pleuropulmonary, retroperitoneal and cardiac-valve fibrosis. In particular, several studies and case reports suggest a causal relationship between drug-induced “restrictive” valvular heart disease and treatment with pergolide.1 Pergolide may induce fibrotic changes in the leaflets and subvalvular apparatus, causing thickening, retraction and stiffening of the valves and resulting in incomplete leaflet coaptation and valvular regurgitation.2 Valvular heart damage has also been reported with the ergot dopamine agonists bromocriptine and cabergoline.3 Recently, Peralta et al.4 assessed the frequency of valvular regurgitation by routine transthoracic echocardiography in 75 PD patients treated with pergolide (n = 29), cabergoline (n = 13), pramipexole or ropinirole (n = 33), and 49 age-matched nonparkinsonian control patients. Patients treated with pergolide and cabergoline had higher frequencies of valvular regurgitation grades 2 and 3 (31% and 47%, respectively) compared with age-matched controls (13%), while there was no difference in the frequency of valvular regurgitation grades 2 and 3 between patients treated with non-ergot compounds (10%) and controls. In a case-control study, Yamamoto et al.5 examined the occurrence of valvular heart disease as assessed by transthoracic echocardiography in 210 consecutive patients with PD. The frequency of valvulopathy was significantly higher in patients treated with cabergoline (68.8%, 11/16; affected patients/total) than in patients who did not receive any dopamine agonist (17.6%, 15/85). The adjusted odds ratio was significantly higher in the cabergoline-treated group (12.96, 95% CI* = 3.59 to 46.85), compared with the pergolide (2.18, 95% CI = 0.90 to 5.30) and pramipexole (1.62, 95% CI = 0.45 to 5.87) treatment groups. The cumulative dose and treatment duration of cabergoline in the valvulopathy subgroup were significantly higher than in the subgroup without valvulopathy. Overall, in PD patients, the available studies suggest increased frequency of valvular heart disease associated with ergot dopamine agonist therapy but not with non-ergot dopamine agonists. Further studies are needed to confirm these results. * confidence interval References Scozzafava J, Takahashi J, Johnston W, Puttagunta L, Martin WR. Valvular heart disease in pergolide-treated Parkinson’s disease. Can J Neurol Sci 2006;33: Van Camp G, Flamez A, Cosyns B, et al. Treatment of Parkinson’s disease with pergolide and relation to restrictive valvular heart disease. Lancet 2004;363: Kim JY, Chung EJ, Park SW, Lee WY. Valvular heart disease in Parkinson’s disease treated with ergot derivative dopamine agonists. Mov Disord 2006;21: Peralta C, Wolf E, Alber H, et al. Valvular heart disease in Parkinson's disease vs. controls: An echocardiographic study. Mov Disord 2006;21: Yamamoto M, Uesugi T, Nakayama T. Dopamine agonists and cardiac valvulopathy in Parkinson disease: a case-control study. Neurology ;67: Pergolide Cabergoline Pramipexole Ropinirole Controls 1. Peralta C, et al. Mov Disord 2006;21: 2. Yamamoto M, et al. Neurology 2006;67:

73 Drug Therapy in Parkinson’s Disease
Section I Drug Therapy in Parkinson’s Disease Other Drug Therapies for Parkinson’s Disease

74 Other Drug Therapies for Parkinson’s Disease
Section I Other Drug Therapies for Parkinson’s Disease Other dopaminergic agents MAO-B* inhibitors Compounds interacting with receptors other than dopaminergic receptors may be useful in some patients Anticholinergics Amantadine Although dopaminergic therapy—levodopa and dopamine agonists—is the most potent and definitive treatment of early Parkinson’s disease, other compounds interacting with receptors other than dopamine receptors may be useful in some patients.1,2 References 1. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004;363: 2. Cersosimo MG, Koller WC. Other drug therapies in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. * monoamine oxidase B Cersosimo MG, Koller WC. In: Principles of Treatment in Parkinson’s Disease; 2005.

75 Other Dopaminergic Agents – MAO-B* Inhibitors (1)
Section I Other Dopaminergic Agents – MAO-B* Inhibitors (1) Selegiline and rasagiline Selective MAO-B inhibitors; however, selectivity is lost at high doses Risk of tyramine-induced hypertension (the “cheese effect”) at high doses Symptomatic effect in Parkinson’s disease Neuroprotective effect in the laboratory Mechanisms of action Irreversible inhibition of MAO-B, which catalyses the oxidative deamination of neuroactive amines Prolongation of dopamine availability Possible enhancement of catecholaminergic neurons by other mechanisms Effect on mitochondrial membrane, anti-apoptotic effect and reduction of oxidative stress with potential neuroprotective properties Two compounds of the propargylamine group, selegiline and rasagiline, both irreversible MAO-B inhibitors, have demonstrated a symptomatic effect in PD patients and neuroprotective efficacy in the laboratory. The inhibition of MAO-B, which catalyses the oxidative deamination of neuroactive amines, results in the prolongation of dopamine activity. Selegiline and rasagiline are relatively selective MAO-B inhibitors; however, this selectivity is lost at high drug doses, i.e. selegiline > 20 mg/day and rasagiline > 2 mg/day, where MAO-A is also inhibited. Therefore, although low, there is a risk of tyramine-induced hypertension (the "cheese effect") at higher doses.1 These agents may enhance the activity of catecholaminergic neurons by mechanisms other than MAO-B inhibition. Other pharmacological activities such as effect on mitochondrial membrane potential activity, anti-apoptotic effect and antioxidant effect may explain potential neuroprotective effects seen in the laboratory.2 References 1. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson's disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006;13: 2. Cersosimo MG, Koller WC. Other drug therapies in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. * monoamine oxidase B Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. Horstink M, et al. Eur J Neurol 2006;13:

76 Other Dopaminergic Agents – MAO-B* Inhibitors (2)
Section I Other Dopaminergic Agents – MAO-B* Inhibitors (2) Selegiline Mild antiparkinsonian effect in de novo Parkinson’s disease No evidence that MAO-B inhibition delays the development of motor fluctuations other than through the delay in introducing levodopa and an ability to use a lower dose Rasagiline 10–15 times more potent than selegiline Antiparkinsonian effect comparable to selegiline: not as great as the dopamine agonists Less effective than dopamine agonists in reducing off-periods in patients optimised on levodopa Selegiline has been available for several years and been shown to be beneficial as adjunctive treatment for Parkinson’s disease.1 This compound appears to have a mild symptomatic effect in some PD patients. Although one study suggests that selegiline use might be associated with excess mortality,2 a recent large meta-analysis indicates that no such effect is evident and confirms the clinical efficacy of this drug in PD as evidenced by a UPDRS (United Parkinson’s Disease Rating Scale) score improvement of 2.7 points at three months.3 There is no evidence, at present, that MAO-B inhibition delays the development of motor fluctuations other than through the delay in introducing levodopa and an ability to use a lower dose. Rasagiline is a propargylamine and so is structurally related to selegiline. It is, however, approximately 10–15 times more potent. Rasagiline has been studied in patients with early PD.4 The degree of motor improvement is comparable to that seen for selegiline in the DATATOP study,5 but not as great as that seen for dopamine agonists. In stable PD patients already taking levodopa, rasagiline has been shown to improve PD control, particularly in reducing off-periods by approximately 0.5 hour.6,7 However, dopamine agonists appear to be more effective in this regard, with a 1–2 hour improvement in PD control in patients optimised on levodopa.8,9 References 1. Cersosimo MG, Koller WC. Other drug therapies in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. Lees AJ. Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson’s disease. Parkinson’s Disease Research Group of the United Kingdom. BMJ 1995;311: 3. Ives NJ, Stowe RL, Marro J, et al. Monoamine oxidase type B inhibitors in early Parkinson’s disease: meta-analysis of 17 randomised trials involving 3525 patients. BMJ 2004;329:593. 4. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004;61:561-6. 5. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. The Parkinson Study Group. N Engl J Med 1993;328: 6. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 2005;62:241-8. 7. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 2005;365: 8. Lieberman A, Ranhosky A, Korts D. Clinical evaluation of pramipexole in advanced Parkinson’s disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology 1997;49:162-8. 9. Lieberman A, Olanow CW, Sethi K, et al. A multicenter trial of ropinirole as adjunct treatment for Parkinson’s disease. Ropinirole Study Group. Neurology 1998;51: * monoamine oxidase B Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. Parkinson Study Group. Arch Neurol 2004;61:561-6.

77 Other Dopaminergic Agents – MAO-B* Inhibitors (3)
Section I Other Dopaminergic Agents – MAO-B* Inhibitors (3) Conclusion Mild to moderate symptomatic motor control in early Parkinson’s disease (PD) Not particularly effective for treating motor fluctuations Relatively safe drugs Overall, MAO-B inhibitors appear to provide only mild to moderate symptomatic control of PD and are not particularly effective in treating motor fluctuations. Although more potent drugs for controlling motor symptoms and motor complications are available, MAO-B inhibitors have a relatively safe profile and may be considered for use in the treatment of some PD patients.1,2 References 1. Cersosimo MG, Koller WC. Other drug therapies in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004;61:561-6. 3. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006 ;13: * monoamine oxidase B Horstink M, et al. Eur J Neurol 2006;13: Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. Arch Neurol 2004;61:561-6.

78 Non-Dopaminergic Antiparkinsonian Drugs – Anticholinergics
Section I Non-Dopaminergic Antiparkinsonian Drugs – Anticholinergics Mechanism of action: State of relative cholinergic sensitivity due to dopamine depletion Cholinergic drugs exacerbate and anticholinergic agents (e.g. trihexyphenidyl, benztropine) improve parkinsonian symptoms Typically used in younger patients with Parkinson’s disease in whom tremor is the major symptom However: Little data on potency and tolerance Common side effects that limit their usefulness Cognitive side effects: memory impairment, acute confusion, hallucinations, sedation, dysphoria Dyskinesias Peripheral antimuscarinic side effects: dry mouth, constipation, accommodation impairment, nausea, urinary retention, impaired sweating, tachycardia Contraindicated in patients with prostate hypertrophy, closed-angle glaucoma, tachycardia, gastrointestinal obstruction, megacolon Anticholinergics were used to treat the symptoms of Parkinson’s disease prior to the introduction of levodopa. Dopamine depletion in PD results in a relative state of cholinergic sensitivity whereby cholinergic drugs exacerbate and anticholinergic agents improve parkinsonian symptoms.1 Relatively little data are available on their potency and tolerance.2-4 Clinical trials have shown a modest benefit for anticholinergics in improving bradykinesia and rigidity,5-7 but at the expense of impaired cognitive function. Benztropine was equivalent to clozapine in producing a mild improvement in tremor.8 Although anticholinergic agents are typically used in younger PD patients in whom tremor is the major symptom, the many side effects limit their usefulness in practice, particularly in older patients.1,9,10 References 1. Cersosimo MG, Koller WC. Other drug therapies in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. Rascol O, Goetz C, Koller W, Poewe W, Sampaio C. Treatment interventions for Parkinson’s disease: an evidence based assessment. Lancet 2002;359: 3. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to Mov Disord 2005;20: 4. EFNS 2006 Guidelines. 5. Cantello R, Riccio A, Gilli M, et al. Bornaprine vs placebo in Parkinson disease: double-blind controlled cross-over trial in 30 patients. Ital J Neurol Sci 1986;7: 6. Martin WE, Loewenson RB, Resch JA, Baker AB. A controlled study comparing trihexyphenidyl hydrochloride plus levodopa with placebo plus levodopa in patients with Parkinson’s disease. Neurology 1974;24:912-9. 7. Cooper JA, Sagar HJ, Doherty SM, Jordan N, Tidswell P, Sullivan EV. Different effects of dopaminergic and anticholinergic therapies on cognitive and motor function in Parkinson’s disease. A follow-up study of untreated patients. Brain 1992;115: 8. Friedman JH, Koller WC, Lannon MC, Busenbark K, Swanson-Hyland E, Smith D. Benztropine versus clozapine for the treatment of tremor in Parkinson’s disease. Neurology 1997;48: 9. Samii A, Nutt JG, Ransom BR. Parkinson’s disease. Lancet 2004;363: 10. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006;13: Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. Samii A, et al. Lancet 2004;363: Horstink M, et al. Eur J Neurol 2006;13:

79 Non-Dopaminergic Antiparkinsonian Drugs – Amantadine
Section I Non-Dopaminergic Antiparkinsonian Drugs – Amantadine Mechanism of action Although the exact mechanism of action is not established, amantadine seems to have dopaminergic, anticholinergic and antiglutamatergic activities Mild and transitory improvement of parkinsonian symptoms More effective in the control of bradykinesia and rigidity than tremor Generally considered unsuitable for monotherapy in Parkinson's disease Mostly used as an adjunct Potential cognitive side effects also limit its use Amantadine has classically been described as having dopaminergic and anticholinergic activities, as well as antagonist activity at the N-methyl-D-aspartate (NMDA) glutamatergic receptors.1 Amantadine produces mild and transitory improvement in Parkinson’s disease symptoms, with benefits usually lasting 6 to 9 months,2 although some studies have suggested that in pure PD patients the effects are more long lasting.3 It is generally considered unsuitable for monotherapy in PD and is mostly used as an adjunct.4 Improvements in bradykinesia and rigidity are generally of the same order of magnitude as the anticholinergics, but their combination is additive.5,6 Amantadine use is also limited by its potential to induce cognitive defects. References 1. Cersosimo MG, Koller WC. Other drug therapies in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. Schwab RS, England AC, Jr., Poskanzer DC, Young RR. Amantadine in the treatment of Parkinson’s disease. JAMA 1969;208: 3. Horstink M, Tolosa E, Bonuccelli U, et al. Review of the therapeutic management of Parkinson’s disease. Report of a joint task force of the European Federation of Neurological Societies and the Movement Disorder Society-European Section. Part I: early (uncomplicated) Parkinson’s disease. Eur J Neurol 2006;13: 4. Factor SA, Molho ES. Transient benefit of amantadine in Parkinson’s disease: the facts about the myth. Mov Disord 1999;14:515-7. 5. Parkes JD, Baxter RC, Marsden CD, Rees JE. Comparative trial of benzhexol, amantadine, and levodopa in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry 1974; 37:422-6. 6. Walker JE, Albers JW, Tourtellotte WW, Henderson WG, Potvin AR, Smith A. A qualitative and quantitative evaluation of amantadine in the treatment of Parkinson’s disease. J Chronic Dis 1972;25: Cersosimo MG, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. Samii A, et al. Lancet 2004;363: Horstink M, et al. Eur J Neurol 2006;13:

80 Section I Surgery

81 Surgical Treatment for Parkinson’s Disease
Section I Surgical Treatment for Parkinson’s Disease Early 20th century First interventions directed at motor cortex and corticospinal tract Some success, particularly with regard to tremor Success complicated by motor paresis Ventrointermediate thalamotomy in the 1950s and 1960s Antitremor effects Currently Levodopa-induced motor complications Severe tremor Procedure-dependent results Surgical approaches to the treatment of PD were considered early in the 20th century. Initially, surgical interventions were directed at the motor cortex and corticospinal tract. They had some success, particularly with respect to tremor; however, they were discarded because of the occurrence of motor paresis. Subsequently, antiparkinsonian benefits without paralysis were reported after lesioning the globus pallidus and the ansa lenticularis.1 Other surgical techniques were then attempted, with the most striking antitremor effects observed with lesions placed in the ventrointermediate (VIM) nucleus of the thalamus; VIM thalamotomy was commonly performed in the 1950s and 1960s. With the advent of levodopa-based dopaminergic therapy, surgery was largely relegated to patients with severe tremor refractory to medication. However, the limitations of levodopa therapy, particularly the occurrence of motor complications (dyskinesias and motor fluctuations), have led to the resurgence of surgical therapy for PD in the past decade. Nevertheless, while drug therapy for PD has been studied in mild, moderate and advanced disease, surgery has been reserved only for patients with either severe motor impairment or levodopa-related motor complications. References 1. Meyers R. The modification of altering tremors, rigidity and festination by surgery of the basal ganglia. Res Publ Res Nerv Ment Dis 1942;21:602. 2. Olanow CW, Schapira AHV. Surgical approches to the treatment of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 3. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to Mov Disord 2005;20: Goetz CG, et al. Mov Disord 2005;20:

