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The Science and Medicine of Parkinsons Disease Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines of Clinical Practice.

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Presentation on theme: "The Science and Medicine of Parkinsons Disease Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines of Clinical Practice."— Presentation transcript:

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2 The Science and Medicine of Parkinsons Disease Applying Science, Expert Analysis, Guidelines, and Landmark Trials to the Front Lines of Clinical Practice Critical Challenges and Landmark Practice Advances Lawrence W. Elmer, MD, PhD Program Chairman Program Chairman Associate Professor of Neurology Director, The Center for Neurological Disorders University of Toledo Toledo, OH Lawrence W. Elmer, MD, PhD Program Chairman Program Chairman Associate Professor of Neurology Director, The Center for Neurological Disorders University of Toledo Toledo, OH

3 CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from TEVA Neuroscience, Inc. Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

4 Program Educational Objectives Participants in the symposium will: Learn to risk stratify, screen for, and evaluate patients with suspected or possible risk for Parkinsons Disease (PD), and identify optimal therapeutic approaches. Learn to undertake a systematic evaluation of patients at risk for PD, including neurological exam and stage this disease. Learn evidence-based approaches to reducing progression of PD, and sequencing pharmacological approaches in patients requiring monotherapy combination therapy for PD. Learn how to manage non-motor aspects of PD. Participants in the symposium will: Learn to risk stratify, screen for, and evaluate patients with suspected or possible risk for Parkinsons Disease (PD), and identify optimal therapeutic approaches. Learn to undertake a systematic evaluation of patients at risk for PD, including neurological exam and stage this disease. Learn evidence-based approaches to reducing progression of PD, and sequencing pharmacological approaches in patients requiring monotherapy combination therapy for PD. Learn how to manage non-motor aspects of PD.

5 Program Faculty Lawrence W. Elmer, MD, PhD Program Chairman Associate Professor of Neurology Director, The Center for Neurological Disorders The University of Toledo Toledo, OH Disorders The University of Toledo Toledo, OH William G. Ondo, MD Associate Professor of Neurology Baylor College of Medicine Houston, TX Lawrence W. Elmer, MD, PhD Program Chairman Associate Professor of Neurology Director, The Center for Neurological Disorders The University of Toledo Toledo, OH Disorders The University of Toledo Toledo, OH William G. Ondo, MD Associate Professor of Neurology Baylor College of Medicine Houston, TX Mark F. Lew, MD, FAAN Professor of Neurology Director, Division of Movement Disorders Vice-Chair Department of Neurology Keck/USC School of Medicine Los Angeles, CA Andrew Siderowf, MD, MSCE Parkinsons Disease and Movement Disorders Center Disorders Center Associate Professor of Neurology University of Pennsylvania Philadelphia, PA Mark F. Lew, MD, FAAN Professor of Neurology Director, Division of Movement Disorders Vice-Chair Department of Neurology Keck/USC School of Medicine Los Angeles, CA Andrew Siderowf, MD, MSCE Parkinsons Disease and Movement Disorders Center Disorders Center Associate Professor of Neurology University of Pennsylvania Philadelphia, PA

6 Faculty COI Disclosures Faculty COI Disclosures Lawrence W. Elmer, MD, PhD Research/Grant Support/Clinical Trials: GSK Consultant: Schwarz-Pharma, TEVA, GSK Speakers Bureau: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Teva, Valeant, Vernalis Mark F. Lew, MD, FAAN Grant/Research Support: Boehringer-Ingelheim, Eisai, GSK, Ipsen, Kyowa, Mentor, NIH, Novartis, Schering Plough, Schwarz Pharma/UCB, Solstice, Solvay, Teva Consultant: Boehringer-Ingelheim, GSK, Ipsen, Kyowa, Novartis, Prestwick, Schwarz Pharma, Solstice, TEVA, Valeant, Vernalis Speakers Bureau: Allergan, Boehringer-Ingelheim, GSK, Novartis, Solstice, Teva, UCB, Valeant Andrew D. Siderowf, MD, MSCE Grant/Research Support: Boehringer-Ingelheim Consultant: Boehringer-Ingelheim, TEVA Speakers Bureau: Boehringer-Ingelheim, Schwarz-Pharma, Teva William G. Ondo, MD Grant/Research Support: Forrest, UCB Speakers Bureau: Boehringer-Ingelheim, GSK, TEVA, Valeant, UCB Lawrence W. Elmer, MD, PhD Research/Grant Support/Clinical Trials: GSK Consultant: Schwarz-Pharma, TEVA, GSK Speakers Bureau: Boehringer-Ingelheim, GSK, Novartis, Pfizer, Teva, Valeant, Vernalis Mark F. Lew, MD, FAAN Grant/Research Support: Boehringer-Ingelheim, Eisai, GSK, Ipsen, Kyowa, Mentor, NIH, Novartis, Schering Plough, Schwarz Pharma/UCB, Solstice, Solvay, Teva Consultant: Boehringer-Ingelheim, GSK, Ipsen, Kyowa, Novartis, Prestwick, Schwarz Pharma, Solstice, TEVA, Valeant, Vernalis Speakers Bureau: Allergan, Boehringer-Ingelheim, GSK, Novartis, Solstice, Teva, UCB, Valeant Andrew D. Siderowf, MD, MSCE Grant/Research Support: Boehringer-Ingelheim Consultant: Boehringer-Ingelheim, TEVA Speakers Bureau: Boehringer-Ingelheim, Schwarz-Pharma, Teva William G. Ondo, MD Grant/Research Support: Forrest, UCB Speakers Bureau: Boehringer-Ingelheim, GSK, TEVA, Valeant, UCB

7 Questions We Will Attempt to Answer in This Science-to-Strategy Summit on PD Critical Issues in Parkinson's Disease How do we make the diagnosis of Parkinson's Disease (PD)? Criteria for diagnosis What are the underlying causes and pathophysiology of PD? Epidemiology? How do we stage patients with PD? What is the natural history? How early should pharmacologic therapy in PD begin? What are the initial starting agents for PD? Why? What do landmark trials tell us about early intervention? A paradigm shift? Critical Issues in Parkinson's Disease How do we make the diagnosis of Parkinson's Disease (PD)? Criteria for diagnosis What are the underlying causes and pathophysiology of PD? Epidemiology? How do we stage patients with PD? What is the natural history? How early should pharmacologic therapy in PD begin? What are the initial starting agents for PD? Why? What do landmark trials tell us about early intervention? A paradigm shift?