82 Surgical Procedures for Parkinson’s Disease
Section I Surgical Procedures for Parkinson’s Disease Ablative procedure Deep brain stimulation Restorative procedure Thalamotomy Unilateral pallidotomy Subthalamotomy VIM nucleus of thalamus GPi STN Cell-based therapies Human foetal nigral cells Porcine foetal nigral cells Retinal pigmented epithelial cells Stem cells Trophic factors Gene therapies Abbreviations: VIM, ventrointermediate; GPi, globus pallidus pars interna; STN, subthalamic nucleus In practice: Potential benefit for advanced disease not controlled with medical therapy Ablative procedures have been largely abandoned Effects not superior to optimised medical therapy Non-dopaminergic features not affected This table lists the surgical treatments that are currently being performed or tested in patients with PD. Surgery targets various brain regions. Because of the predominance of neuronal overactivity in the subthalamic nucleus (STN) and globus pallidus pars interna (GPi) in PD, deep brain stimulation (DPS) targets these two structures in particular. Some studies—cell transplantation studies for example—evaluate the possibility of replacing degenerated dopamine cells with foetal nigral dopaminergic neurons or stem cells, while others look to gene therapies for the delivery of trophic factors or other proteins with a potential to improve PD symptoms.1-3 In practice, the available evidence shows that surgery in PD is of potential benefit to patients with advanced disease which can no longer be adequately controlled with medical therapy.4,5 High-frequency DBS is largely preferred to ablative interventions because of significantly fewer side effects, particularly compared with bilateral procedures. The antiparkinsonian effects obtained with surgical procedures are usually not superior to optimised medical therapy and non-dopaminergic features are not corrected. The benefits reside mainly in the reduction of dyskinesia and a reduction of “off” periods. Restorative techniques remain mostly investigational. References 1. Olanow CW, Schapira AHV. Surgical approches to the treatment of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. Metman LV, O’Leary ST. Role of surgery in the treatment of motor complications. Mov Disord 2005;20 (Suppl 11):S45-56. 3. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP. Pallidal vs subthalamic nucleus deep brain stimulation in Parkinson disease. Arch Neurol 2005;62: 4. Goetz CG, Poewe W, Rascol O, Sampaio C. Evidence-based medical review update: pharmacological and surgical treatments of Parkinson’s disease: 2001 to Mov Disord 2005;20: 5. Pahwa R, Factor SA, Lyons KE, et al. Practice Parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66: Goetz CG, et al. Mov Disord 2005;20: Pahwa R, et al. Neurology 2006;66:

83 Management of Non-Motor Symptoms
Section I Management of Non-Motor Symptoms

84 Non-Motor Features of Parkinson’s Disease
Section I Non-Motor Features of Parkinson’s Disease Cognitive and other psychiatric symptoms Sleep disorders Autonomic dysfunctions (including gastrointestinal symptoms) Depression Cognitive decline Delirium, hallucinations, psychosis* Dementia Obsessional behaviour* Confusion Panic attacks Insomnia Daytime sleepiness and excessive daytime sleepiness Parasomnias Abnormal simple and complex nocturnal movements RLS and PLMS RBD and REM loss atonia Non-REM sleep-related movement disorders Vivid dreaming Sleep-disordered breathing Bladder dysfunction Urgency Nocturia Frequency Sweating Orthostatic hypotension Sexual dysfunction Hypersexuality* Erectile impotence Constipation Sialorrhoea Weight loss Weight gain* Dry eyes Other symptoms Pain, paresthesia, diplopia, olfactory disturbances and fatigue The widespread and progressive neurodegeneration in the PD brain leads to the emergence of a variety of features that are collectively grouped under the title of non-motor symptoms. These are predominantly, but not exclusively, the consequence of loss of non-dopaminergic pathways. The non-motor symptoms of PD range from neuropsychiatric problems such as depression, apathy, anxiety disorders and hallucinations, to fatigue, gait and balance disturbances, hypophonia, sleep disorders, sexual dysfunction, bowel problems, drenching sweats, sialorrhoea and pain. These symptoms are often the most troubling for patients and contribute significantly to morbidity and impaired quality of life.1 Diplopia is a frequent symptom even in early PD although the neurological basis is not known. The non-motor symptoms encountered in PD patients are listed in the table.2-5 References 1. Hely MA, Morris JG, Reid WG, Trafficante R. Sydney Multicenter Study of Parkinson’s disease: non-L-dopa-responsive problems dominate at 15 years. Mov Disord 2005;20:190-9. 2. Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006;5: 3. Tetrud JW. Management of advanced Parkinson’s disease. In: Ebadi M, Pfeiffer RF, eds. Parkinson’s Disease. Boca Raton: CRC Press; 2005. 4. Sawabini KA, Juncos JL, Watts RL. Depression, psychosis, and cognitive dysfunction in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 5. Stocchi F. Gastrointestinal, urological, and sleep problems in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. * possibly drug-induced Abbreviations: REM, rapid eye movement; RBD, REM sleep behaviour disorder; RLS, restless legs syndrome; PLMS, periodic leg movements of sleep Chaudhuri KR, et al. Lancet Neurol 2006;5: Tetrud JW. In: Parkinson’s Disease; 2005.

85 Section I Management of Non-Motor Symptoms in Parkinson’s Disease – Diagnosis and Evaluation Non-motor symptoms are frequently overlooked Depression, anxiety, fatigue and sleep not discussed with more than 50% of patients1 Despite a probable frequency of depression of 40–50% in PD patients2 Difficult diagnosis in some cases Role of neurologists in identifying and differentiating symptoms Non-motor scales Improve the identification of non-motor symptoms Evaluate therapeutic interventions In recent decades, much emphasis has been given to PD motor symptoms. The non-motor symptoms such as neuropsychiatric and autonomic dysfunctions have only recently been considered important treatment issues. Consequently, these symptoms are still frequently overlooked. Although depression, anxiety, fatigue and sleep problems frequently occur in PD patients,1 a recent prospective study of 101 PD patients shows that neurologists do not discuss these symptoms with more than 50% of their patients.2 Various reasons may explain this under-recognition: limited consultation time; perception of the patient and caregiver that these symptoms are not related to PD; consultation focus on motor symptoms only; expectation that these symptoms will be managed by the family doctor. Neurologists are best qualified to identify non-motor symptoms because diagnosing them can often be difficult, e.g. depression may be missed in a patient with bradyphrenia and mask-like face. To improve the identification of non-motor symptoms and to evaluate therapeutic interventions, quantitative and validated instruments for the evaluation of non-motor symptoms have been developed.3 References 1. Cummings JL. Depression and Parkinson’s disease: a review. Am J Psychiatry 1992;4: 2. Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2002;8:193-7. 3. Chaudhuri KR, Healy DG, Schapira AH; National Institute for Clinical Excellence. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 2006;5: 1. Shulman LM, et al. Parkinsonism Relat Disord 2002;8:193-7. 2. Cummings JL. Am J Psychiatry 1992;149:

86 Non-Motor Symptoms in Parkinson’s Disease – Assessment Tools
Section I Non-Motor Symptoms in Parkinson’s Disease – Assessment Tools Non-motor feature Scale Neuropsychiatric symptoms Mini Mental Test; Hospital Anxiety and Depression Scale Hamilton Depression Rating Scale; Beck Depression Inventory Autonomic symptoms SCOPA-Aut Sleep Parkinson's Disease Sleep Scale; SCOPA-Sleep; Epworth Sleepiness Scale Fatigue Fatigue Severity Scale; PF-16 Health-related quality of life PDQ 39; PDQ 8; PDQUALIF; PD Quality of Life Questionnaire; SCOPA-PS (psychological aspect); EQ-5D Comprehensive assessment The Parkinson's disease NMS scale (in development); the Parkinson's disease NMS questionnaire (NMSQuest); Revised UPDRS (not validated); wearing-off patient questionnaire This table lists PD-specific and PD-related assessment and evaluation tools relevant to non-motor symptoms in PD.1 Reference 1. Chaudhuri KR, Healy DG, Schapira AH. National Institute for Clinical Excellence. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5: Abbreviations: NMSQuest, non-motor symptom questionnaire for Parkinson's disease; UPDRS, unified Parkinson's disease rating scale; SCOPA, scales for outcomes in Parkinson's disease; PDQUALIF, Parkinson's disease quality of life scale; PDQ, Parkinson's disease questionnaire Chaudhuri KR, et al. Lancet Neurol 2006;5:

87 Section I Treatment of Non-Motor Symptoms in Parkinson’s Disease – Neuropsychiatric Disorders Treatment approach Anxiety, panic attacks Treat wearing-off SSRIs Benzodiazepines Depression Tricyclic antidepressants Pramipexole Hallucinations and psychosis Discontinue: sedatives, hypnotics, narcotic analgesics, anticholinergics, amantadine, MAO-B inhibitors Taper or discontinue dopamine agonists if possible Clozapine or quetiapine if needed Cognitive and psychiatric symptoms may have catastrophic effects on the quality of life of patients, as well as a negative effect on caregivers. Neuropsychiatric symptoms range from anxiety, apathy and depression to frank dementia.1,2 Psychosis is the key factor leading to the need for nursing home placement.3 Anxiety and panic attacks can be prominent in PD and may sometimes be related to “wearing-off.” Dopaminergic treatment is indicated in this setting, although additional anxiolytic therapy may be needed in some patients. Depression affects about 40% of PD patients and is the most significant predictor of quality of life in the disease.4 This table summarises therapeutic interventions effective in the management of depression in PD patients. Depression, and to some extent apathy (anhedonia), may respond to tricyclics such as amitriptyline or to selective serotonin reuptake inhibitors (SSRIs). Pramipexole may be useful as an antidepressant, independenty of its action to improve the motor features of PD.5-8 Section III of this slide series is dedicated to this frequent debilitating condition in PD. Hallucinations, if caused by drug treatment, usually respond to a reduction in dose. In some patients, however, dose reduction is difficult because of the re-emergence of motor features, thereby necessitating the introduction of atypical neuroleptics such as clozapine or quetiapine.5,8 Hallucinations are an important symptom of diffuse Lewy body disease, and their emergence early in the course of PD is a risk factor for dementia. References 1. Aarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1999;67:492-6. 2. Thanvi BR, Munshi SK, Vijaykumar N, Lo TC. Neuropsychiatric non-motor aspects of Parkinson’s disease. Postgrad Med J 2003;79:561-5. 3. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson’s disease: a population-based, prospective study. J Am Geriatr Soc 2000;48: 4. Oertel WH, Hoglinger GU, Caraceni T, et al. Depression in Parkinson’s disease. An update. Adv Neurol 2001;86: 5. Miyasaki JM, Shannon K, Voon V, et al. Practice Parameter: evaluation and treatment of depression, psychosis, and dementia in Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66: 6. Lemke MR, Fuchs G, Gemende I, et al. Depression and Parkinson’s disease. J Neurol 2004;251(Suppl 6):VI/24-7. 7. Sawabini KA, Juncos JL, Watts RL. Depression, psychosis, and cognitive dysfunction in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 8. Lieberman A. Depression in Parkinson’s disease – a review. Acta Neurol Scand 2006;113:1-8. Abbreviations: SSRI, selective serotonin reuptake inhibitors; MAO-B, monamine oxidase B Lemke MR, et al. J Neurol 2004;251(Suppl 6):VI/24-7. Sawabini KA, et al. In: Principles of Treatment in Parkinson's Disease; 2005. Lieberman A. Acta Neurol Scand 2006;113:1-8. Miyasaki JM, et al. Neurology 2006;66:

88 Section I Treatment of Non-Motor Symptoms in Parkinson’s Disease – Autonomic Dysfunction Treatment option Bladder urgency Oxybutinin Tolterodine Amitriptyline (if concomitant depression) Erectile dysfunction Sildenafil Apomorphine Sialorrhoea Simple measures: chewing gum, sucking sweets Anticholinergic drugs (glycopyrrolate) Botulinum toxin for refractory cases Constipation Consider dopamine agonists Adequate fluid intake, exercise Aperients: psyllium fibre, lactulose, polyethylene glycol Orthostatic hypotension Adjust dopamine agonist dose if needed Fludrocortisone Midodrine Autonomic dysfunction is a variable feature in PD.1 One of the most common manifestations of autonomic dysfunction in PD is bladder urgency, often leading to incontinence. Bladder abnormalities particularly cause problems at night, but can be improved by a range of therapeutic options, including non-pharmacological and pharmacological strategies. Pharmacological strategies include the use of oxybutinin or tolderodine or, in patients with concomitant depression, amitriptyline.2 Viagra or apomorphine can, in selected cases, usefully manage the erectile dysfunction associated with PD.3,4 Sialorrhoea and drooling are often the result of reduced frequency of swallowing and may be helped by such simple measures as chewing gum or sucking sweets. Anticholinergic drugs may sometimes help, but often cause unwanted side effects. Botulinum toxin can be used for refractory cases.5 Constipation may respond to dopaminergic drugs and bowel training. Aperients often need to be added.2,5 Orthostatic hypotension, which is usually not very severe in PD patients, may need therapeutic interventions if it becomes problematic. In such circumstances, the dosage of dopaminergic agents, which may exacerbate the underlying autonomic dysfunction, should be adjusted; fludrocortisone and midodrine may be useful in some cases.6 References 1. Jost WH. Autonomic dysfunctions in idiopathic Parkinson’s disease. J Neurol 2003;250(Suppl 1):I28-30. 2. Stocchi F. Gastrointestinal, urological, and sleep problems in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 3. Raffaele R, Vecchio I, Giammusso B, Morgia G, Brunetto MB, Rampello L. Efficacy and safety of fixed-dose oral sildenafil in the treatment of sexual dysfunction in depressed patients with idiopathic Parkinson’s disease. Eur Urol 2002;41:382-6. 4. O’Sullivan JD. Apomorphine as an alternative to sildenafil in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2002;72:681. 5. Tetrud JW. Management of advanced Parkinson’s disease. In: Ebadi M, Pfeiffer RF, eds. Parkinson’s Disease. Boca Raton: CRC Press; 2005. 6. Goldstein DS. Dysautonomia in Parkinson’s disease: neurocardiological abnormalities. Lancet Neurol 2003;2: Stocchi F. In: Principles of Treatment in Parkinson’s Disease; 2005. Raffaele R, et al. Eur Urol 2002;41:382-6. O'Sullivan JD. J Neurol Neurosurg Psychiatry 2002;72:681. Tetrud JW. In: Parkinson’s Disease; 2005. Goldstein DS. Lancet Neurol 2003;2:

89 Section I Treatment of Non-Motor Symptoms in Parkinson’s Disease – Sleep Disturbances Treatment option Insomnia Non-pharmacological: sleep hygiene Pharmacological: benzodiazepines, zopiclone, zolpidem RBD Benzodiazepine (clonazepam) RLS Dopamine agonists Levodopa Opiates EDS Caffeine Modafinil Reduce dopaminergic drug dose Switch from one dopamine agonist to another Management of sleep problems requires that the exact nature of the sleep disturbance be established and that any concurrent medication or psychological factors that may affect sleep be identified. Both non-pharmacological and pharmacological treatments should then be considered.1 Sleep hygiene entails a well-ventilated bedroom at a comfortable temperature and an adjustable bed with a firm, non-slippery mattress. Regular exercise and the avoidance of caffeinated drinks, smoking and heavy meals are also recommended. A warm bath two hours before bedtime and a light bedtime snack have been shown to be useful in some cases. Other measures may include relaxation exercises, reading at bedtime and a flexible sleep schedule.2 Rapid eye movement sleep behaviour disorder (RBD) seems to be very common in PD patients and often precedes disease onset. The patient is generally unaware of the symptoms and RBD is, therefore, generally more annoying for the spouse than the patient. Benzodiazepines such as clonazepam have been reported to reduce RBD activity.3 Excessive daytime sleepiness (EDS) in PD patients is likely multifactorial. Lack of adequate night-time sleep, and medications are usually implicated. All dopaminergic drugs can contribute to EDS. Reducing the dose or switching from one dopamine agonist to another could provide some relief, although insomnia may occur. The use of caffeine and modafinil administration may be useful.3 Patients suffering from RLS may have important sleep disturbances. Dopamine agonists, the first-line therapeutic agents for this disorder, should be considered. Levodopa and opiates may be useful in some circumstances.3,4 References 1. Adler CH, Thorpy MJ. Sleep issues in Parkinson’s disease. Neurology 2005;64(12 Suppl 3):S12-20. 2. Stocchi F. Gastrointestinal, urological, and sleep problems in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 3. Barone P, Amboni M, Vitale C, Bonavita V. Treatment of nocturnal disturbances and excessive daytime sleepiness in Parkinson’s disease. Neurology 2004;63(8 Suppl 3):S35-8. 4. Phillips B. Movement disorders: a sleep specialist’s perspective. Neurology 2004;62(5 Suppl 2):S9-16. Abbreviations: RBD, rapid eye movement (REM) sleep behaviour disorder; RLS, restless legs syndrome; EDS, excessive daytime sleepiness Adler CH, Thorpy MJ. Neurology 2005;64(12 Suppl 3):S12-20. Stocchi F. In: Principles of Treatment in Parkinson’s Disease; 2005. Barone P, et al. Neurology 2004;63(8 Suppl 3):S35-8. Phillips B. Neurology 2004;62(5 Suppl 2):S9-16.

90 Disease Modification (Neuroprotection)
Section I Disease Modification (Neuroprotection)

91 Disease Modification in Parkinson’s Disease – Summary
Section I Disease Modification in Parkinson’s Disease – Summary Rationale for Neuroprotection Evaluating Neuroprotection Approaches in Neuroprotection Clinical trials Antioxidants and monoamine oxidase type-B inhibitors Anti-excitotoxic agents Bioenergetic agents Coenzyme Q10 Dopamine Agonists Rationale for the use of dopamine agonists as potential neuroprotective agents Possible mechanisms for neuroprotection Experimental basis Neuroimaging Perspectives in Neuroprotection

92 Disease Modification (Neuroprotection)
Section I Disease Modification (Neuroprotection) Rationale

93 Treatment of Parkinson’s Disease
Section I Treatment of Parkinson’s Disease Reduce Motor Symptoms (see algorithm on slide 49) Reduce Motor Complications Slow Disease Progression Limit Neuropsychiatric and Non-Dopaminergic Symptoms Early dopamine agonist therapy Continuous dopamine stimulation Deep brain stimulation Antidyskinesia drugs, amantadine, dopamine transport inhibitors, glutamatergic drugs, and GABA* Block Neurodegenerative Process Improved mitochondrial function Oxidative stress Protein aggregation Apoptosis, necrosis Dementia Depression Postural instability Freezing Autonomic failure This figure summarises the current approaches in the treatment of PD. Efforts are focused on the reduction of motor complications mostly related to levodopa therapy, the management of non-motor features, and the development of neuroprotective therapies early in the course of the disease to slow, stop or reverse disease progression. The decline in striatal dopamine owing to the degeneration of nigrostriatal neurons is the basis for symptomatic treatment of PD with the dopamine precursor levodopa. However, levodopa therapy induces motor complications (motor fluctuations and dyskinesias) in most patients after a period of 5–10 years. Moreover, levodopa does not alter disease progression. Finally, over time, the majority of patients develop features such as freezing, falling, autonomic dysfunction and dementia that do not adequately respond to dopamine replacement therapy. Consequently, despite the benefits associated with levodopa treatment, patients with advanced disease suffer unacceptable levels of functional disability. These limitations have led to the search for agents to slow the progression of neurodegeneration in PD, thereby preventing or slowing clinical progression, or even reverse deficits by restoring normal function to defective neurons. It is accepted that such a strategy will be successful only if degeneration is ameliorated in multiple neurotransmitter systems, preventing the progression of both motor and non-motor features. The drugs that have received the most attention in relation to neuroprotection include the monoamine oxidase (MAO) type-B inhibitors and dopamine agonists. Others, including coenzyme Q10, growth factors, anti-apoptotic agents and glutamate inhibitors, have also been the subject of clinical trials in PD.1 If implemented early in the course of the disease, effective neuroprotective agents may not only alter the natural progression of PD, but also delay or minimise complications associated with levodopa therapy.2 References 1. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004;291: 2. Olanow CW, Jankovic J. Neuroprotective therapy in Parkinson’s disease and motor complications: a search for a pathogenesis-targeted, disease-modifying strategy. Mov Disord 2005;20(Suppl 11):S3-10. * Gamma-aminobutyric acid Restorative Therapies Cells, genes, trophic factors Schapira AH, Olanow CW. JAMA 2004;291: Olanow CW, Jankovic J. Mov Disord 2005;20(S11):S3-10.

94 Neuroprotection – Definitions
Section I Neuroprotection – Definitions Neuroprotection (disease modification) Prevent further neuronal cell death in order to slow or halt disease progression Does not necessarily affect the underlying pathophysiological biochemical mechanisms Neurorescue Salvage of dying neurons by reversal of established metabolic abnormalities Neurorestoration (is not neuroprotection) Increasing the number of dopaminergic neurons Cell implantation Nerve growth factors Most motor symptoms of PD such as bradykinesia and rigidity are related to the deficiency of dopamine in the striatum. Neuroprotective therapy, or disease modification, aims at preventing further neuronal cell death, thus slowing or stopping disease progression. Neuroprotection involves the prevention of neuronal cell death and the maintenance of neuronal function without necessarily affecting the underlying pathophysiological biochemical mechanisms. The process of neuroprotection may, in part, also be achieved through neurorescue. Neurorescue, for its part, involves the salvage of dying neurons by reversing established metabolic abnormalities and the restoration of normal neuronal function and survival. Neurorestoration involves increasing the number of dopaminergic neurons by cell implantation or nerve growth factor administration. Therefore, neurorestoration should be distinguished from neuroprotection.1 Reference 1. Schapira AH. Science, medicine, and the future: Parkinson’s disease. BMJ 1999;318:311-4. Schapira AH. BMJ 1999;318:311-4.

95 Disease Modification (Neuroprotection)
Section I Disease Modification (Neuroprotection) Evaluation

96 Neuroprotection – Evaluation
Section I Neuroprotection – Evaluation Decreased loss of neurons in the dopaminergic and other neurotransmitter systems Impossible to assess directly in life Surrogate markers: Clinical rating scales (e.g. UPDRS*) Time to clinical endpoints (e.g. time to levodopa therapy requirement) Neuroimaging (-CIT SPECT,† fluorodopa PET‡) Basically, neuroprotective effects of therapeutic interventions should be documented by decreased loss of dopaminergic and other neurotransmitter system neurons. Because this measurement is impossible to obtain in life, alternative, indirect outcome measures have been considered. These include clinical rating scales such as the Unified Parkinson’s Disease Rating Scale (UPDRS), time to clinical endpoints (e.g. time to levodopa therapy requirement), neuroimaging (SPECT, PET), and mortality. Reference Clarke CE. Neuroprotection and pharmacotherapy for motor symptoms in Parkinson’s disease. Lancet Neurol 2004;3: * Unified Parkinson's Disease Rating Scale † single photon emission computed tomography ‡ positron emission tomography Clarke CE. Lancet Neurol 2004;3:

97 Section I Issues in the Evaluation of Neuroprotective Effects of Drugs in Parkinson’s Disease Outcome measure Issue Suggested solution Clinical measure* Differentiation of symptomatic from neuroprotective effects Prolonged washout of drug Delayed-start studies Neuroimaging† SWEDD‡ Discrimination with progressive supranuclear palsy or multiple system atrophy Appropriate sample size calculations taking into account misdiagnosis Lack of correlation between clinical outcomes and neuroprotection Larger or longer studies Modification of radionuclide tracer pharmacokinetics by the putative neuroprotective agent Repeat imaging to assess any differential effect of the drug All Small magnitude of neuroprotective effect Appropriate sample size Lack of meaning to patients Inclusion of quality-of-life parameters and mortality evaluation For the purpose of evaluating neuroprotective effects of therapeutic interventions in PD, optimal outcome measures should parallel the number of surviving neurons. All available markers have problems in correctly mirroring the number of surviving neurons—catecholaminergic and dopaminergic. The limitations of these evaluations are listed in the table, which limits itself to the dopaminergic system and cites possible solutions to overcome these issues. Clinical measures Because the intervention drugs may have symptomatic effects, outcome measurements based on clinical scales and parameters may confound the neuroprotective and symptomatic effects. Possible solutions include appropriate washout period at the end of trials or studies including only patients without the need for symptomatic treatment, i.e. those in the very early stage of the disease. Neuroimaging outcomes Patients may have normal baseline radionuclide imaging scans, i.e. scans without evidence of dopaminergic deficit (SWEDD) because of misdiagnosis (10%) but also because of lack of sensitivity. Indeed, some authors estimate that over 70% of patients with normal scans will have PD.1 The solution may reside in longitudinal studies showing those patients who were misdiagnosed. Neuroimaging cannot reliably discriminate between idiopathic PD and other conditions characterised by dopaminergic deficit such as progressive supranuclear palsy and multiple system atrophy. Postsynaptic dopamine receptor imaging, e.g. iodobenzamide (IBZM) SPECT, allows for such a differential diagnosis in non-treated patients, something that is not always possible. Studies should, therefore, include appropriate numbers of patients, taking into account misdiagnosed patients. Poor sensitivity to change and poor reproducibility also call for caution as they may result in substantial differences in the decrease of radionuclide uptake as the disease progresses. Better standardisation of neuroimaging technologies and blinded evaluations of the results should overcome these difficulties in the future.2 Other limitations include the alteration of ligand pharmacokinetics by medication. The lack of correlation with clinical outcomes may possibly be solved by larger and longer studies showing clinical effects. References 1. Clarke CE. A “cure” for Parkinson’s disease: can neuroprotection be proven with current trial designs? Mov Disord 2004;19:491-8. 2. Clarke CE. Neuroprotection and pharmacotherapy for motor symptoms in Parkinson’s disease. Lancet Neurol 2004;3: * clinical rating scales, time to endpoint, mortality; † β-CIT single photon emission computed tomography (SPECT) or fluorodopa positron emission tomography (PET); ‡ scans without evidence of dopaminergic deficit Clarke CE. Mov Disord 2004;19:491-8. Clarke CE. Lancet Neurol 2004;3:

98 Disease Modification (Neuroprotection)
Section I Disease Modification (Neuroprotection) Approaches

99 Neurorescue and Neuroprotection in Parkinson’s Disease
Section I Neurorescue and Neuroprotection in Parkinson’s Disease Neurorescue (yellow line) Restore damaged neurons that are at risk of death (area between curves) to normal function Age-related loss will probably be attenuated with ongoing treatment Neuroprotection (green line) Prevents further neuronal loss other than by attenuated age- related loss Putative time course for loss of dopamine neurons from substantia nigra and clinical expression Threshold for clinical symptoms 0% 100% Percentage of Substantia Nigra Neurons Remaining 40 80 Years Diagnosis The graph illustrates the putative impact of neuroprotection and neurorescue over the course of disease progression. It is currently understood that apoptosis plays an important role in neuronal loss in PD.1,2 Apoptotic cell death is relatively rapid, preceded by a pre-apoptotic phase where, theoretically, it is still possible to reverse metabolic abnormalities and rescue damaged neurons by restoring normal neuronal function and survival. Effective early neurorescue of neurons at risk of death would clinically result in an improvement in symptoms or, with the prospect of future preclinical identification of PD, delay the symptomatic phase of the disease and halt its progression. Neuroprotection, which involves the prevention of neuronal cell death without necessarily affecting the underlying pathogenic biochemical mechanisms, would also halt disease progression. Inevitably, there will be some overlap between neuroprotection and neurorescue in terms of clinical benefits.3 References 1. Tatton NA, Maclean-Fraser A, Tatton WG, Perl DP, Olanow CW. A fluorescent double-labeling method to detect and confirm apoptotic nuclei in Parkinson’s disease. Ann Neurol 1998;44(3 Suppl 1):S142-8. 2. Hartmann A, Hirsch EC. Parkinson’s disease. The apoptosis hypothesis revisited. Adv Neurol 2001;86: 3. Schapira AH. Science, medicine, and the future: Parkinson’s disease. BMJ 1999;318:311-4. Schapira AH. BMJ 1999;318:311-4. © 1999 BMJ Publishing Group Ltd.