8 Questions We Will Attempt to Answer in This Science-to-Strategy Summit on PD Critical Issues in Parkinson's Disease Do patients do better with monotherapy or combination therapy? Under what circumstances? How should we sequence pharmacologic agents in PD? How do we manage the side effects of drug therapy in PD? Strategies? What do studies suggest about disease modification? How do we manage the non-motor, co-morbid conditions of PD? What are those conditions? How does receptor selectivity impact our approach to drug therapy? Safety? What is the role of MAO-B inhibition in PD? Which agents? Why? Critical Issues in Parkinson's Disease Do patients do better with monotherapy or combination therapy? Under what circumstances? How should we sequence pharmacologic agents in PD? How do we manage the side effects of drug therapy in PD? Strategies? What do studies suggest about disease modification? How do we manage the non-motor, co-morbid conditions of PD? What are those conditions? How does receptor selectivity impact our approach to drug therapy? Safety? What is the role of MAO-B inhibition in PD? Which agents? Why?

9 Parkinsons Disease Background A Clinical Diagnosis Cardinal Signs: Rest tremor, bradykinesia, rigidity and loss of postural reflexes Non-Motor Symptoms: Autonomic dysfunction, cognitive/ neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain Other Clinical Features and Secondary Motor Symptoms: Hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes) A Clinical Diagnosis Cardinal Signs: Rest tremor, bradykinesia, rigidity and loss of postural reflexes Non-Motor Symptoms: Autonomic dysfunction, cognitive/ neurobehavioral abnormalities, sleep disorders and sensory abnormalities such as anosmia, paresthesias and pain Other Clinical Features and Secondary Motor Symptoms: Hypomimia, dysarthria, dysphagia, sialorrhoea, micrographia, shuffling gait, festination, freezing, dystonia, glabellar reflexes)

10 Parkinsons Disease Epidemiology A Widespread Problem As many as one million Americans suffer from Parkinson's disease This is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig's disease (ALS) Incidence of Parkinsons increases with age, but an estimated 15 percent of people with PD are diagnosed before the age of 50 Approximately 40,000 Americans are diagnosed with Parkinson's disease each year: This number does not reflect the thousands of cases that go undetected. Parkinsons Disease Foundation, Inc. 2007 A Widespread Problem As many as one million Americans suffer from Parkinson's disease This is more than the combined number of people diagnosed with multiple sclerosis, muscular dystrophy and Lou Gehrig's disease (ALS) Incidence of Parkinsons increases with age, but an estimated 15 percent of people with PD are diagnosed before the age of 50 Approximately 40,000 Americans are diagnosed with Parkinson's disease each year: This number does not reflect the thousands of cases that go undetected. Parkinsons Disease Foundation, Inc. 2007

11 Parkinsons Disease Costs Staggering Resources Expended Combined direct and indirect cost of Parkinsons, including treatment, social security payments and lost income from inability to work, is estimated to be more than $5.6 billion per year in the U.S. alone Parkinsons Disease Foundation, Inc. 2007 Staggering Resources Expended Combined direct and indirect cost of Parkinsons, including treatment, social security payments and lost income from inability to work, is estimated to be more than $5.6 billion per year in the U.S. alone Parkinsons Disease Foundation, Inc. 2007

12 The Problem: Loss of Dopaminergic and Non-Dopaminergic Neurons The Problem: Loss of Dopaminergic and Non-Dopaminergic Neurons A Lang, Neurology 2007;68;948-952.

13 H. Braak, et al., Cell Tissue Res (2004) 318: 121–134. Progressive Parkinsons Disease Pathology Progressive Parkinsons Disease Pathology

14 Stages of Parkinsons Disease Mild symptoms, no disability Mild symptoms, no disability Non-pharmacological approaches Non-pharmacological approaches Moderate symptoms with some disability Moderate symptoms with some disability Multiple treatments available including l-dopa Multiple treatments available including l-dopa Progression of symptoms Progression of symptoms Levodopa required +/- other meds Levodopa required +/- other meds Early ModerateAdvanced Disease progresses Disease progresses Non-motor complications may outweigh motor disturbances Non-motor complications may outweigh motor disturbances Adjunctive Drug Therapy for Advanced PD Report of the Quality Standards Subcommittee of the American Academy of Neurology 2006

15 Early Diagnosis and Intervention In Parkinsons Disease Can We Affect Clinical Outcomes with Early Therapy: What the Evidence Tells Us Mark F. Lew, MD Professor Of Neurology Director Division Of Movement Disorders Vice-chair Department Of Neurology Keck/USC School Of Medicine Los Angeles, California Mark F. Lew, MD Professor Of Neurology Director Division Of Movement Disorders Vice-chair Department Of Neurology Keck/USC School Of Medicine Los Angeles, California The Science and Medicine of Parkinsons Disease The Science and Medicine of Parkinsons Disease

16 Parkinsons Disease: Old News Chronic progressive neurodegenerative disorder Chronic progressive neurodegenerative disorder Characterized by loss of dopaminergic neurons in the substantia nigra Characterized by loss of dopaminergic neurons in the substantia nigra Clinical features of Parkinsons Disease Clinical features of Parkinsons Disease Tremor, rigidity and bradykinesia Tremor, rigidity and bradykinesia Postural instability in later stages Postural instability in later stages Autonomic failure (constipation, orthostasis, impotence) Autonomic failure (constipation, orthostasis, impotence) Neuropsychiatric dysfunction (depression, dementia) Neuropsychiatric dysfunction (depression, dementia) Chronic progressive neurodegenerative disorder Chronic progressive neurodegenerative disorder Characterized by loss of dopaminergic neurons in the substantia nigra Characterized by loss of dopaminergic neurons in the substantia nigra Clinical features of Parkinsons Disease Clinical features of Parkinsons Disease Tremor, rigidity and bradykinesia Tremor, rigidity and bradykinesia Postural instability in later stages Postural instability in later stages Autonomic failure (constipation, orthostasis, impotence) Autonomic failure (constipation, orthostasis, impotence) Neuropsychiatric dysfunction (depression, dementia) Neuropsychiatric dysfunction (depression, dementia) Playfer. Postgrad Med. 1997;73:257-264; Olanow Et Al. Neurology. 2001;56 (Suppl 5):s1-s88; Barbosa Et Al. Psychiatr Clin North Am. 1997;20:769-790;.Bhatia Et Al. Hosp Med. 1998;59:469-480.