100 Neuroprotection in Parkinson’s Disease – Clues and Targets
Section I Neuroprotection in Parkinson’s Disease – Clues and Targets AETIOLOGY Genetic factors Environmental factors Aetiological and pathogenetic factors in Parkinson’s disease and possible neuroprotective approaches Gene-environment interaction PATHOGENESIS Antioxidants (e.g. vitamin E, vitamin C, iron chelators) Oxidative stress Monoamine oxidase B inhibitors (e.g. selegiline, rasagiline) Mitochondrial dysfunction Bioenergetic agents (e.g. coenzyme Q10) Excitotoxicity Antiglutamatergic agents (e.g. N-methyl-D-aspartate [NMDA] receptor antagonists) Calcium channel blockers Inflammation Anti-inflammatory agents (e.g. COX-2 inhibitors) The cause of neurodegeneration in PD is likely multifactorial in terms of both aetiology and pathogenesis. Genetic factors are known to cause PD in a small number of patients with a familial form of the disease while a complex interaction between genetic and environmental factors seems to be implicated in most sporadic cases. This slide gives a schematic overview of the aetiological and pathogenetic factors in PD and shows the array of molecular targets and candidate drugs with putative neuroprotective effects in PD.1,2 The relative contribution of each of these factors to neurodegeneration varies with the individual patient. However, it is currently understood that each of these aetiopathogenic factors can potentially interfere with the capacity of the ubiquitin-proteasome system to clear unwanted proteins. Hence, protein mishandling, i.e. protein accumulation and aggregation, appears to be a common feature in the various aetiopathogenic forms of PD.3 Signal-mediated apoptosis appears to play a key role in cell death in PD.4 Although the precise signals that are involved have not yet been completely defined, several drugs, including dopamine agonists, have been shown to have anti-apoptotic properties with potential neuroprotective effects in PD. References 1. Olanow CW, Schapira AH, Agid Y. Neuroprotection for Parkinson’s disease: prospects and promises. Ann Neurol 2003;53(Suppl 3):S1-2. 2. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004;291: 3. McNaught KS, Olanow CW. Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson’s disease. Ann Neurol 2003;53(Suppl 3):S73-84. 4. Tatton WG, Chalmers-Redman RC, Brown D, et al. Apoptosis in Parkinson’s disease: signals for neuronal degradation. Ann Neurol 2003;53(Suppl 3):S61-72. Protein handling dysfunction with Levy body formation Proteosomal enhancers Abbreviations: COX-2, cyclo-oxygenase-2; GDNF, glial-derived neurotrophic factor Heat shock proteins Schapira AH, Olanow CW. JAMA 2004;291: Neuronal dysfunction Trophic factors (e.g. GDNF, nurturin) © 2004 American Medical Association. All rights reserved. Apoptosis Anti-apoptotic agents (e.g. dopamine agonists, caspase inhibitors, propargylamines)

101 Disease Modification (Neuroprotection)
Section I Disease Modification (Neuroprotection) Clinical Trials

102 Section I Neuroprotection Trials – Antioxidants and Monoamine Oxidase Type-B Inhibitors (1) Rationale1 Role of oxidative stress in the pathogenesis of neuronal cell death Increased levels of iron (promote oxidative stress) in SN* Decreased levels of glutathione (the major brain antioxidant) Evidence of oxidative damage to carbohydrates, lipids, proteins and DNA in SNpc† Oxidative metabolism of levodopa and/or dopamine Candidate drugs1,2 -tocopherol (vitamin E) The most potent lipid-soluble antioxidant in plasma Selegiline Inhibits the MAO-B‡ oxidation of MPTP§ (responsible for MPTP toxicity) Possibly inhibits the oxidation of other toxins that contribute to neuronal degeneration Might block the MAO-B-dependent oxidative metabolism of levodopa/dopamine Rasagline Another potent MAO-B inhibitor Has also shown protective effects in laboratory models2 The putative neuroprotective effects of several pharmacological agents in PD have been evaluated in several clinical trials.1 Slides give an overview of the rationale for considering these drugs in PD and the results from selected clinical studies. Antioxidants and monoamine oxidase type-B inhibitors There is considerable evidence supporting the role of oxidative stress in the pathogenesis of cell death in PD.1 Post-mortem analyses of PD patients document increased levels of iron, which promote oxidative stress, and decreased levels of glutathione, the major brain antioxidant. There is also evidence of oxidative damage to carbohydrates, lipids, proteins and DNA in the SNpc of PD patients. Moreover, the oxidative metabolism of levodopa and dopamine can generate reactive oxygen species that can induce or increase oxidative stress. These findings have prompted clinical trials on the use of antioxidant agents in an effort to obtain neuroprotection in PD. Agents studied include -tocopherol, which is the most potent lipid-soluble antioxidant in plasma, and selegiline, a propargylamine, which inhibits MAO-B oxidation of MPTP to MPP+ (1-methyl-4-phenylpyridinium ion), believed to be responsible for MPTP toxicity. Indeed, if PD is related to an MPTP-like protoxin, selegiline inhibition of MAO-B may also prevent the oxidation of other toxins contributing to neurodegeneration. Furthermore, selegiline may also inhibit the MAO-B-dependent oxidative metabolism of levodopa and dopamine and the related free radical damage to SNpc neurons. Rasagiline, another propargylamine with potent MAO-B inhibition capacities, has also shown protective effects in laboratory models.2 References Stocchi F, Olanow CW. Neuroprotection in Parkinson’s disease: clinical trials. Ann Neurol 2003;53(Suppl 3):S87-97. Olanow CW. Rationale for considering that propargylamines might be neuroprotective in Parkinson’s disease. Neurology May 23;66(10 Suppl 4):S69-79. * substantia nigra; † substantia nigra pars compacta; ‡ monoamine oxidase type-B; §1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine 1. Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97. 2. Olanow CW. Neurology 2006;66(10 Suppl 4):S69-79.

103 Section I Neuroprotection Trials – Antioxidants and Monoamine Oxidase Type-B Inhibitors (2) DATATOP* study -tocopherol: no effect on the time-to-levodopa requirement Selegiline: delayed need for levodopa SELEDO† study Selegiline: less requirement for increased levodopa doses SINDEPAR‡ Selegiline: less deterioration in UPDRS§ score TEMPO** Rasagiline: more deterioration in UPDRS score if delayed start Limitations Selegiline has symptomatic effects in Parkinson’s disease Prevents any conclusion as to neuroprotective effect Same limitation is valid for other MAO-B inhibitors (lazabemide, rasagiline) The DATATOP study was a prospective, randomised, double-blind, placebo-controlled study that included 800 patients with PD.1,2 After randomisation to either selegiline, -tocopherol (vitamin E), a combination of both or placebo, the patients were followed up with no other treatment until clinical deterioration calling for initiation of symptomatic levodopa therapy, i.e. the primary endpoint. Selegiline, but not -tocopherol, resulted in a significant delay for levodopa requirement compared with placebo (26 versus 15 months; P < ). However, the main limitation of this study after careful analysis was the potential confounding symptomatic effect of selegiline on the results. The TEMPO3 study examined the neuroprotective potential of rasagiline, another irreversible MAO-B inhibitor. This double-blind, parallel group, randomised, delayed-start clinical trial included 404 subjects with early PD. Patients were randomised to receive rasagiline 1 or 2 mg/day for 1 year or placebo for 6 months, followed by rasagiline 2 mg/day for 6 months. The degree of motor improvement was comparable to that seen for selegiline in the DATATOP study, but not as great as that seen for the dopamine agonists. In addition, patients who received rasagiline 1 or 2 mg/day for 12 months had less functional decline, as assessed by the Unified Parkinson’s Disease Rating Scale (UPDRS), than patients who received placebo for 6 months. These results support a neuroprotective action of the drug, but additional confirmatory trials are required before this drug can be accepted as neuroprotective. Although the subsequent SELDO and SINDEPAR trials aimed to confirm the neuroprotective effect of selegiline to support the DATATOP results, neither one resolved the confounding issue of the drug’s short- and long-term symptomatic antiparkinsonian effect. This limitation is also valid for MAO-B inhibitors such as lazabemide and rasagiline.1 References 1. Stocchi F, Olanow CW. Neuroprotection in Parkinson’s disease: clinical trials. Ann Neurol 2003;53(Suppl) 3:S87-97. 2. Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ; Quality Standards Subcommittee of the American Academy of Neurology. Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66: 3. Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004;61:561-6. * Deprenyl and Tocopherol Antioxidant Therapy of PD; † Selegiline-L-dopa; ‡ Sinemet-Deprenyl-Parlodel; § Unified Parkinson's Disease Rating Scale; ** rasagiline mesylate (TVP-1012) in Early Monotherapy for Parkinson's disease Outpatients Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97. Parkinson Study Group. Arch Neurol 2004; 61:561-6.

104 Neuroprotection Trials – Anti-excitotoxic Agents (1)
Section I Neuroprotection Trials – Anti-excitotoxic Agents (1) Rationale Neuronal activity in the STN* is increased in PD STN uses the excitatory neurotransmitter glutamate and projects to the GPi†, pedunculopontine nucleus and SNpc‡ Potential excitotoxic damage of these targets NMDA§ receptor antagonists may protect dopamine neurons from glutamate-mediated toxicity A retrospective study suggests decreased rate of PD progression after administration of amantadine (an NMDA receptor antagonist) It has been suggested that excess glutamatergic stimulation and subsequent excitotoxicity contribute to neurodegeneration in PD, thus raising the hypothesis of neuroprotective effects for anti-excitotoxic drugs.1 Neuronal activity in the STN is increased in parkinsonian animals and humans. The STN uses the excitatory neurotransmitter glutamate and projects to the GPi, pedunculopontine nucleus and SNpc. Logically, these targets might be subject to excitotoxic damage.2 NMDA receptor antagonists have been reported to protect dopamine neurons from glutamate-mediated toxicity in tissue culture and in rodent and primate PD models. A retrospective study has also suggested a decreased rate of PD progression after early use of amantadine, an NMDA receptor antagonist.3 References 1. Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994;330: 2. Rodriguez MC, Obeso JA, Olanow CW. Subthalamic nucleus-mediated excitotoxicity in Parkinson’s disease: a target for neuroprotection. Ann Neurol 1998;44(3 Suppl 1):S 3. Stocchi F, Olanow CW. Neuroprotection in Parkinson’s disease: clinical trials. Ann Neurol 2003;53(Suppl 3):S87-97. * subthalamic nucleus; † globus pallidus interna; ‡ substantia nigra pars compacta § N-methyl-D-aspartate Rodriguez MC, et al. Ann Neurol 1998;44(3 Suppl 1):S Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S87-97.

105 Neuroprotection Trials – Anti-excitotoxic Agents (2)
Section I Neuroprotection Trials – Anti-excitotoxic Agents (2) Remacemide hydrochloride (low-affinity NMDA channel blocker) No symptomatic effect in Parkinson’s disease No neuroprotective benefit in Huntington’s disease No formal study of neuroprotection in Parkinson’s disease Riluzole (sodium channel blocker) No neuroprotective effect confirmed in Parkinson’s disease patients Remacemide hydrochloride is a low-affinity NMDA channel blocker. A double-blind placebo-controlled study shows no symptomatic effect in patients with PD.1 Remacemide has also failed in showing neuroprotective benefit in patients with Huntington’s disease, even when combined with coenzyme Q10.2 Moreover, there are no formal trials with remacemide and neuroprotection in PD.3 Riluzole, approved for use in the treatment of amyotrophic lateral sclerosis, is another antiglutamatergic drug acting through sodium channel blockade and a subsequent decrease in glutamate release in overactive glutamatergic neurons.3 Although preclinical studies have shown the capacity of riluzole to protect dopamine neurons in rodent and primate models of PD, clinical studies have failed to confirm any neuroprotective effect in PD patients.3,4 References 1. Parkinson Study Group. A muticenter randomized, placebo-controlled trial of remacemide hydrochloride as monotherapy for PD. Neurology 2000;54: 2. Huntington’s Disease Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology 2000;57: 3. Stocchi F, Olanow CW. Neuroprotection in Parkinson’s disease: clinical trials. Ann Neurol 2003;53(Suppl 3):S87-97. 4. Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ; Quality Standards Subcommittee of the American Academy of Neurology. Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66: Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S Suchowersky O, et al. Neurology 2006;66:

106 Neuroprotection Trials – Bioenergetic Agents
Section I Neuroprotection Trials – Bioenergetic Agents Rationale Reduction in the activity of mitochondrial respiratory complex I in the SNpc* in Parkinson’s disease Selective complex I inhibitors such as MPTP† and rotenone induce parkinsonism Inhibition of complex I results in increased free radical generation Free radicals, in turn, can damage the respiratory chain, reducing complex I and IV activities in particular Creatine and coenzyme Q10 protect dopamine neurons in MPTP-treated rodents Candidate drugs: bioenergetic agents Mitochondrial enhancers Counteract oxidative stress It has been demonstrated that there is a reduction in complex I activity of the mitochondrial respiratory chain in the substantia nigra pars compacta (SNpc) in PD.1,2 In addition, the selective complex I inhibitors MPTP and rotenone (a pesticide) induce degeneration of dopaminergic neurons3,4 and provide both a model of PD and a basis for the evaluation of neuroprotective effects of mitochondrial enhancers or bioenergetics.5 Inhibition of complex I results in increased free radical generation and could, therefore, contribute to the oxidative damage seen in the SNpc in PD. In turn, free radicals can further damage the respiratory chain, thus reducing the activity of complex I and IV in particular.6 Also, reduced ATP formation in response to complex I hypoactivity metabolically compromises the cell. Because reduced ATP formation, free radical generation and reduction in mitochondrial membrane potential have been considered as mechanisms implicated in the inhibition of complex I leading to parkinsonian syndrome, bioenergetic agents such as creatine, coenzyme Q10, ginkgo biloba, nicotinamide, riboflavin, acetylcarnitine and lipoic acid have been considered for neuroprotection in PD. Creatine and coenzyme Q10 have been shown to protect dopamine neurons in MPTP-treated rodents.7 References 1. Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD. Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 1990;54:823-7. 2. Mizuno Y, Ohta S, Tanaka M, et al. Deficiencies in complex I subunits of the respiratory chain in Parkinson’s disease. Biochem Biophys Res Commun 1989;163: 3. Beal MF. Experimental models of Parkinson’s disease. Nat Rev Neurosci 2001;2: 4. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000;3: 5. Olanow CW, Jankovic J. Neuroprotective therapy in Parkinson’s disease and motor complications: a search for a pathogenesis-targeted, disease-modifying strategy. Mov Disord 2005;20(Suppl 11):S3-10. 6. Schapira AH. Mitochondrial disease. Lancet 2006;368:70-82. 7. Stocchi F, Olanow CW. Neuroprotection in Parkinson’s disease: clinical trials. Ann Neurol 2003;53(Suppl 3):S87-97. * substantia nigra pars compacta; † 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Stocchi F, Olanow CW. Ann Neurol 2003;53(Suppl 3):S Schapira AH. Mitochondrial disease. Lancet 2006;368:70-82.

107 Neuroprotective Trials – Coenzyme Q10
Section I Neuroprotective Trials – Coenzyme Q10 Coenzyme Q10 both enhances respiratory chain function and scavenges free radicals Pilot phase II study in early patients with de novo Parkinson’s disease 1200 mg/day, but not lower doses, produce significant improvement in UPDRS* scores compared with placebo at 16 months Limitations Short-term improvement in ADL† scores consistent with a symptomatic effect Therefore, neuroprotective beneficial effect of coenzyme Q10 needs confirmation Coenzyme Q10 is a lipophilic component of the respiratory chain that transfers electrons to complex III from complexes I and II, from fatty acids and from branched-chain amino acids. Exogenous administration of coenzyme Q10 both enhances respiratory chain function (ATP) and scavenges free radicals, thus raising the possibility of neuroprotective effects in PD through beneficial effects on PD pathogenesis.1 A pilot study with three different doses of coenzyme Q10 (300, 600 or 1200 mg/day) in early untreated PD patients showed that those patients who received the highest dose had significantly lower increases in clinical scores, i.e. less disability, compared with placebo at 16 months.2 This finding is consistent with a neuroprotective effect. However, patients in the highest coenzyme Q10 group also showed short-term improvement in activities of daily living scores. Therefore, as noted by the investigators, the results must be regarded as provisional, and further studies with coenzyme Q10 alone or in combination with other putative disease-modifying therapies are needed to confirm the neuroprotective beneficial effect of this agent. References 1. Schapira AH. Mitochondrial disease. Lancet 2006;368:70-82. 2. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002;59: * Unified Parkinson's Disease Rating Scale; † activities of daily living (part II of UPDRS) Shults CW, et al. Arch Neurol 2002;59:

108 Disease Modification (Neuroprotection)
Section I Disease Modification (Neuroprotection) Dopamine Agonists

109 Section I Rationale for Use of Dopamine Agonists as Neuroprotective Agents in Parkinson’s Disease Already in use for symptomatic relief Appropriate initial symptomatic treatment in most PD patients Limitations of levodopa therapy in Parkinson’s disease Possible contribution to cell damage The ELLDOPA study does not resolve the issue of whether or not levodopa is toxic in Parkinson’s disease Long-term use associated with motor complications Laboratory evidence suggests neuroprotective benefits Neuroimaging studies support putative neuroprotection with pramipexole and ropinirole Understanding and interfering with the causes and mechanisms of cell death in PD lay the groundwork for neuroprotective interventions in this disorder. It is likely that these factors will vary in different individuals. Consequently, it may prove difficult to develop a single therapy providing neuroprotection for all PD patients and may be necessary to use a combination of agents interacting with the degenerative process at various levels. Currently, the development of neuroprotective agents still requires a definition of clinical outcome measures before a product can be labelled neuroprotective in PD by regulatory authorities. In this context, the most realistic approach for developing a neuroprotective drug in the near future is to consider agents such as the dopamine agonists (DAs), for these agents have already been approved for a symptomatic indication in PD. The arguments supporting DAs as agents with neuroprotective benefits in PD are as follows:1,3 1. Problems and limitations related to levodopa therapy in PD. Levodopa use is limited to symptomatic treatment. It does not delay the progression of PD. There are theoretical reasons for concerns about levodopa’s potential contribution to cell damage in PD.2 The ELLDOPA study, designed to determine whether levodopa is toxic and accelerates the progression of PD, shows conflicting results. Drug-naïve patients initiated on levodopa therapy had less clinical deterioration than patients who received placebo, thus supporting a possible neuroprotective effect; however, neuroimaging results (SPECT) show that patients who received levodopa had a higher rate of reduced striatal β-CIT uptake compared with placebo, suggesting a toxic rather than a protective effect. 2. Laboratory evidence showing the capacity of DAs to protect dopaminergic and non-dopaminergic neurons. 3. Clinical studies further supporting this putative neuroprotective effect with other DAs, namely pramipexole and ropinirole. References 1. Schapira AH, Olanow CW. Rationale for the use of dopamine agonists as neuroprotective agents in Parkinson’s disease. Ann Neurol 2003;53(Suppl 3):S 2. Olanow CW. Oxidation reactions in Parkinson’s disease. Neurology 1990;40(10 Suppl 3):32-7. 3. Olanow CW, Jankovic J. Neuroprotective therapy in Parkinson’s disease and motor complications: a search for a pathogenesis-targeted, disease-modifying strategy. Mov Disord 2005;20(Suppl 11):S3-10. Olanow CW, et al. Mov Disord 2005;20(Suppl 11):S3-10. Schapira AHV, et al. Ann Neurol 2003;53(Suppl 3):S

110 Levodopa and Neurodegeneration
Section I Levodopa and Neurodegeneration Powerful symptomatic effect Concerns that levodopa may hasten neurodegeneration Oxidative metabolism Potential to generate cytotoxic free radicals Evidence of levodopa toxicity to cultured dopamine neurons No convincing evidence that levodopa is toxic in in vivo models or in patients with Parkinson’s disease Despite the known symptomatic benefit of levodopa in patients with PD, there are concerns that it may hasten neurodegeneration. Levodopa can generate toxic oxidative metabolites that might accelerate neuronal degeneration in PD. Levodopa and dopamine undergo an oxidative metabolism that yields reactive oxygen species, which in excess could induce oxidative damage to cellular components and initiate apoptosis.1 Levodopa has been shown to be toxic to cultured dopamine neurons2; however, there is no convincing evidence that levodopa is toxic in in vivo models or in patients with Parkinson’s disease.3 References 1. Olanow CW, Jenner P, Brooks D. Dopamine agonists and neuroprotection in Parkinson’s disease. Ann Neurol 1998;44(3 Suppl 1):S 2. Olanow CW. A radical hypothesis for neurodegeneration. Trends Neurosci 1993;16: 3. Agid Y, Olanow CW, Mizuno Y. Levodopa: why the controversy? Lancet 2002;360:575. Agid Y. Lancet 2002;360:575.

111 Levodopa and Neurodegeneration – The ELLDOPA Study (1)
Section I Levodopa and Neurodegeneration – The ELLDOPA Study (1) Early Parkinson’s disease Randomised, double blind, placebo-controlled N = 361 Carbidopa/levodopa: 37.5/150 mg, 75/300 mg, 150/600 mg 40 weeks followed by a 2-week withdrawal Primary outcome: UPDRS* between baseline and 42 weeks Neuroimaging study in 142 patients Baseline and week 40 Striatal DAT† density assessed by 123I--CIT‡ SPECT§ The Early versus Late L-DOPA (ELLDOPA) trial investigated the possibility that levodopa may be toxic in PD patients but produced conflicting results.1 In this study, untreated PD patients were randomised to a total daily dose of 150 mg, 300 mg or 600 mg of levodopa or placebo. -CIT SPECT was used as an endpoint for integrity of the nigrostriatal system. Reference 1. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’ disease. N Engl J Med 2004;351: * Unified Parkinson's Disease Rating Scale; † dopamine transporter; ‡ 2β-carbomethoxy-3β-(4-iodophenyl)tropane; § single photon emission computed tomography Fahn S, et al. N Engl J Med 2004;351:

112 Levodopa and Neurodegeneration – The ELLDOPA Study (2)
Section I Levodopa and Neurodegeneration – The ELLDOPA Study (2) % Change in striatal 123I-β-CIT† uptake CALM-CIT vs. ELLDOPA CIT -8 -6 -4 -2 2 4 6 8 10 12 14 18 22 26 30 34 38 42 46 Week Change in Total UPDRS from Baseline Placebo 150mg 300mg 600mg ELLDOPA – UPDRS* Changes -30 -20 -10 20 40 50 (39) (36) (35) (33) (32) Elldopa 600 Elldopa 300 Elldopa 150 Elldopa Placebo Calm-Levodopa Calm-Pramipexole ELLDOPA at 9 months Scan Time (months) Levodopa was associated with a significant increase in declining rates of imaging marker uptake over nine months compared with placebo, a finding consistent with a toxic effect. The graph on the right shows percent changes in 123I--CIT uptake both in the ELLDOPA1 and CALM-PD2 studies. The concomitant display of CALM-PD neuroimaging results is intended to provide a basis for comparison. Indeed, results obtained with levodopa in ELLDOPA are close to those obtained in CALM-PD patients who received levodopa alone, whereas the results obtained in the ELLDOPA placebo group are comparable to those seen in patients who received pramipexole in CALM-PD. Clinical evaluation, however, showed that patients on levodopa had better UPDRS scores (graph on left) compared with placebo after two weeks of washout. This would, in contrast, be indicative of a protective effect of levodopa. However, intellectual parsimony would dictate that the simplest explanation for this clinical effect is that the washout period was too brief to eliminate the symptomatic benefits of levodopa. References 1. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351: 2. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287: * Unified Parkinson’s Disease Rating Scale † 2β-carbomethoxy-3β-(4-iodophenyl)tropane Fahn S, et al. N Engl J Med 2004;351: Parkinson Study Group. JAMA 2002;287: Copyright © 2004 Massachusetts Medical Society.

113 Levodopa and Neurodegeneration – The ELLDOPA Study (3)
Section I Levodopa and Neurodegeneration – The ELLDOPA Study (3) Patients on levodopa had significantly better UPDRS* scores compared with those who received placebo Less deterioration in patients on levodopa even after the two-week washout period Possible persistent benefit of levodopa, suggesting that levodopa is protective; or Insufficient washout period to exclude persistent symptomatic effect Significantly greater rate of decline in the imaging biomarker uptake in patients on levodopa Consistent with a possible levodopa toxic effect Conclusion Conflicting results: do not permit a clear determination of whether or not levodopa is toxic Patients randomised to all levodopa doses had significantly better UPDRS scores than patients on placebo, with less deterioration from baseline seen on the highest dose.1 These results could suggest that patients on higher doses of levodopa sustain functional benefits that persist even after a two-week washout period and do not document any levodopa neuronal toxicity. However, it is possible that a two-week washout period is not sufficient to exclude a persistent symptomatic effect.2 Furthermore, the results of the patient subgroup who underwent 123I-β-CIT* SPECT† imaging at baseline and at 9 months show a greater decline in radioligand uptake1 in favour of a levodopa-induced toxic effect. Hence, these conflicting results from the ELLDOPA study do not permit a clear determination of whether or not levodopa is toxic.3 * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography References 1. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351: 2. Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ; Quality Standards Subcommittee of the American Academy of Neurology. Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66: 3. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004;291: * Unified Parkinson's Disease Rating Scale Fahn S, et al. N Engl J Med 2004;351:

114 Section I Dopamine Agonists – Possible Mechanisms for Neuroprotection in Parkinson’s Disease (1) Levodopa-sparing Delay in levodopa use Reduced levodopa dose requirement Potential reduction of oxidative radicals derived from levodopa metabolism Antioxidant effects Direct free radical scavenging effect at higher concentrations than those achieved in routine treatment Autoreceptor effect Antioxidant effect through activation of presynaptic receptors Dopamine agonists might provide neuroprotection in PD through various possible mechanisms.1 These include levodopa-sparing, stimulation of dopamine autoreceptors, direct free radical scavenging, inhibition of STN-mediated excitotoxicity, and activation of dopamine receptors with signal-mediated anti-apoptotic effects. Levodopa-sparing: By reducing the required doses of levodopa, treatment with dopamine agonists may result in reduced production of oxidative radicals derived from the metabolism of levodopa. Moreover, initial monotherapy with a dopamine agonist permits a delay in the introduction of levodopa in PD patients. Thus, dopamine agonists can reduce the cumulative levodopa dose and the total amount of oxidative radicals produced over the course of the disease, as well as the related oxidative stress applied to the substantia nigra. Nevertheless, it has not yet been clearly established whether or not levodopa is toxic to PD patients. There is substantial evidence that dopamine agonists can act as free radical scavengers both in vitro and in vivo. However, this effect requires concentrations higher than those achieved during routine use in PD patients. Dopamine agonists may exert an antioxidant effect through the activation of presynaptic autoreceptors that inhibit dopamine synthesis, release and metabolism, thus decreasing free radical production.2 References 1. Schapira AH, Olanow CW. Rationale for the use of dopamine agonists as neuroprotective agents in Parkinson’s disease. Ann Neurol 2003;53(Suppl 3):S 2. Carter AJ, Muller RE. Pramipexole, a dopamine D2 autoreceptor agonist, decreases the extracellular concentration of dopamine in vivo. Eur J Pharmacol 1991;200:65-72. Schapira AH, Olanow CW. Ann Neurol 2003;53(Suppl 3):S

115 Section I Dopamine Agonists – Possible Mechanisms for Neuroprotection in Parkinson’s Disease (2) Amelioration of subthalamic nucleus-mediated excitotoxicity Anti-apoptotic effects Possible direct or receptor-mediated effect on mitochondrially based pro-apoptotic intracellular signals Pramipexole Decreases apoptotic cell death in SHSY-5Y neuronal-derived dopaminergic cells exposed to toxins Induces increased expression of anti-apoptotic proteins BcL-xL and BcL-2 Induces up-regulation of several genes associated with neuroprotective effects Physiological and metabolic studies indicate that the subthalamic nucleus (STN), which uses glutamate as its neurotransmitter, is overactive in PD. Excess glutamate release might induce excitotoxic damage in STN targets that include the globus pallidus interna, the pedunculopontine nucleus and the SNpc. Dopaminergic agents have been shown to suppress STN overactivity and metabolic alterations in parkinsonian models1 and might prevent STN-mediated excitotoxicity in PD patients.2 There is evidence supporting the hypothesis that dopamine agonists exert a beneficial neuroprotective effect through an anti-apoptotic effect. It has been suggested that mitochondrially derived pro-apoptotic signals induced by a variety of stresses (e.g. free radicals, respiratory chain dysfunction, impaired calcium ion homeostasis) play a major role in initiating and regulating apoptosis in degenerative conditions such as PD.3 Dopamine agonists may have neuroprotective effects though a direct or receptor-mediated effect on these mitochondrially derived pro-apoptotic signals. Pramipexole is perhaps the best studied of the dopamine agonists in this regard.2 It has been shown to decrease apoptotic cell death in SHSY-5Y neuronal-derived dopaminergic cells exposed to a variety of toxins, including MPP+ (1-methyl-4-phenylpyridinium ion), the specific mitochondrial complex I inhibitor rotenone, and dopamine. Pramipexole has also been shown to induce increased expression of the anti-apoptotic proteins BcL-xL and BcL-2. Studies also indicate that pramipexole induces up-regulation of several genes associated with neuroprotective effects. References 1. Herrero MT, Levy R, Ruberg M, et al. Consequence of nigrostriatal denervation and L-dopa therapy on the expression of glutamic acid decarboxylase messenger RNA in the pallidum. Neurology 1996;47: 2. Schapira AH, Olanow CW. Rationale for the use of dopamine agonists as neuroprotective agents in Parkinson’s disease. Ann Neurol 2003;53(Suppl 3):S 3. Schapira AH. Mitochondrial disease. Lancet 2006;368:70-82. Schapira AH, Olanow CW. Ann Neurol 2003;53(Suppl 3):S

116 Trophic factors (e.g. BDNF) inhibit apoptosis
Section I Cellular Dysfunctions in Parkinson’s Disease and Targets for Dopamine Agonists in Neuroprotection Caspase activation Apoptosis (nuclear changes & cell death) Free radicals Cytochrome c Mitochondrial damage MPTP/MPP+ TNF- receptor Excitotoxicity Glutamate receptor (NMDA)  Ca2+ BcL-2, BcL-xL inhibit release of cytochrome c Trophic factors (e.g. BDNF) inhibit apoptosis Protein aggregation The figure summarises the cellular dysfunctions in the pathogenesis of PD as a basis for possible targets for dopamine agonists with regard to neuroprotection. Although necrosis may contribute to cell death in PD, programmed cell death (apoptosis) appears to be the primary mechanism whereby dopaminergic neurons die in PD. Oxidative stress may be one of the most important causes of apoptotic nigral cell death.1-4 Apoptosis is characterised by condensation of chromatin and DNA fragmentation, followed by cell death.2 Caspase activation in the cytoplasm is a critical step in initiating the final stages of apoptosis.5 Numerous pathways can lead to caspase activation; however, in Parkinson’s disease model systems (e.g. MPTP toxicity), cytochrome c release from the mitochondria appears to be an important step in caspase activation.1,5,6 Cytochrome c is released when mitochondria are damaged by oxidative stress or, experimentally, by MPTP toxicity.1,6 BcL-2 and BcL-xL are anti-apoptotic because they inhibit the release of cytochrome c.1,7 Free radicals and reactive oxygen species may contribute to mitochondrial damage,1,4 and mitochondrial damage can in turn lead to the release of free radicals and increased cellular oxidation.3 Cytokines and tumour necrosis factor- (TNF-) activate intracellular pathways that also activate caspases, leading to apoptosis.8 Excess glutamate causes excitotoxicity through activation of the N-methyl-D-aspartate (NMDA) glutamate receptor, leading to excess intracellular Ca2+ and toxic nitric oxide production.9 Dopaminergic neurons in PD are characterised by protein aggregates of -synuclein and other proteins. The removal of these aggregates and misfolded proteins is dependent on the ubiquitin-proteasome system. In both familial and sporadic PD, there are defects in 26/20S proteasome subunits, which result in an accumulation of misfolded protein aggregates. These damaged proteins may contribute to cytotoxicity, mitochondrial dysfunction and cell death.10 References 1. Blum D, Torch S, Lambeng N, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001;65: 2. Tatton WG, Chalmers-Redman RC, Brown D, et al. Apoptosis in Parkinson’s disease: signals for neuronal degradation. Ann Neurol 2003;53(Suppl 3):S61-72. 3. Jenner P. Oxidative stress in Parkinson’s disease. Ann Neurol 2003;53(Suppl 3):S26-38. 4. Yoo MS, Chun HS, Son JJ, et al. Oxidative stress regulated genes in nigral dopaminergic neuronal cells: correlation with the known pathology in Parkinson’s disease. Mol Brain Res 2003;110:76-84. 5. Nuñez G, Benedict MA, Hu Y, et al. Caspases: the proteases of the apoptotic pathway. Oncogene 1998;17: 6. Du Y, Dodel RC, Bales KR, et al. Involvement of a caspase-3-like cysteine protease in 1-methyl-4-phenylpyridium-mediated apoptosis of cultured cerebellar granule neurons. J Neurochem 1997;69: 7. Jacotot E, Costantini P, Laboureau E, et al. Mitochondrial membrane permeabilization during the apoptotic process. Ann NY Acad Sci 1999;887:18-30. 8. Hartmann A, Mouatt-Prigent A, Faucheux BA, et al. FADD: a link between TNF family receptors and caspases in Parkinson’s disease. Neurology 2002;58: 9. Dawson VL, Dawson TM. Nitric oxide neurotoxicity. Chem Neuroanat 1996;10: 10. McNaught K St P, Olanow CW. Proteolytic stress: a unifying concept for the etiopathogenesis of Parkinson’s disease. Ann Neurol 2003;53(Suppl 3):S73-86. Abbreviations: BDNF, brain-derived neurotrophic factor; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, 1-methyl-4-phenylpyridinium; TNF-, tumour necrosis factor-; NMDA, N-methyl-D-aspartate. Blum D, et al. Prog Neurobiol 2001;65: Tatton WG, et al. Ann Neurol 2003;53(Suppl 3):S61-72.