17 Parkinsons Disease: Epidemiology Approximately 1 million patients in US Approximately 1 million patients in US 40,000 to 60,000 new cases/year 40,000 to 60,000 new cases/year Average age of onset is 60 years, predominantly males Average age of onset is 60 years, predominantly males Affects up to 0.3% of general population Affects up to 0.3% of general population 1% to 3% of those older than 65 years 1% to 3% of those older than 65 years Prevalence increasing as the population ages Prevalence increasing as the population ages Approximately 1 million patients in US Approximately 1 million patients in US 40,000 to 60,000 new cases/year 40,000 to 60,000 new cases/year Average age of onset is 60 years, predominantly males Average age of onset is 60 years, predominantly males Affects up to 0.3% of general population Affects up to 0.3% of general population 1% to 3% of those older than 65 years 1% to 3% of those older than 65 years Prevalence increasing as the population ages Prevalence increasing as the population ages Rajput Et Al. Ann Neurol. 1984;16:278-282. Barbosa Et Al. Psychiatr Clin North Am. 1997;20:769-790. Olanow Et Al. Neurology. 2001;56 (11 Suppl 5):s1-s88.Schrag Et Al. Bmj. 2000;321:21-22.

18 When to Start Therapy? Wait until patient is simply bothered by symptoms? Wait until patient is simply bothered by symptoms? Wait until patient has functional disability? Wait until patient has functional disability? Wait until patient really needs treatment? Wait until patient really needs treatment? As soon as a diagnosis is made? As soon as a diagnosis is made? Wait until patient is simply bothered by symptoms? Wait until patient is simply bothered by symptoms? Wait until patient has functional disability? Wait until patient has functional disability? Wait until patient really needs treatment? Wait until patient really needs treatment? As soon as a diagnosis is made? As soon as a diagnosis is made?

19 Is the Gold Standard Really Golden? Levodopa/carbidopa: Dopamine precursor Levodopa/carbidopa: Dopamine precursor Most effective therapy: Gold standard? Most effective therapy: Gold standard? Early side effects: Nausea and hypotension Early side effects: Nausea and hypotension Long term side effects: Dyskinesias and motor fluctuations such as wearing off Long term side effects: Dyskinesias and motor fluctuations such as wearing off Levodopa/carbidopa: Dopamine precursor Levodopa/carbidopa: Dopamine precursor Most effective therapy: Gold standard? Most effective therapy: Gold standard? Early side effects: Nausea and hypotension Early side effects: Nausea and hypotension Long term side effects: Dyskinesias and motor fluctuations such as wearing off Long term side effects: Dyskinesias and motor fluctuations such as wearing off Olanow et al. Neurology. 2001;56 (suppl 5):S1-S88. Jankovic and Tolosa. Parkinsons Disease and Movement Disorders. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 1998:177-190. Sinemet (carbidopa-levodopa). Complete prescribing information. Merck & Co. Inc.; Bristol-Myers Squibb Co.; April 2002. Barbosa et al. Psychiatr Clin North Am. 1997;20:769-790.

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21 2004;351 (Dec 9):2498-2508 Landmark Trials in Parkinsons Disease Landmark Trials in Parkinsons Disease

22 Goal and Purpose of Trial To determine if levodopa alters the natural history of PD. Does it hasten it, slow it down, or does it have no effect? Corollary: Should levodopa be started earlier or later in the natural history of this disease? To determine if levodopa alters the natural history of PD. Does it hasten it, slow it down, or does it have no effect? Corollary: Should levodopa be started earlier or later in the natural history of this disease?

23 Placebo 150mg 300mg 600mg Medications withdrawn Baseline THE ELLDOPA STUDY CHANGE IN TOTAL UPDRS FROM BASELINE NEJM 2004;351 (Dec 9):2498-2508

24 Dopaminergic AES ELLDOPA Trial Placebo150mg/d300mg/d600mg/dp-Value ENROLLED90928891 Any 33 / 37% 33 / 36% 27 / 31% 37 / 41% 0.5177 Wearing-off 12 / 13% 15 / 16% 16 / 18% 27 / 30% 0.0596 Dyskinesia 3 / 3% 3 / 3% 2 / 2% 2 / 2% 15 / 16% 0.0001 On-off 3 / 3% 3 / 3% 1 / 1% 1 / 1% 0 / 0% 0 / 0% 3 / 3% 3 / 3%0.2602 Dystonia 19 / 21% 14 / 16% 12 / 13% 0.3001 Freezing 13 / 14% 9 / 10% 9 / 10% 6 / 7% 6 / 7% 5 / 5% 5 / 5%0.1497 N / Percent NEJM 2004;351 (Dec 9):2498-2508

25 Dopamine Agonists vs. Levodopa 45 20 34 23 Rascol et al. N Engl J Med 2000;342:1484-1491; Parkinson Study Group. Arch Neurol 2004; 61:1044-1053. (%)(%) 74 74 52 63 47 54 25 0 20 40 60 80 100 1st 1stComplication Wearing off Dyskinesia Levodopa (n=89) Ropinirole (n=179) Levodopa (n=150) Pramipexole (n=151) 0 20 40 60 80 100 Wearing off Dyskinesia Courtesy K. Lyons, PhD. 2006

26 Side Effects of Dopamine Agonists vs. Levodopa Rascol O et al. (2000), N Engl J Med 342(20):1484-1491; Parkinson Study Group (2000), JAMA 284(15):1931-1938; PSG (2004), Arch Neurol 61(7):1044-1053 LevodopaRopiniroleLevodopaPramipexole Somnolence19%27%21.3%36.4% Peripheral edema 5.6%14%14.7%42.4% Hallucinations5.6%17%8%14.6% Nausea49%49%38%38.4% Postural hypotension 12%12%15%9%

27 Old School Thinking

28 Does Early Diagnosis = Early Treatment? If we had a therapy that was shown to be... If we had a therapy that was shown to be... 1) Efficacious compared to placebo 1) Efficacious compared to placebo 2) Safe and well tolerated 2) Safe and well tolerated 3) Potentially disease modifying 3) Potentially disease modifying This would compelling argument that everyone with PD should take this medication as soon as they were diagnosed without delay. This would compelling argument that everyone with PD should take this medication as soon as they were diagnosed without delay. If we had a therapy that was shown to be... If we had a therapy that was shown to be... 1) Efficacious compared to placebo 1) Efficacious compared to placebo 2) Safe and well tolerated 2) Safe and well tolerated 3) Potentially disease modifying 3) Potentially disease modifying This would compelling argument that everyone with PD should take this medication as soon as they were diagnosed without delay. This would compelling argument that everyone with PD should take this medication as soon as they were diagnosed without delay. Initiating Treatment for Parkinsons Disease

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30 Double-Blind Active Treatment Phase Double-Blind Placebo-Controlled Phase Delayed Rasagiline 2 mg/day Rasagiline 1 mg/day 6 Months 6 Months 6 Months Parkinson Study Group. Arch Neurol 2002; 59:1937-43. N=404 Parkinson Study Group. Arch Neurol. 2004; 61:561-566. Randomization Rasagiline 2 mg/day Rasagiline 2mg/day TEMPO: Delayed-Start Design N=138 At 6 months in Delayed Start: N=138 At 6 months in Delayed Start: Placebo group receives 2mg Placebo group receives 2mg N=132 N=134 N=124 Placebo X N=124 N=132

31 Baseline Demographics and Clinical Characteristics Parameter Patients ever Treated with Rasagiline in TEMPO (N = 398) Age, y ± SD 60.9 ± 10.8 Caucasian, n (%) 377 (94.7%) Male, n (%) 253 (63.6%) PD duration, years ± SD 1.2 ± 1.2 Total UPDRS, mean ± SD 26.1 ± 11.5 Hoehn & Yahr stage ± SD 1.9 ± 0.5 Parkinson Study Group. Arch Neurol. 2002; 59:1937-43.

32 TEMPO: Primary Efficacy Measure Treatment Effect on Total UPDRS at 6 Months (Primary Analysis: Adjusted Mean ± SE) 0.51 -0.13 4.075.00.0 1.0 2.0 3.0 4.0 P < 0.0001 Placebo Rasagiline 2 mg Rasagiline 1 mg P < 0.0001 Parkinson Study Group. Arch Neurol. 2002; 59:1937-43. Improvement Mean Change from baseline in Total UPDRS

33 14263242528420 TEMPO: 12-Month Results TEMPO: 12-Month Results Mean Change in Total UPDRS Mean Change in Total UPDRS Parkinson Study Group. Arch Neurol. 2004; 61:561-566. Week 0 -2 1 2 3 4 Delayed-Start UPDRS Change Placebo Rasagiline 1 mg Rasagiline 2 mg Delayed-rasagiline 2 mg

34 Symptomatic versus Disease-Modifying Effects Delayed-start Symptomimprovement Time Time Delayed-start Delayed-start does not catch up Symptomimprovement Delayed-start catches up Design contributed by R. Hauser

35 TEMPO: Adverse Event Frequency Similar To Placebo % of patients reporting Parkinson Study Group. Arch Neurol. 2002; 59:1937-43. 0246 8 10 12 141618 Pain Back Pain Arthralgia Nausea Asthenia Dizziness Accidental Injury Headache Infection Rasagiline 1mg Rasagiline 2mg Placebo

36 TEMPO: Study Conclusions In early PD patients: In early PD patients: Rasagiline effectively manages symptoms over 1 year Rasagiline effectively manages symptoms over 1 year Frequency of AEs similar to placebo Frequency of AEs similar to placebo Results from delayed start design suggests: …Effects of rasagiline on the progression of disability in patients with PD cannot be fully explained by its symptomatic effect and may be due to disease modifying activity of the drug. …Effects of rasagiline on the progression of disability in patients with PD cannot be fully explained by its symptomatic effect and may be due to disease modifying activity of the drug. In early PD patients: In early PD patients: Rasagiline effectively manages symptoms over 1 year Rasagiline effectively manages symptoms over 1 year Frequency of AEs similar to placebo Frequency of AEs similar to placebo Results from delayed start design suggests: …Effects of rasagiline on the progression of disability in patients with PD cannot be fully explained by its symptomatic effect and may be due to disease modifying activity of the drug. …Effects of rasagiline on the progression of disability in patients with PD cannot be fully explained by its symptomatic effect and may be due to disease modifying activity of the drug. Parkinson Study Group. Arch Neurol. 2004; 61:561-566

37 Old School Revisited

38 TEMPO Long Term, Open Label Follow Up TEMPO Long Term, Open Label Follow Up To examine the effect of early- versus delayed-start rasagiline on long-term PD symptom progression Some patients have been followed for up to 8.5 years Lew Et Al Submitted For Publication European Journal Of Neurology

39 TEMPO: 2 Years Monotherapy M. Lew Presented 9/2005 EFNS

40 Change From Baseline: Total UPDRS Long-term Rasagiline Therapy Without Dopaminergics M. Lew Presented 9/2005 EFNS

41 Percent Change From Baseline UPDRS For Early versus Delayed Rasagiline M.Lew Presented EFNS 9/2005

42 Conclusions: Early Treatment Early versus delayed rasagiline therapy is associated with less PD symptom progression at 1 year 1 Early versus delayed rasagiline therapy is associated with less PD symptom progression at 1 year 1 Current long-term analysis shows this advantage persists in patients treated for up to 6 years 2 Current long-term analysis shows this advantage persists in patients treated for up to 6 years 2 Treating early with rasagiline is beneficial for PD patients Treating early with rasagiline is beneficial for PD patients Early versus delayed rasagiline therapy is associated with less PD symptom progression at 1 year 1 Early versus delayed rasagiline therapy is associated with less PD symptom progression at 1 year 1 Current long-term analysis shows this advantage persists in patients treated for up to 6 years 2 Current long-term analysis shows this advantage persists in patients treated for up to 6 years 2 Treating early with rasagiline is beneficial for PD patients Treating early with rasagiline is beneficial for PD patients 1 Parkinson Study Group. Arch Neurol. 2004;61:561-566 2 Lew EFNS 2005

43 Adjunctive Drug Therapy for Advanced Parkinsons Disease Combination Strategies and Sequencing Pharmacotherapy Lawrence Elmer, MD, PhD Program Chairman Associate Professor Department of Neurology University of Toledo College of Medicine Lawrence Elmer, MD, PhD Program Chairman Associate Professor Department of Neurology University of Toledo College of Medicine The Science and Medicine of Parkinsons Disease

44 Stages of Parkinsons Disease Mild symptoms, no disability Mild symptoms, no disability Non-pharmacological approaches Non-pharmacological approaches Moderate symptoms with some disability Moderate symptoms with some disability Multiple treatments available including l-dopa Multiple treatments available including l-dopa Progression of symptoms Progression of symptoms Levodopa required +/- other meds Levodopa required +/- other meds Early ModerateAdvanced Disease progresses Disease progresses Non-motor complications may outweigh motor disturbances Non-motor complications may outweigh motor disturbances Adjunctive Drug Therapy for Advanced PD Report of the Quality Standards Subcommittee of the American Academy of Neurology 2006