117 Section I Dopamine Agonists – Inhibition of Multiple Pathways of Cellular Dysfunction Caspase activation Apoptosis (nuclear changes & cell death) Free radicals Cytochrome c Mitochondrial damage MPTP/MPP+ TNF- receptor Excitotoxicity Glutamate receptor (NMDA)  Ca2+ Pramipexole increases Bcl-2, Bcl-xl Pramipexole may induce up-regulation of a trophic factor Protein aggregation = Inhibition This figure illustrates various pathways of cellular dysfunction that may be inhibited by dopamine agonists as suggested by available studies.1-3 References Gu M, Iravani MM, Cooper JM, King D, Jenner P, Schapira AH. Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. J Neurochem 2004;91: Blum D, Torch S, Lambeng N, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001;65: Tatton WG, Chalmers-Redman RC, Brown D, et al. Apoptosis in Parkinson’s disease: signals for neuronal degradation. Ann Neurol 2003;53(Suppl 3):S61-72. Abbreviations: NMDA, N-methyl-D-aspartate; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; MPP+, 1-methyl-4-phenylpyridinium; TNF-, tumour necrosis factor- Gu M, et al. J Neurochem 2004;91: Blum D, et al. Prog Neurobiol 2001;65: Tatton WG, et al. Ann Neurol 2003; 53(Suppl 3):S61-72.

118 Mitochondrial-Mediated Apoptotic Cell Death in SHSY-5Y Cells
Section I Mitochondrial-Mediated Apoptotic Cell Death in SHSY-5Y Cells MPP+ Rotenone Free radicals Cytochrome c release* Caspase activation* Apoptotic cell death* Pore opening* ATP production * blocked by pramipexole The figure illustrates mitochondrial apoptotic cell death in SHSY-5Y neuronal-derived dopaminergic cells when exposed to a variety of toxins, including 1-methyl-4-phenylpyridinium ion (MPP+) and the specific mitochondrial complex I inhibitor rotenone. MPP+ and rotenone have both been shown to induce cell death by apoptosis in the cell model systems used in the neuroprotective models for pramipexole. Investigation of the mechanism of pramipexole action has shown that this compound can prevent the fall in mitochondrial membrane potential, reduce the release of cytochrome c, prevent activation of caspase 3, and reduce apoptotic cell death in response to MPP+ and rotenone.1,2 Thus, pramipexole may exert activity at the mitochondrial level or, more proximally, in the toxin pathway. In separate experiments, pramipexole has been shown to prevent mitochondrial pore opening in response to high calcium levels in isolated mitochondria. This finding suggests that pramipexole may have a direct action on the mitochondrion. References 1. Gu M, Iravani MM, Cooper JM, King D, Jenner P, Schapira AH. Pramipexole protects against apoptotic cell death by non-dopaminergic mechanisms. J Neurochem 2004;91: 2. Cassarino DS, Fall CP, Smith TS, Bennett JP Jr. Pramipexole reduces reactive oxygen species production in vivo and in vitro and inhibits the mitochondrial permeability transition produced by the parkinsonian neurotoxin methylpyridinium ion. J Neurochem 1998;71: Gu M, et al. J Neurochem 2004;91: Copyright © 2004, Blackwell Publishing Ltd.

119 Pramipexole Protects Against MPTP Toxicity in Primates
Section I Pramipexole Protects Against MPTP Toxicity in Primates Abbreviations: MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TH-ir, tyrosine hydroxylase-immunoreactive TH-ir cell counts at the level of the 3rd cranial nerve Group A, animal controls Group B, MPTP only Group C, pramipexole prior to MPTP Group D, pramipexole coincident with MPTP Group E, pramipexole after MPTP * P < 0.05; NS, non significant TH-ir neuronal counts in the rostrocaudal plane 50 100 150 200 250 300 Group A Group B Group C Group D Group E Treatment Group NS * Mean TH+ve Cell Counts at 3rd Nerve Mean Counts of TH+ve Neurons 500 1000 1500 2000 2500 3000 Rostrocaudal Distance (m) On the basis of the observation that pramipexole protects neuronal cells against dopaminergic toxins in vitro, Iravani et al.1 conducted a study demonstrating that pramipexole prevents MPTP toxicity in vivo in primates. Common marmosets were repeatedly treated with pramipexole before, coincidentally with or after low-dose MPTP treatment aimed at inducing a partial lesion of the substantia nigra. The two figures illustrate nigral dopaminergic cell survival represented by mean cell counts of nigral TH-immunoreactive (ir) neurons following exposure to MPTP and the various pramipexole regimens. The figure on the left depicts TH-ir neuronal counts in the rostracaudal plane. Each data point represents mean ± SEM (n = 4) of TH-ir cell counts measured at regular 100-µm intervals. The figure on the right depicts mean nigral TH-ir cell counts at the level of the 3rd cranial nerve. Data were compared using one-way ANOVA with Tukey-Kramer multiple analysis post-test (P < 0.05). Animals pretreated with pramipexole had a significantly greater number of surviving tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta. Pramipexole pretreatment also prevented degeneration of striatal dopamine terminals. Treatment with pramipexole concurrently with or following MPTP did not prevent TH-positive cell loss. Therefore, pramipexole pretreatment appears to induce adaptive changes that protect against dopaminergic cell loss in primates. Reference 1. Iravani MM, Haddon CO, Cooper JM, Jenner P, Schapira AH. Pramipexole protects against MPTP toxicity in non-human primates. J Neurochem 2006;96: Iravani MM, et al. J Neurochem 2006;96: Copyright © 2006, Blackwell Publishing Ltd.

120 Neuroprotection Trials – Evaluation of Dopamine Agonist Efficacy
Section I Neuroprotection Trials – Evaluation of Dopamine Agonist Efficacy Limitations of clinical measures Confounded by symptomatic benefits Biological markers Accurate assessment of dopaminergic nigrostriatal system Possible confound of drug effects on imaging Experience has shown that, as a result of confounding factors, clinical outcomes have limitations in evaluating neuroprotective benefits of agents with known or unknown symptomatic effects in PD. Consequently, efforts have been focused on biological markers of nigrostriatal degeneration. Although the dopaminergic nigrostriatal system is not the only neuronal system that degenerates in PD, it is the most visible one and the one that has been most conducive to current measurements.1,2 However, possible effects of drugs on imaging tracers handling may confound the results. References 1. Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ; Quality Standards Subcommittee of the American Academy of Neurology. Practice Parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66: 2. Ahlskog JE. Slowing Parkinson’s disease progression: recent dopamine agonist trials. Neurology 2003;60:381-9. Suchowersky O, et al. Neurology 2006;66: Ahlskog JE. Neurology 2003;60:381-9.

121 Dopamine Nuclear Imaging
Section I Dopamine Nuclear Imaging Radioligands that label nigrostriatal neurons 123I--CIT* Labels the dopamine transporter (DAT) protein, selectively expressed on dopaminergic neurons Uses SPECT† technology 18F-dopa‡ Is transported into dopaminergic neurons and concentrated within synaptic vesicles as 18F-dopamine Uses PET§ technology Objective estimation of the extent of neuronal loss in patients with Parkinson’s disease Most neuroimaging investigation efforts during the past few years have focused on the dopaminergic nigrostriatal system because it is the most visible system in PD and currently the one that can be measured easier than others systems. Parkinsonian symptoms occur when striatal dopaminergic terminals are reduced to approximately 30–50% of normal,1 with a progressive decline thereafter. Imaging of the dopaminergic system uses radioactively labelled ligands (radioligands) that label nigrostriatal neurons. Two tracers are most commonly used. After intravenous injection, 123I-β-CIT labels the dopamine transporter protein, which is selectively expressed on dopaminergic neurons; SPECT is used for neuroimaging with this ligand. 18F-dopa is another radioligand that, after intravenous injection, is transported into dopaminergic neurons and is concentrated within synaptic vesicles as 18F-dopamine, which generates the imaging signal.2 Imaging with 123I-β-CIT and 18F-dopa shows declining values with more severe and long-standing PD. Thus, SPECT and PET provide an objective estimation of the extent of neuronal loss in PD. References 1. Lee CS, Samii A, Sossi V, et al. In vivo positron emission tomographic evidence for compensatory changes in presynaptic dopaminergic nerve terminals in Parkinson’s disease. Ann Neurol 2000;47: 2. Ahlskog JE. Slowing Parkinson’s disease progression: recent dopamine agonist trials. Neurology 2003;60:381-9. * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography ‡ 18F-6-fluorodopa § positron emission technology Lee CS, et al. Ann Neurol 2000;47: Ahlskog JE. Neurology 2003;60:381-9.

122 Dopamine Nuclear Imaging: Where Do Ligands Bind?
Section I Dopamine Nuclear Imaging: Where Do Ligands Bind? D2 receptors (IBZM*, raclopride) Presynaptic Postsynaptic Dopamine receptors DOPA Dopamine Neuronal dopamine metabolism (F-dopa) Radioactively labelled ligands (radioligands) target specific neurotransmitter receptors and can often identify subpopulations of neurons in the brain. In PD, imaging of the dopaminergic system uses radioligands directed at targets that include molecular components of the dopamine synthetic pathways, the dopamine vesicular transporter (which concentrates dopamine into vesicles to facilitate its release from dopaminergic neurons into the synapse), the dopamine membrane transporter (DAT) (which removes dopamine from the synapse and recycles it back into the neuron), and the dopamine receptor in the postsynaptic membrane. Imaging with 18F-dopa reflects dopaminergic neuron synthetic function, whereas imaging with radioligands for DAT (such as 123I-β-CIT) reflects nerve terminal integrity.1 Reference 1. Marek K, Seibyl J.  TechSight. Imaging. A molecular map for neurodegeneration. Science 2000;289: Dopamine transporters (β-CIT, others) * 123I-iodobenzamide Marek K, et al. Science ;289: © 2000 American Association for the Advancement of Science.

123 Neuroimaging in Parkinson’s Disease
Section I Neuroimaging in Parkinson’s Disease Early-Stage PD Control Late-Stage PD Fluorodopa PET* Mid-Stage PD 123I--CIT† SPECT‡ © 2004 American Medical Association. All rights reserved. The top and bottom figures display, respectively, fluorodopa PET and 123I--CIT SPECT imaging in healthy controls and in patients with PD at various stages of disease progression. In PD, as shown, striatal uptake of the markers is asymmetrically reduced. This reduction is more pronounced in the posterior portion of the putamen. As the disease worsens, the uptake of the radioligands is further reduced. This decline can be quantified and serve as a marker of disease progression.1 Reference 1. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004;291: * positron emission tomography † 2β-carbomethoxy-3β-(4-iodophenyl)tropane ‡ single photon emission computed tomography Schapira AH, Olanow CW. JAMA 2004;291:

124 Section I Neuroprotection Trials with Dopamine Agonists – CALM-PD and REAL-PET Studies Patients with early Parkinson’s disease CALM-PD Pramipexole versus levodopa 123I--CIT* SPECT† to follow the rate of loss of dopaminergic nigrostriatal cell density REAL-PET Ropinirole versus levodopa 18F-dopa‡ PET§ to follow the rate of loss of dopaminergic nigrostriatal cell density Two studies have sought to determine whether the neuroprotective benefits of dopamine agonists seen in the laboratory can be reproduced in patients to modify the course of PD. The CALM-PD study used β-CIT SPECT to follow the rate of loss of dopamine transporter as a marker of dopaminergic nigrostriatal cell density.1 Patients with early PD were randomised to pramipexole or levodopa and followed for a total of four years. Levodopa supplementation was allowed in both arms. The REAL-PET ropinirole study used a similar trial design, but utilised PET to follow loss of nigrostriatal cell density with fluorodopa.2 References 1. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287: 2. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003;54: * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography ‡ 18F-6-fluorodopa § positron emission tomography Parkinson Study Group. JAMA 2002;287: Whone AL, et al. Ann Neurol 2003;54:

125 Neuroprotection Trials with Dopamine Agonists – CALM-PD Study
Section I Neuroprotection Trials with Dopamine Agonists – CALM-PD Study Early, symptomatic patients with Parkinson’s disease Multicentre, double-blind, randomised Initial treatment with pramipexole (n = 42) or carbidopa/levodopa (n = 40) Four-year follow-up In vivo imaging of the dopamine transporter with 123I--CIT* SPECT† Progression of dopaminergic degeneration CALM-PD (Comparison of the agonist pramipexole with levodopa on motor complications of PD) was a randomised, multicentre, parallel-group, double-blind, controlled clinical trial that compared initial treatment with pramipexole and levodopa in early, symptomatic Parkinson’s disease with regard to the development of dopaminergic motor complications.1 At 22 American and Canadian sites, 301 eligible subjects requiring antiparkinsonian therapy to treat emerging disability were enrolled in CALM-PD and randomised to (i) active pramipexole and placebo levodopa or (ii) placebo pramipexole and active levodopa.2 Eighty-two (82) of the 301 patients, enrolled between November 1996 and August 1997, who had early PD participated in the imaging study, which used in vivo imaging of DAT with 123I-β-CIT SPECT to assess the progression of dopaminergic degeneration.3 References 1. Parkinson Study Group. A randomized controlled trial comparing pramipexole with levodopa in early Parkinson’s disease: design and methods of the CALM-PD Study. Clin Neuropharmacol 2000;23:34-44. 2. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 2000;284: 3. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287: * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography Parkinson Study Group. JAMA 2002;287:

126 CALM-PD – Striatal 123I--CIT* Uptake (SPECT†)
Section I CALM-PD – Striatal 123I--CIT* Uptake (SPECT†) 10 (n=82) pramipexole (39) (35) levodopa -10 (33) (%) Mean Change from Baseline (39) -20 (36) -30 (32) In the CALM-PD study, patients randomised to receive pramipexole alone or in combination with levodopa had a significantly slower rate of decline in striatal β-CIT uptake (assessed by SPECT) compared with patients who received levodopa alone after 2, 3 and 4 years of treatment.1 The points represent mean percentage loss of uptake from baseline; error bars, standard deviation. Reference 1. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287: 10 20 30 40 50 Scan Interval (months) * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † single photon emission computed tomography Parkinson Study Group. JAMA 2002;287: © 2002 American Medical Association. All rights reserved.