45 Early or Moderate Stage Management of PD Level A – MAO-B inhibitors – selegiline, rasagiline Level A – MAO-B inhibitors – selegiline, rasagiline Level A – Dopamine agonists – pramipexole, ropinirole, rotigotine – caution in elderly, cognitive impairment, young males (?) Level A – Dopamine agonists – pramipexole, ropinirole, rotigotine – caution in elderly, cognitive impairment, young males (?) Level A - Carbidopa/levodopa – immediate release Level A - Carbidopa/levodopa – immediate release Level B - Carbidopa/levodopa – controlled release Level B - Carbidopa/levodopa – controlled release Recommended Years 1-5 (possibly more?) Questionable Co-enzyme Q10 Co-enzyme Q10 Amantadine Amantadine Therapeutic Agents Adjunctive Drug Therapy for Advanced PD Miyasaki, JM, et al., Neurology 2002;58:11–17 O. Suchowersky, et al., Neurology 2006; 66: 976-982

46 Long-term Treatment of Parkinsons Disease Associated with Motor Complications Adjunctive Drug Therapy for Advanced PD

47 Goals of Current Therapeutic Strategies Adjunctive Drug Therapy for Advanced PD

48 DA GABA ACh Striatum Substantia Nigra LevodopaLevodopa Anticholinergics Sites of Action of PD Drugs: 1960s Adjunctive Drug Therapy for Advanced PD

49 DA GABA ACh Striatum Levodopa Amantadine Selegiline Dopamine agonists Bromocriptine Bromocriptine Pergolide Pergolide Anticholinergics BBB Carbidopa Carbidopa Benserazide Benserazide MAO-B Sites of Action of PD Drugs: 1990s Adjunctive Drug Therapy for Advanced PD

50 DA GABA ACh Striatum Substantia Nigra Levodopa Amantadine Selegiline Dopamine agonists Bromocriptine Bromocriptine Pergolide Pergolide Pramipexole Pramipexole Popinirole Popinirole Baclofen Anticholinergics BBB Carbidopa Carbidopa Benserazide Benserazide Tolcapone Tolcapone Entacapone Entacapone MAO-B Sites of Action of PD Drugs: 2000 Adjunctive Drug Therapy for Advanced PD

51 DA GABA ACh Striatum Substantia Nigra Levodopa Amantadine Selegiline Zydis selegiline Rasagiline Dopamine agonists Apomorphine Apomorphine Bromocriptine Bromocriptine Pergolide Pergolide Pramipexole Pramipexole Ropinirole Ropinirole Rotigotine Rotigotine Baclofen Anticholinergics BBB Carbidopa Carbidopa Benserazide Benserazide Tolcapone Tolcapone Entacapone Entacapone MAO-B Stalevo®(carbidopa/levodopa/entacapone) Parcopa® Sites of Action of PD Drugs: 2008 Adjunctive Drug Therapy for Advanced PD

52 Singh, et al, Progress in Neurobiology, 81:29-44 (2007). Sites of Action of Pharmacological Therapies Currently Prescribed for PD

53 Sites of Action of PD Drug Treatment: Emerging Adjunctive Drug Therapy for Advanced PD DA GABA ACh Striatum Substantia Nigra Other Receptor Targets Serotonergic Antagonists Adenosine Antagonists AMPA Antagonists Adrenergic Antagonists Dopamine agonists Controlled-release Novel DAs Nasal sprays Other transdermal MAO-B Extended levodopa delivery systems

54 Advanced Management of PD Treating Motor Fluctuations Level A – entacapone, rasagiline Level A – entacapone, rasagiline Level B – pramipexole, ropinirole, tolcapone - caution hepatotoxicity Level B – pramipexole, ropinirole, tolcapone - caution hepatotoxicity Level C – apomorphine, cabergoline, and selegiline Level C – apomorphine, cabergoline, and selegiline Level C (surgical) – STN deep brain stimulation Level C (surgical) – STN deep brain stimulation Level C (dyskinesias) - amantadine Level C (dyskinesias) - amantadine Disregarded – bromocriptine, sustained release carbidopa/levodopa Disregarded – bromocriptine, sustained release carbidopa/levodopa Evidence Years 1-3 and following Adjunctive Drug Therapy for Advanced PD Pahwa, R., et al., Neurology 2006;66:983–995

55 Published Reductions in OFF Time: Moderate to Advanced PD Pahwa, R., et al., Neurology 2006;66:983–995 Appendix E-1 DrugDurationActivePlacebo Treatment Effect pramipexole 32 week 31%* (1.8 h) 7% (0.2 h) 24% (1.6 h) pramipexole 40 week 15%*3% 12% ropinirole 12 week 23%*4% 19% ropinirole 26 week 11.7%*5% 6.7% ODT selegiline 12 week 32% (2.2 h)* 9% (0.6 h) 23% (1.6 h) rasagiline (0.5mg) 26 week 23% (1.4h)* 15% (0.9 h) 8% (0.5 h) rasagiline (1.0mg) 26 week 29% (1.8h)* 15% (0.9 h) 14% (0.9 h) rasagiline 18 week 21% (1.2 hr)* 7% (0.4 h) 14% (0.8 h) tolcapone (100mg tid) 12 week 32% (2.3 h) 20% (1.4 h) 12% (0.9 h) tolcapone (200mg tid) 12 week 48% (3.2 h)* 20% (1.4 h) 28% (1.8 h) tolcapone (100mg tid) 12 week 31.5%*11% 20.5% entacapone 18 week 21% (1.2 h)* 7% (0.4 h) 14% (0.8 h) entacapone 24 week 25.8% (1.6 h)* 13.4% (0.9 h) 12.4% (0.7 h) entacapone 24 week 23.6% (1.3 h)* 1.9% (0.1 h) 21.7% (1.2 h)

56 Goals of Current Therapeutic Strategies Adjunctive Drug Therapy for Advanced PD

57 Plasma Levels – Rotigitine CDS Adjunctive Drug Therapy for Advanced PD

58 Adjunctive Transdermal System Adjunctive Drug Therapy for Advanced PD

59 UPDRS Motor Scores Following Intermittent SC Apomorphine R. Pfeiffer, L. Gutmann, K. Hull, Jr., P. Bottini, J. Sherry; Parkinsonism & Related Disorders, 13:93-100 (2007).

60 Effect Of Tolcapone On Levodopa- Induced Improvement In PD Motor score improvement Minutes Roberts et al, 1994. LD dose 4040 4242 4 4646 4848 410 412 414 416 4040460412041804240 4Tolcapone 4Placebo

61 Percentage Reduction in Off-time and Levodopa with COMT Inhibition Rajput, A. H. et al. Neurology. 1997 Oct;49(4):1066-71. 2 -20 -21 -32 -24 -48 -60 -50 -40 -30 -20 -10 0 10 % Reduction in off time % Reduction in Ldopa dose Placebo Tolcapone 100 mg tid Tolcapone 200 m tid

62 Adjunctive Drug Therapy for Advanced PD Lew M, Kricorian G., World Congress of Neurology 2005 Long-term Surveillance of Tolcapone Hepatotoxicity

63 Entacapone prolongs the half-life of levodopa by 85%, with no change in C max or T max Entacapone prolongs the half-life of levodopa by 85%, with no change in C max or T max Increases levodopa exposure by 35% Increases levodopa exposure by 35% Effect of Entacapone on Levodopa Pharmacokinetics Buottinen HM, et al. J Neurol Neurosurg Psychiatry. 1996. Diagnosis and Treatment of Parkinsons Disease: Update 2004

64 Entacapone in Fluctuating PD Five (5) pivotal randomized, placebo- controlled, double blind studies Five (5) pivotal randomized, placebo- controlled, double blind studies Increase in on time of approximately 1 to 2 hours Increase in on time of approximately 1 to 2 hours Reduction in off time 1 to 1.5 hours Reduction in off time 1 to 1.5 hours Reduction in daily levodopa dose of Reduction in daily levodopa dose of 33 to 140 mg 33 to 140 mg Improvement in UPDRS on score Improvement in UPDRS on score Five (5) pivotal randomized, placebo- controlled, double blind studies Five (5) pivotal randomized, placebo- controlled, double blind studies Increase in on time of approximately 1 to 2 hours Increase in on time of approximately 1 to 2 hours Reduction in off time 1 to 1.5 hours Reduction in off time 1 to 1.5 hours Reduction in daily levodopa dose of Reduction in daily levodopa dose of 33 to 140 mg 33 to 140 mg Improvement in UPDRS on score Improvement in UPDRS on score Ruottinen 1996; PSG 1997; Rinne 1998; Poewe 2002; Brooks 2003.

65 Zydis Selegiline: Reduction in Off Time at 12 Weeks 32%* *p<0.001 Observation Period Adjunctive Drug Therapy for Advanced PDWaters CH, et al., Mov Disord 2004;19:426-32

66 Adjunctive Drug Therapy for Advanced PD Lew M, Kricorian G. Long-term treatment of Parkinson's disease with a novel MAO-B inhibitor: analysis of safety and efficacy J Neurol Sci 2005;238 Suppl 1:S363 Zydis Selegiline: Long-term Follow-up

67 Adjunctive Drug Therapy for Advanced PD Lew M, Kricorian G. Long-term treatment of Parkinson's disease with a novel MAO-B inhibitor: analysis of safety and efficacy J Neurol Sci 2005;238 Suppl 1:S363 Zydis Selegiline: Long-term Follow-up – Concomitant Meds Zydis Selegiline CharacteristicContinuing (n=171),n (%) Prior Placebo (n=83),n (%) All Patients (n=254) ),n (%) Dopamine agonists Anticholinergics 4 (2.3) 3 (1.8) 2 (2.4) 0 (0) 6 (2.4) 3 (1.2)

68 Rasagiline: Reduction in OFF Time Similar to Entacapone Change from Baseline Hours) Change from Baseline (Hours) -1.20 -1.18 -0.40 Rasagiline 1 mg Entacapone 200 mg Placebo-LD/DDIPlacebo-LD/DDI-0.2-0.2-0.7-0.7 -2.2-2.2 -1.2-1.2 P = 0.0001 P < 0.0001 Adjusted Means ±SE Rascol. Lancet. 2005; 365:947-54. All patients on LD/DDI Improvement Adjunctive Drug Therapy for Advanced PD

69 2468101216202414182226 PRESTO: Change From Baseline in Total Daily OFF (Hours) by Visit 0.50.0 -0.5 -1.5 -2.0 -2.5 Week Rasagiline 0.5 mg Rasagiline 1 mg Placebo 0 Hours

70 Adjunctive Drug Therapy for Advanced PD Heinz Reichmann, Wolfgang Jost World Congress on Parkinsons Disease and Related Disorders, 2007 Open Label Study of Rasagiline in Fluctuating Patients: Delayed Benefit? Baseline 4 weeks 4 months Median total daily OFF time (Diary) *** N=545 ***# *** p< 0.001 vs. baseline # p<0.001 vs. 4 weeks

71 Concomitant Medication Usage in PRESTO Rasagiline Characteristic Placebo (n=159) 0.5 mg/day (n=164) 1 mg/day (n=149) Dopamine agonists Entacapone Amantadine 111 (69.8) 61 (38.4) 38 (23.9) 113 (68.9) 55 (33.5) 34 (20.7) 106 (71.1) 49 (32.9) 26 (17.4) Data = N (%) Elmer, L and the Parkinson Study Group. MDS, 2005

72 Rasagiline 1.0 mg/day Rasagiline 0.5 mg/day Placebo Without COMT-I (n=307) With COMT-I (n=165) All patients on LD/CD *p<0.05; ***p<0.001 vs placebo Change from baseline in mean Total daily OFF time (hours) Rasagiline with and without Concomitant COMT-I Adjunctive Drug Therapy for Advanced PDElmer, L and the Parkinson Study Group. MDS, 2005 *** *

73 Rasagiline 1.0 mg/day Placebo All patients on LD/DDI Change from baseline in mean Total daily OFF time (hours) Without DAs (n=91) With DAs (n=217) ***p<0.001 vs placebo Rasagiline with and without Concomitant DA Adjunctive Drug Therapy for Advanced PDElmer, L and the Parkinson Study Group. MDS, 2005 ***

74 Cognitive and Behavioral Adverse Events Comparison of Rasagiline with Other Agents % Incidence of CBAEs above placebo (from package inserts) % Incidence of CBAEs above placebo (from TEMPO and PRESTO ) EntacaponePramipexoleRopiniroleRasagiline As Monotherapy Sleep disorder Sleep disorder5N/AN/A Somnolence Somnolence1334N/A Depression DepressionN/AN/A3 Abnormal dreams Abnormal dreamsN/AN/A>1 Hallucinations Hallucinations64N/A Confusion Confusion34N/A As Adjunctive Therapy Sleep disorder Sleep disorderN/A1N/A1 Somnolence Somnolence23121.6 Depression DepressionN/AN/AN/AN/A Abnormal dreams Abnormal dreamsN/A112.7 Hallucinations HallucinationsN/A1361 Confusion ConfusionN/A37>1 Elmer L, et al., J Neurol Sci 2006;248(1-2):78-83.