127 Neuroprotection Trials with Dopamine Agonists – REAL-PET Study
Section I Neuroprotection Trials with Dopamine Agonists – REAL-PET Study Early, symptomatic patients with Parkinson’s disease Multicentre, double-blind, randomised Initial treatment with ropinirole (n = 68) or carbidopa/levodopa (n = 59) Two-year follow-up In vivo imaging of dopamine terminals with 18F-dopa* PET† Progression of dopaminergic degeneration In the REAL-PET (Requip as Early Therapy versus L-dopa) study, patients with untreated PD were randomised to initiate treatment with either the dopamine agonist ropinirole or levodopa.1 If symptoms remained inadequately controlled, patients in the ropinirole group could receive levodopa. 18F-dopa PET at 4 weeks and again at 4 years after treatment initiation was used to determine the rates of loss of dopamine-terminal function. Reference 1. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson's disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003;54: * 18F-6-fluorodopa † positron emission tomography Whone AL, et al. Ann Neurol 2003;54:

128 REAL-PET – Putamen 18F-dopa‡ Uptake (PET†)
Section I REAL-PET – Putamen 18F-dopa‡ Uptake (PET†) % change in putamen F-dopa Ki (n) Ropinirole (63) L-dopa (58) % Change from Baseline in 18F-dopa Uptake * The primary outcome measure in the REAL-PET study was the mean percentage reduction in side-to-side average putamen 18F-dopa uptake as an influx constant (Ki).1 Central statistical parametric mapping (SPM) analysis showed that there was less reduction in 18F-dopa uptake in the putamen and substantia nigra with ropinirole compared with placebo: 22.87% in the levodopa group versus 14.09% in the ropinirole group, a relatively significant difference of 38% (P < ). Reference 1. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003;54: * P < ‡ 18F-6-fluorodopa † positron emission tomography Whone AL, et al. Ann Neurol 2003;54: Copyright © 2003 American Neurological Association.

129 Scan Interval (months)
Section I Percentage Change in Putamen 123I--CIT* and 18F-dopa† Uptake by Treatment 10 -10 % Change from Baseline CALM-PD CIT Pramipexole Levodopa -20 REAL-PET Ropinirole -30 Levodopa This figure illustrates the decrease in radioligand uptake in two distinct multicentre, double-blind, randomised controlled studies comparing pramipexole versus levodopa (CALM-PD study) and ropinirole versus levodopa (REAL-PET study) in treatment-naïve patients with early, symptomatic Parkinson's disease.1,2 Both studies show that treatment with the dopamine agonists pramipexole and ropinirole (with or without levodopa) resulted in significantly less reduction in radioligand uptake by nigrostriatal dopaminergic cells, particularly in the putamen, compared with patients treated with levodopa alone. References 1. Parkinson Study Group. Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA 2002;287: 2. Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: The REAL-PET study. Ann Neurol 2003;54: 10 20 30 40 50 Scan Interval (months) * 2β-carbomethoxy-3β-(4-iodophenyl)tropane † 18F-6-fluorodopa Parkinson Study Group. JAMA 2002;287: Whone AL, et al. Ann Neurol 2003;54:

130 Section I Neuroprotection Trials with Dopamine Agonists – Conclusions from Neuroimaging Studies Early Parkinson’s disease Initial treatment with pramipexole or ropinirole Significant delay in the rate of decline of a surrogate marker of nigrostriatal function Possible interpretations Real reduction in the rate of cell loss in the substantia nigra Consistent with laboratory findings No corresponding clinical benefits over levodopa with either drug Longer follow-up is needed Levodopa toxicity Controversial Pharmacological difference in the ability of dopamine agonists or levodopa to regulate the dopamine transporter or fluorodopa metabolism Insufficient information to confirm The CALM-PD and REAL-PET studies demonstrate that the dopamine agonists pramipexole and ropinirole are associated with a significant delay in the rate of decline of a surrogate imaging marker of nigrostriatal function. One interpretation of these findings is that these two dopamine agonists slow the rate of cell loss in the substantia nigra of PD patients. This is consistent with laboratory findings. However, neither drug showed corresponding clinical benefits over levodopa and it can be argued that the time course of the trials was too short to permit such an effect to be detected in the context of viable compensatory mechanisms and powerful symptomatic effects. Such clinical benefits will only become apparent with longer follow-up. Another possible interpretation is that levodopa is toxic to nigral neurons, consistent with the levodopa oxidative metabolism and the potential to generate cytotoxic free radicals.1 However, the available evidence is controversial.2 Finally, it has been proposed that the differences between the effects of levodopa and dopamine agonists seen in the CALM-PD and REAL-PET studies are not related to any direct effect of the drugs on dopamine neuron survival or degeneration, but rather to a pharmacological difference in the ability of these drugs to regulate the dopamine transporter or fluorodopa metabolism. A review of the studies investigating the effects of levodopa and dopamine agonists on transporter and fluorodopa metabolism reveals that the data are conflicting and that, at present, there is insufficient information for or against such an effect.3 References 1. Olanow CW. A radical hypothesis for neurodegeneration. Trends Neurosci 1993;16: 2. Agid Y, Olanow CW, Mizuno Y. Levodopa: why the controversy? Lancet 2002;360:575. 3. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004;291: Olanow CW. Trends Neurosci 1993;16: Agid Y, et al. Lancet 2002;360:575. Schapira AH, Olanow CW. JAMA 2004;291:

131 Neuroprotection Trials with Dopamine Agonists – Conclusions
Section I Neuroprotection Trials with Dopamine Agonists – Conclusions Combination of in vitro, in vivo and clinical trials: Supports but does not prove disease-modifying effect of pramipexole and ropinirole in Parkinson’s disease Compelling evidence to stimulate further research In practice: The decision to introduce putative neuroprotective therapy for Parkinson’s disease: A matter of judgment and personal approach on the part of the patient and the physician The challenge of defining reliable methods for detecting disease progression In conclusion, both the CALM-PD and REAL-PET studies demonstrate that dopamine agonist therapy with pramipexole or ropinirole in patients with PD is associated with a significant delay in the rate of decline of a surrogate imaging marker of nigrostriatal function.1 This finding, combined with in vitro and in vivo laboratory evidence, suggests, but does not prove, that these compounds have a neuroprotective effect. It is compelling evidence that calls for further research. In practice, these results lay the groundwork for the decision-making process when considering the introduction of putative neuroprotective therapy in PD. The limitations of the available information also underscore the immediate challenge of defining reliable methods to detect disease progression and assess putative neuroprotective agents. Reference 1. Schapira AH, Olanow CW. Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 2004;291: Schapira AH, Olanow CW. JAMA 2004;291:

132 Disease Modification (Neuroprotection)
Section I Disease Modification (Neuroprotection) Perspectives

133 Perspectives in Neuroprotection
Section I Perspectives in Neuroprotection Presymptomatic detection of Parkinson’s disease Value of Parkinson’s disease biomarkers Prove neuroprotective benefits of current and future agents Appropriate trial designs Initiate treatment before clinical symptoms occur Identify and remove/modify possible environmental contribution to Parkinson’s disease aetiology While neuroprotection or neurorescue would be valuable to patients at any stage of the disease, such therapeutic interventions would be most valuable to those with early PD. Recent advances in PD genetics and neuroimaging offer the perspective of identifying and treating susceptible individuals before clinical features even appear.1 Such an approach would potentially be of primary relevance to the members of families with the more rare inherited form of PD. However, as knowledge about the genetic and environmental factors contributing to the aetiology of PD progresses, the application of such treatments would obviously extend to sporadic PD. In any case, there is a clear need to develop both tools for presymptomatic detection of PD and correctly designed future neuroprotective clinical trials in order to establish the neuroprotective benefits of therapeutic agents.2,3 References 1. Schapira AH. Science, medicine, and the future: Parkinson’s disease. BMJ 1999;318:311-4. 2. Clarke CE. A "cure" for Parkinson’s disease: can neuroprotection be proven with current trial designs? Mov Disord 2004;19:491-8. 3. Kieburtz K. Designing neuroprotection trials in Parkinson’s disease. Ann Neurol 2003;53(Suppl 3):S100-7. Schapira AH. BMJ 1999;318:311-4. Clarke CE. Mov Disord 2004;19:491-8. Kieburtz K. Ann Neurol 2003;53(Suppl 3):S100-7.

134 Perspectives in Neuroprotection – Parkinson’s Disease Biomarkers
Section I Perspectives in Neuroprotection – Parkinson’s Disease Biomarkers Clinical Olfaction (UPSIT*) Sleep - RBD† Gut Cardiac Skin Motor analysis Speech Cognition Depression Personality changes Imaging – Phenotomics SPECT‡/PET§-DAT** PET F-Dopa MRI-spectroscopy Functional MRI Nigral transcranial ultrasound Genetics Synuclein, LRRK2 Parkin DJ1, PINK1 Laboratory Proteomics Transcriptomics Metabolomics Neuronal loss in PD occurs beyond the dopaminergic system and results in autonomic, affective and cognitive deficits. Biomarkers are parameters that can be objectively measured and evaluated as an indicator of a normal or pathogenic biological process, or as pharmacological responses to a therapeutic intervention. Some biomarkers can be considered surrogate markers, i.e. markers intended to substitute for a clinical endpoint. It is expected that appropriate biomarkers will help in the diagnosis of symptomatic and presymptomatic PD or provide surrogate endpoints to demonstrate clinical efficacy of neuroprotective interventions.1 Current knowledge offers the perspective of PD detection before the onset of motor symptoms. Numerous preclinical symptoms of PD such as RBD and hyposmia have already been identified,2-4 while others are in the process of being confirmed or identified. To these, one may also add the importance of nigral ultrasound findings. This slide lists the available confirmed or candidate biomarkers that may help us screen patients at risk for PD. References 1. Michell AW, Lewis SJ, Foltynie T, Barker RA. Biomarkers and Parkinson’s disease. Brain 2004;127: 2. Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters ECh, Berendse HW. Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 2004;56: 3. Stiasny-Kolster K, Doerr Y, Moller JC, et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005;128: 4. Sommer U, Hummel T, Cormann K, et al. Detection of presymptomatic Parkinson’s disease: combining smell tests, transcranial sonography, and SPECT. Mov Disord 2004;19: * University of Pennsylvania Smell Identification Test; † rapid eye movement (REM) sleep behaviour disorder; ‡ single photon emission computed tomography; § positron emission tomography; ** dopamine transporter Michell AW, et al. Brain 2004;127: Ponsen MM, et al. Ann Neurol 2004;56: Stiasny-Kolster K, et al. Brain 2005;128: Sommer U, et al. Mov Disord 2004;19:

135 Section I Physical Therapy

136 Role of Physical Therapy in Parkinson’s Disease
Section I Role of Physical Therapy in Parkinson’s Disease Hypometria, bradykinesia, rigidity and disturbed postural control compromise patient mobility and quality of life1 Bedtime mobility Transfers Gait Balance loss, falling Need for an individualised programme Exercise Posture awareness Pain control Patient/family education for safety, stress reduction, movement enhancement and comprehension strategies Only 3–29% of patients regularly consult a paramedical therapist (physical, occupational, speech)2 There is evidence that patients with PD benefit from physical therapy added to their standard medication.1 Medications cannot completely control the disease in the long term. Moreover, motor complications are mostly associated with levodopa. In addition, cognitive impairment occurs after a number of years. These limitations of drug treatment thus lay the basis for physical therapy as an integral part of disease management in PD from the time of diagnosis to the advanced stages. The movement disturbances characterizing PD such as hypometria, bradykinesia, rigidity and postural-control disturbance compromise patient mobility in a variety of settings, e.g. bedtime mobility, transfers and gait. Consequently, an individualised programme for exercise, posture awareness, and pain control, and referral to a physical, occupational or speech therapist could significantly contribute to improved quality of life. Patient/family education programmes could provide additional information on issues related to safety, stress reduction, movement enhancement and comprehension strategies. Nevertheless, despite the expanded interest in these approaches, surveys show that only 3–29% of PD patients regularly consult a paramedical therapist.2 References 1. de Goede CJ, Keus SH, Kwakkel G, Wagenaar RC. The effects of physical therapy in Parkinson’s disease: a research synthesis. Arch Phys Med Rehabil 2001;82: 2. Deane KH, Ellis-Hill C, Jones D, et al. Systematic review of paramedical therapies for Parkinson’s disease. Mov Disord 2002;17: 1. De Goede CJ, et al. Arch Phys Med Rehabil 2001;82: 2. Deane KH, et al. Mov Disord 2002;17:

137 Physical Therapy in Early Parkinson’s Disease
Section I Physical Therapy in Early Parkinson’s Disease Enhances patient mobility by encouraging an active lifestyle Provides information on treatment options beyond medication Exercise may enhance dopaminergic pathways in PD Technique Goal Multidimensional exercise routine Address deficit in balance, mobility and risk of falls Promote spinal flexibility to delay and reduce significant limitations Strengthen core muscles of stability Fitness Maintain activity tolerance and cardiovascular fitness Caution: some fitness equipment may be inappropriate, e.g. treadmill Posture training Improve posture control and prevent falls Worksite evaluation* Identify areas of difficulty Optimise work conditions, task performance and safety Relaxation techniques Reduce stress and exacerbation of PD-related symptoms Physical therapy (PT) in the early stages of PD seeks to enhance patient mobility by encouraging an active lifestyle that maximises quality of life.1,2 A large variety of PT methods have been evaluated in PD. In early-stage PD, when the patient is independent and ambulatory, PT aims at teaching exercises designed to delay or prevent the aggravation of motor impairment and that may maintain or even increase functional capacities. Because the majority of PD patients have balance disturbances and increased risk of falling,3 a major goal of PT is to improve postural control and prevent falls. Developing safe awareness of posture and gait is often beneficial during the early stages of PD to prevent or delay posture or gait changes. In contrast, although aerobic exercises benefit PD patients as much as those without PD,4 fitness equipment such as the treadmill might accentuate pathological gait characteristics of PD.5-7 Worksite evaluation may help in determining areas of difficulty and in making recommendations for improved body mechanics, task performance and safety. Relaxation activities are aimed at reducing stress and exacerbations of PD-related symptoms in some patients. References 1. Wichmann R. The role of physical therapy in management of Parkinson’s disease. In: Ebadi M, Pfeiffer RF, eds. Parkinson’s Disease. Boca Raton: CRC Press; 2005. 2. Lugassy M, Garcies JM. Physical therapy in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 3. Koller WC, Glatt S, Vetere-Overfield B, Hassanein R. Falls and Parkinson’s disease. Clin Neuropharmacol 1989;12: 4. Bergen JL, Toole T, Elliott RG 3rd, Wallace B, Robinson K, Maitland CG. Aerobic exercise intervention improves aerobic capacity and movement initiation in Parkinson’s disease patients. Neuro Rehabilitation 2002;17:161-8. 5. Zijlstra W, Rutgers AW, Van Weerden TW. Voluntary and involuntary adaptation of gait in Parkinson’s disease. Gait Posture 1998;7:53-63. 6. Ouchi Y, Kanno T, Okada H, et al. Changes in dopamine availability in the nigrostriatal and mesocortical dopaminergic systems by gait in Parkinson’s disease. Brain 2001;124: 7. Reuter I, Harder S, Engelhardt M, Baas H. The effect of exercise on pharmacokinetics and pharmacodynamics of levodopa. Mov Disord 2000;15:862-8. * Approximately 30% of patients with PD remain professionally active. Wichmann R. In: Parkinson’s Disease; 2005. Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.