75 Deep Brain Stimulation: Reduction in Off Time The Deep-Brain Stimulation for Parkinsons Disease Study Group. N Engl J Med 2001;345:956-963. Baseline Six Months 27% ON 50% OFF 23% ON w/dysk 74% ON 19% OFF 7% ON w/dysk All P values < 0.001

76 Conclusions: Advanced Treatment Combination therapy reasonable to consider before levodopa introduced Combination therapy reasonable to consider before levodopa introduced Adjunctive therapy with multiple agents from different classes has been demonstrated to be effective and well- tolerated Adjunctive therapy with multiple agents from different classes has been demonstrated to be effective and well- tolerated Entacapone, zydis selegiline, and rasagiline have lower incidence of cognitive and behavioral side effects compared to dopamine agonists as adjunctive agents. Long-acting dopamine agonists are promising options for advanced management of Parkinsons disease. Entacapone, zydis selegiline, and rasagiline have lower incidence of cognitive and behavioral side effects compared to dopamine agonists as adjunctive agents. Long-acting dopamine agonists are promising options for advanced management of Parkinsons disease. Combination therapy reasonable to consider before levodopa introduced Combination therapy reasonable to consider before levodopa introduced Adjunctive therapy with multiple agents from different classes has been demonstrated to be effective and well- tolerated Adjunctive therapy with multiple agents from different classes has been demonstrated to be effective and well- tolerated Entacapone, zydis selegiline, and rasagiline have lower incidence of cognitive and behavioral side effects compared to dopamine agonists as adjunctive agents. Long-acting dopamine agonists are promising options for advanced management of Parkinsons disease. Entacapone, zydis selegiline, and rasagiline have lower incidence of cognitive and behavioral side effects compared to dopamine agonists as adjunctive agents. Long-acting dopamine agonists are promising options for advanced management of Parkinsons disease.

77 Andrew Siderowf, MD, MSCE Parkinsons Disease and Movement Disorders Center Disorders Center Associate Professor of Neurology University of Pennsylvania Philadelphia, PA Andrew Siderowf, MD, MSCE Parkinsons Disease and Movement Disorders Center Disorders Center Associate Professor of Neurology University of Pennsylvania Philadelphia, PA MAO Selectivity From Prozac to Parmesan The Science and Medicine of Parkinsons Disease

78 Physiological Background Monoamine oxidase (MAO) Monoamine oxidase (MAO) Enzyme responsible for degradation of catecholamines (dopamine, noradrenaline) and serotonin Enzyme responsible for degradation of catecholamines (dopamine, noradrenaline) and serotonin Two isoforms Two isoforms MAO-A: Primarily in the liver and GI tract MAO-A: Primarily in the liver and GI tract MAO-B: Primarily in the brain MAO-B: Primarily in the brain The selectivity of MAO-B inhibition is dose-related The selectivity of MAO-B inhibition is dose-related At low doses, only MAO-B is inhibited At low doses, only MAO-B is inhibited At higher doses, MAO-A is also inhibited At higher doses, MAO-A is also inhibited Monoamine oxidase (MAO) Monoamine oxidase (MAO) Enzyme responsible for degradation of catecholamines (dopamine, noradrenaline) and serotonin Enzyme responsible for degradation of catecholamines (dopamine, noradrenaline) and serotonin Two isoforms Two isoforms MAO-A: Primarily in the liver and GI tract MAO-A: Primarily in the liver and GI tract MAO-B: Primarily in the brain MAO-B: Primarily in the brain The selectivity of MAO-B inhibition is dose-related The selectivity of MAO-B inhibition is dose-related At low doses, only MAO-B is inhibited At low doses, only MAO-B is inhibited At higher doses, MAO-A is also inhibited At higher doses, MAO-A is also inhibited Mendelsohn MJ. In: Ford M et al (eds). Clinical Toxicology. 2001. Youdim MBH et al. Br J Pharmacol. 2001;132:500-506.

79 Relative Functions of MAO-A and MAO-B Functions via deamination Functions via deamination Type A Type A Predominates in the gut Predominates in the gut Serotonin (5-HT) and noradrenaline (NA)Serotonin (5-HT) and noradrenaline (NA) Inhibitors are active as antidepressants: Phenelzine (Nardil); transylcypromine (Parnate)Inhibitors are active as antidepressants: Phenelzine (Nardil); transylcypromine (Parnate) Tyramine in the intestineTyramine in the intestine Type B Type B 80% located within CNS 80% located within CNS Dopamine in the CNS Dopamine in the CNS Inhibitors have anti-PD effects Inhibitors have anti-PD effects Functions via deamination Functions via deamination Type A Type A Predominates in the gut Predominates in the gut Serotonin (5-HT) and noradrenaline (NA)Serotonin (5-HT) and noradrenaline (NA) Inhibitors are active as antidepressants: Phenelzine (Nardil); transylcypromine (Parnate)Inhibitors are active as antidepressants: Phenelzine (Nardil); transylcypromine (Parnate) Tyramine in the intestineTyramine in the intestine Type B Type B 80% located within CNS 80% located within CNS Dopamine in the CNS Dopamine in the CNS Inhibitors have anti-PD effects Inhibitors have anti-PD effects

80 Rasagiline vs. Selegiline In vitro studies In vitro studies Both are selective and highly potent Both are selective and highly potent MAO-B IC 50 in human and rat brain 20-90 fold lower than for MAO-A inhibition MAO-B IC 50 in human and rat brain 20-90 fold lower than for MAO-A inhibition In vivo studies In vivo studies Oral acute administration in rodents Oral acute administration in rodents Rasagiline more potent that selegiline Rasagiline more potent that selegiline Ratio of MAO-B ED50 in brain or liver from 1/3 to 1/13Ratio of MAO-B ED50 in brain or liver from 1/3 to 1/13 Selectivity maintained over treatmentSelectivity maintained over treatment Irreversible inhibition studies Irreversible inhibition studies Recovery of MAO activity following chronic drug administrationRecovery of MAO activity following chronic drug administration In vitro studies In vitro studies Both are selective and highly potent Both are selective and highly potent MAO-B IC 50 in human and rat brain 20-90 fold lower than for MAO-A inhibition MAO-B IC 50 in human and rat brain 20-90 fold lower than for MAO-A inhibition In vivo studies In vivo studies Oral acute administration in rodents Oral acute administration in rodents Rasagiline more potent that selegiline Rasagiline more potent that selegiline Ratio of MAO-B ED50 in brain or liver from 1/3 to 1/13Ratio of MAO-B ED50 in brain or liver from 1/3 to 1/13 Selectivity maintained over treatmentSelectivity maintained over treatment Irreversible inhibition studies Irreversible inhibition studies Recovery of MAO activity following chronic drug administrationRecovery of MAO activity following chronic drug administration