138 Physical Therapy in Moderate Parkinson’s Disease
Section I Physical Therapy in Moderate Parkinson’s Disease Progression of the disease Decreased mobility skills Increased gait disturbances; possible festination and/or freezing Significant balance problems in many patients and episodes of falling Possible motor fluctuations Technique Goal Compensatory mobility strategies Maximise functional independence Attention strategies and sensory cueing Improve magnitude in motor tasks by substitution of deficient motor cues provided by basal ganglia with external cues Gait training Overcome motor fluctuations and freezing Gait-assistive devices Maximise safety when ambulating Early physical therapy in the event of fracture or other illness Initiate timely mobilisation to reduce the risk of complications Adjustment of daily exercise Perform adapted and safe routine exercises As increased motor difficulties and reduced mobility skills develop with disease progression in PD, patients will face more problems in performing such routine activities as getting out of bed, rising from a chair or getting into a car. Gait abnormalities worsen. Patients may experience motor fluctuations, significant balance problems and their first episodes of falling.1 Physical therapy should then shift from the teaching of exercises to the teaching of compensation/compensatory strategies to maximise functional independence.2 Cueing techniques seek to improve magnitude in motor tasks by substituting external auditory, visual or proprioceptive cues for the deficient internal motor cues normally provided by the basal ganglia.3 Gait training enables patients to cope more efficiently with motor fluctuations and freezing episodes. If needed, gait-assistive devices can maximise safety when ambulating. If a fracture or another illness occurs, physical therapy referral should be immediate in order to initiate timely mobilisation that would reduce the risk of complications inherent to prolonged bed rest or inactivity. References 1. Wichmann R. The role of physical therapy in management of Parkinson’s disease. In: Ebadi M, Pfeiffer RF, eds. Parkinson’s Disease. Boca Raton: CRC Press; 2005. 2. Lugassy M, Garcies JM. Physical therapy in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 3. Muller V, Mohr B, Rosin R, Pulvermuller F, Muller F, Birbaumer N. Short-term effects of behavioral treatment on movement initiation and postural control in Parkinson’s disease: a controlled clinical study. Mov Disord 1997;12: Wichmann R. In: Parkinson’s Disease; 2005. Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.

139 Physical Therapy in Advanced Parkinson’s Disease
Section I Physical Therapy in Advanced Parkinson’s Disease Optimise functional independence by compensation strategies for worsening motor impairment Emphasis on discipline in order to avoid risky activities such as walking and swallowing Detect depression Technique Goal Continued instruction Teach the fundamental difference between automatic and consciously controlled movements Emphasise the need to switch to conscious movements for almost all daily motor activities Behavioural strategies Substitute deficient motor cues provided by basal ganglia with external cues Wheelchair and body mechanics Engage in safe ambulation and transfers Instruction in proper positioning Prevent risk of aspiration while eating Avoid habits that worsen flexed posture (excessive pillows) Appropriate daily exercise programme Maximise flexibility and improve patient comfort Pain control (heat, cold, massage, etc.) Control excessive rigidity and agitation Patients with advanced PD face increasing immobility and require assistance with almost all activities of daily living. Many patients develop cognitive changes that further affect independence and safety. The role of PT remains to provide appropriate compensation strategies for worsening motor impairments and optimise functional independence.1 Omitting some of the strategies may make activities such as walking and swallowing precarious, with possibly serious consequences. Therefore, it becomes very important for the patient to consistently apply the compensation strategies already learned. These strategies include the adaptation of the home environment in order to lessen the effects of impairment and to optimise safety. One key compensatory strategy in advanced PD is to increase the amount of attention devoted to any activity because motor activities such as walking, talking, writing and standing up are no longer automatic and require, therefore, active concentration and even mental rehearsal.2,3 References Muller V, Mohr B, Rosin R, Pulvermuller F, Muller F, Birbaumer N. Short-term effects of behavioral treatment on movement initiation and postural control in Parkinson’s disease: a controlled clinical study. Mov Disord 1997;12: Wichmann R. The role of physical therapy in management of Parkinson’s disease. In: Ebadi M, Pfeiffer RF, eds. Parkinson’s Disease. Boca Raton: CRC Press; 2005. Lugassy M, Garcies JM. Physical therapy in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. Wichmann R. In: Parkinson’s Disease; 2005. Lugassy M, Garcies JM. In: Principles of Treatment in Parkinson’s Disease; 2005.

140 Section I Future Treatments

141 Rationale for New Therapeutic Approaches
Section I Rationale for New Therapeutic Approaches Success of dopaminergic treatment in controlling motor symptoms Research focus on dopamine systems Limitation Pathophysiology Involvement of non-dopaminergic systems Clinical Loss of drug efficacy with disease progression Lack of control over most non-motor symptoms To date, treatment of PD is largely based on dopamine replacement therapy, either through levodopa or dopamine agonists.1 Currently, only anticholinergics and glutamate antagonists are used as non-dopaminergic medications for the treatment of motor symptoms. Dopaminergic treatment has been successful in controlling motor symptoms in the early stages of PD. However, as the disease progresses, treatment becomes less effective. Moreover, some motor and non-motors symptoms do not respond to dopaminergic therapy. Pathological changes in non-dopaminergic systems should, therefore, play a significant role in these features. Consequently, new therapeutic approaches are required.2 References 1. Schapira AHV, Olanow CW. The medical management of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. Jenner P. Novel therapeutic approaches in the treatment of Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. Schapira AHV, Olanow CW. In: Principles of Treatment in Parkinson’s Disease; 2005. Jenner P. In: Principles of Treatment in Parkinson’s Disease; 2005.

142 Novel Therapeutic Approaches for Parkinson’s Disease
Section I Novel Therapeutic Approaches for Parkinson’s Disease Target/Approach Goal Dopaminergic system Dopamine agonists Refined interaction with dopamine agonist receptors Dopamine reuptake blockers Highly potent specific blockers with antiparkinsonian effect and reduced induction of involuntary movements Continuous dopaminergic stimulation Long-acting agonists for a more physiological replacement therapy Non-dopaminergic systems Other monoamine transmitters Interaction with noradrenergic and serotoninergic receptors for the control of motor symptoms and reduced motor complications Cholinergic and GABAergic systems Avoidance of dyskinesias Potential for the control of cognitive deficits Glutamatergic systems Selective agonists to suppress dyskinesia and improve the response to dopaminergic treatment Opioid receptors Control of levodopa-induced dyskinesias Cannabinoid receptors Control of motor symptoms Adenosine receptors Antagonists for symptomatic antiparkinsonian effect Improvements in the pharmacological treatment of PD are aimed at maintaining long-term control of the disease and providing relief from motor and non-motor PD symptoms that do not respond to available dopaminergic agents. The table summarises the directions that these new approaches and drugs are taking.1 The enormous potential for innovation in the development of these pharmacological approaches should lead to significant improvements in patient quality of life. Reference 1. Schapira AH, Bezard E, Brotchie J, et al. Novel pharmacological targets for the treatment of Parkinson’s disease. Nat Rev Drug Discov 2006;5: Schapira, et al. Nature Rev Drug Discov 2006;5:

143 Section III – Depression in Parkinson’s Disease

144 Depression in Parkinson’s Disease – Summary
Section I Depression in Parkinson’s Disease – Summary Overview Epidemiology and Pathophysiology Burden Diagnosis and Evaluation Treatment

145 Section I Overview

146 Neuropsychiatric Non-Motor Symptoms of Parkinson’s Disease
Section I Neuropsychiatric Non-Motor Symptoms of Parkinson’s Disease Anxiety Anhedonia Apathy Depression The strongest predictor of quality of life in Parkinson’s disease Dementia Neuropsychiatric non-motor symptoms of Parkinson’s disease range from anxiety, anhedonia, apathy and depression to dementia.1, 2 The presence of depression has been shown to be the strongest predictor of quality of life in PD patients.3, 4 References 1. Aarsland D, Larsen JP, Lim NG, et al. Range of neuropsychiatric disturbances in patients with Parkinson’s disease. Neurol Neurosurg Psychiatry 1999;67:492-6. 2. Thanvi BR, Munshi SK, Vijaykumar N, Lo TC. Neuropsychiatric non-motor aspects of Parkinson’s disease. Postgrad Med J 2003;79:561-5. 3. Global Parkinson’s Disease Survey Steering Committee. Factors impacting on quality of life in Parkinson’s disease: results from an international survey. Mov Disord 2002;17:60-7. 4. Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000;69: Global Parkinson’s Disease Survey Steering Committee. Mov Disord 2002;17:60-7. Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69:

147 Patterns of Depression in Parkinson’s Disease
Section I Patterns of Depression in Parkinson’s Disease Off-period related Typically associated with motor symptoms (akinesia, rigidity, dystonia) Often associated with other non-motor symptoms, e.g. pain, anxiety, panic (delusions, hallucinations) Related to medication timing Treatment: Adjustment of antiparkinsonian medication Additional treatment interventions when needed Not off-period related In the majority of patients with depression and Parkinson’s disease No clear relationship with motor symptoms or medication timing May precede motor symptoms No clear relationship with PD severity and stage Need for treatment approaches specific to the depressive symptoms Depression may occur as a manifestation of off-periods in patients with Parkinson’s disease.1 The distinction with not off-period related depression is important because the treatment is entirely different. Off-period related depression is mostly associated with clear-cut off-periods and, in some cases, can be difficult to differentiate. This type of depression particularly occurs in patients treated with suboptimal doses that result in prolonged off-periods, with associated dystonia, anxiety, depression or pain. Because the symptoms coincide with treatment initiation, they are sometimes thought to be a side effect of the medication. However, the symptoms improve with an increase in medication. Most often, off-period related depression is easily recognised in patients with fluctuations and severe off-periods. The majority of depression in PD is not off-period related (at least not related to severe off-periods). There is no clear relationship between depressive symptoms and motor symptoms or medication timing. This depression may precede the onset of motor symptoms and thus represents a non-motor symptom that may be an early marker for PD.2 This section deals mostly with not off-period related depression that requires treatment interventions targeting the depressive symptoms per se. References 1. Sawabini KA, Juncos JL, Watts RL. Depression, psychosis, and cognitive dysfunction in Parkinson’s disease. In: Schapira AHV, Olanow CW, eds. Principles of Treatment in Parkinson’s Disease. Philadelphia, PA: Butterworth Heinemann; 2005. 2. Lieberman A. Depression in Parkinson’s disease – a review. Acta Neurol Scand 2006;113:1-8. Sawabini KA, et al. In: Principles of Treatment in Parkinson’s Disease; 2005. Lieberman A. Acta Neurol Scand 2006;113:1-8.

148 Epidemiology and Pathophysiology
Section I Epidemiology and Pathophysiology

149 Depression in Parkinson’s Disease – Epidemiology
Section I Depression in Parkinson’s Disease – Epidemiology Frequency of depression in Parkinson’s disease: probably 40–50% Compared to a 16% prevalence of depression in the general population (USA) Depression is the most common psychiatric complication in PD patients Exact epidemiological data are lacking Frequency varies between 4 and 70% depending on: Criteria used Population studied Frequency higher in studies from research centres than from community-based studies Severity of depression in PD patients 50% moderate to severe 50% mild Bimodal distribution: increased rates at the onset and a later peak in advanced disease Severity of depression correlates with reduced quality of life Depression is the most common psychiatric complication in Parkinson’s disease, probably affecting 40–50% of patients.1 By comparison, the prevalence of depression in the general US population is estimated to be 16%.2 However, exact epidemiological data are lacking and the frequency of depression varies between 4 and 70% depending on diagnostic criteria and the study population.3 In particular, studies from research centres that attract PD patients report higher depression prevalence rates than community-based studies. Severity of depression and anxiety correlates with reduced quality of life in PD patients.4 Although depression in PD is generally considered mild to moderate, some 50% of depressive PD patients suffer from moderate to severe depression. References 1. Cummings JL. Depression and Parkinson’s disease: a review. Am J Psychiatry 1992;149: 2. Kessler RC, Berglund P, Demler O, et al. National Comorbidity Survey Replication. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289: 3. Lieberman A. Depression in Parkinson’s disease – a review. Acta Neurol Scand 2006;113:1-8. 4. Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinson’s disease? J Neurol Neurosurg Psychiatry 2000;69: Cummings JL. Am J Psychiatry 1992;149: Lieberman A. Acta Neurol Scand 2006;113:1-8. Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69:

150 Depression in Parkinson’s Disease Is Under-Recognised
Section I Depression in Parkinson’s Disease Is Under-Recognised Association between Parkinson’s disease and depression is well known1,2 Depression in PD is insufficiently treated Pathophysiology not well understood Prospective study on PD patients (n = 101)3 Standardised testing: depression in 44% of patients Treating neurologist Depression identified in 21% of patients Diagnostic accuracy of 35% During routine office visits, neurologists fail to identify depression more than half of the time Need for improving diagnostic accuracy and timely therapeutic interventions Although the association between Parkinson’s disease and depression is well established, treatment of depression in PD patients is often insufficient.1-2 In a prospective study, Shulman et al.3 evaluated the diagnosis of depression, anxiety, fatigue and sleep disorders by two movement disorder specialists in 101 patients with PD at a movement disorder centre at the University of Miami, FL, USA. Standardised testing was used for diagnosing depression. The results were compared with the reports of specialists on their immediate impressions regarding the presence or absence of the four problems mentioned, including depression, after a routine office visit. Standardised testing identified depression in 44% of patients, whereas neurologists identified this condition in only 21% of PD patients. The diagnostic accuracy of the treating neurologist for depression was 35%. Consequently, this study demonstrates that during routine office visits, neurologists may fail to diagnose depression in the majority of PD patients who suffer from this condition. Awareness of this under-recognition should give rise to new therapeutic approaches aimed at improving diagnostic accuracy and timely intervention. References 1. Livingston G, Watkin V, Milne B, Manela MV, Katona C. The natural history of depression and the anxiety disorders in older people: the Islington community study. J Affect Disord 1997;46: 2. Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinson’s disease? Neurol Neurosurg Psychiatry 2000;69: 3. Shulman LM, Taback RL, Rabinstein AA, Weiner WJ. Non-recognition of depression and other non-motor symptoms in Parkinson’s disease. Parkinsonism Relat Disord 2002;8:193-7. 1. Livingston G, et al. J Affect Disord 1997;46: 2. Schrag A, et al. J Neurol Neurosurg Psychiatry 2000;69: 3. Shulman LM, et al. Parkinsonism Relat Disord 2002;8:193-7.

151 Causes of Depression in Parkinson’s Disease
Section I Causes of Depression in Parkinson’s Disease Reactive (chronic disease) Coincidental (high prevalence in age group) Parkinson’s disease-related causes Disturbance of monoaminergic pathways Dopaminergic, serotonergic and noradrenergic systems Many factors can cause depressive symptoms in patients with Parkinson’s disease: The stress of being diagnosed with a chronic illness can cause depressive symptoms in patients with PD, a potentially debilitating disorder. There may also be some coincidental depression. However, other major factors are involved, as depression may precede the diagnosis of PD. There is now increasing evidence that depressive symptoms are related to the disease process in PD via disturbances in the monoaminergic pathways between brain stem nuclei and prefrontal and orbito-frontal cortical areas.1 While widespread dopamine deficiency is the main feature of