81 Concurrent Antidepressant and MAOI Use SSRIs are commonly used antidepressants that enhance serotonin levels in the CNS SSRIs are commonly used antidepressants that enhance serotonin levels in the CNS MAO-A inhibition increases levels of serotonin MAO-A inhibition increases levels of serotonin Theoretically, patients receiving rasagiline or selegiline concurrently with SSRIs may be at increased risk of developing serotonin syndrome Theoretically, patients receiving rasagiline or selegiline concurrently with SSRIs may be at increased risk of developing serotonin syndrome SSRIs are commonly used antidepressants that enhance serotonin levels in the CNS SSRIs are commonly used antidepressants that enhance serotonin levels in the CNS MAO-A inhibition increases levels of serotonin MAO-A inhibition increases levels of serotonin Theoretically, patients receiving rasagiline or selegiline concurrently with SSRIs may be at increased risk of developing serotonin syndrome Theoretically, patients receiving rasagiline or selegiline concurrently with SSRIs may be at increased risk of developing serotonin syndrome

82 Role of Serotonin Functions Sleep Sleep Emotion Emotion Appetite Appetite Thermoregulation Thermoregulation Emesis Emesis Pain Pain Behavior Behavior Vascular tone Vascular tone GI motility GI motilityFunctions Sleep Sleep Emotion Emotion Appetite Appetite Thermoregulation Thermoregulation Emesis Emesis Pain Pain Behavior Behavior Vascular tone Vascular tone GI motility GI motility Sites of Action Cardiovascular system Cardiovascular system GI tract GI tract Brain Brain Sites of Action Cardiovascular system Cardiovascular system GI tract GI tract Brain Brain Boyer EW, et al. N Eng J Med, 2005; 352 (11):1112-1120.

83 Symptoms of Serotonin Toxicity A Life Threatening Syndrome Cognitive Symptoms Cognitive Symptoms Confusion Confusion Agitation Agitation Anxiety Anxiety Confusion Confusion Agitation Agitation Anxiety Anxiety Autonomic Symptoms Autonomic Symptoms Hyperthermia Hyperthermia Diaphoresis Diaphoresis Tachycardia Tachycardia Hypertension Hypertension Hyperthermia Hyperthermia Diaphoresis Diaphoresis Tachycardia Tachycardia Hypertension Hypertension Somatic Symptoms Somatic Symptoms Myoclonus Myoclonus Hyperreflexia Hyperreflexia Muscle rigidity Muscle rigidity Tremor Tremor Myoclonus Myoclonus Hyperreflexia Hyperreflexia Muscle rigidity Muscle rigidity Tremor Tremor Sorenson, Susan, Pharm D. Utox Update, 2002; 4(4):1-2. Boyer EW, et al. N Eng J Med, 2005; 352(11):1112-1120.

84 Mechanism of Serotonin Toxicity Synapticgap Receptor Tryptophan Synaptic terminal 5-HTP 5-HT 5-HT TrpH AADC 5-HT 5-HT 5-HIAA 5-HT Waitlling, KJ. The RBI Handbook of Receptor Classification and Signal Transduction. RBI. Fifth Edition, 2001: 72-73. Boyer EW, et al. N Eng J Med, 2005; 352 (11):1112-1120. Antidepressants 5-HT 5-HT 5-HT X X MAOIs 5-HT= Serotonin 5-HT= Serotonin TrpH= Tryptophan hydroxylase TrpH= Tryptophan hydroxylase 5-HTP= 5-hydroxy- tryptophan 5-HTP= 5-hydroxy- tryptophan AADC= Aromatic acid decarboxylase AADC= Aromatic acid decarboxylase MAO-A= Monoamine oxidase type A MAO-A= Monoamine oxidase type A 5-HIAA=5-Hydroxy- indoleacetic acid 5-HIAA=5-Hydroxy- indoleacetic acid

85 Antidepressant Use (%) in Parkinsons Patients Source: 2006 Scientific Advisory Meeting Summary. Parkinsons Disease Stage

86 Medications Number of Patients Total Years of Exposure* All Antidepressants 275 (20.2%) 349.2 SSRIs 141 (10.4%) 161.3 Tricyclics 115 (8.4%) 138.5 Other Other 61 (4.5%) 66.2 66.2 *Range: 1 day to 6.2 years Other: bupropion, mianserin, mirtazapine, nefazodone, trazodone Other: bupropion, mianserin, mirtazapine, nefazodone, trazodone Antidepressants That Were Used in Rasagiline Clinical Trials n=1361 subjects exposed to rasagiline

87 SSRIs (n) Citalopram(26) Citalopram(26) Escitalopram(6) Escitalopram(6) Fluoxetine(7) Fluoxetine(7) Fluvoxamine(2) Fluvoxamine(2) Paroxetine(59) Paroxetine(59) Sertraline(69) Sertraline(69) Venalfaxine(2) Venalfaxine(2) SSRIs (n) Citalopram(26) Citalopram(26) Escitalopram(6) Escitalopram(6) Fluoxetine(7) Fluoxetine(7) Fluvoxamine(2) Fluvoxamine(2) Paroxetine(59) Paroxetine(59) Sertraline(69) Sertraline(69) Venalfaxine(2) Venalfaxine(2) Tricyclics (n) Tricyclics (n) Amitriptyline (106) Amitriptyline (106) Clomipramine (4) Clomipramine (4) Doxepin (1) Doxepin (1) Nortriptyline (5) Nortriptyline (5) Tricyclics (n) Tricyclics (n) Amitriptyline (106) Amitriptyline (106) Clomipramine (4) Clomipramine (4) Doxepin (1) Doxepin (1) Nortriptyline (5) Nortriptyline (5) Other (n) Other (n) Buprion (5) Buprion (5) Mianserin (2) Mianserin (2) Mirtazapine (13) Mirtazapine (13) Nefazodone (2) Nefazodone (2) Trazodone (45) Trazodone (45) Other (n) Other (n) Buprion (5) Buprion (5) Mianserin (2) Mianserin (2) Mirtazapine (13) Mirtazapine (13) Nefazodone (2) Nefazodone (2) Trazodone (45) Trazodone (45) Specific Antidepressants Used in Rasagiline Clinical Trials

88 Serotonin Syndrome and the Combined Use of Selegiline and an Antidepressant Aim: To better estimate the frequency of serotonin syndrome in patients with PD treated with deprenyl and an antidepressant Surveyed all investigators in Parkinsons Study Group (PSG) Surveyed all investigators in Parkinsons Study Group (PSG) 47 (75%) of investigators responded 47 (75%) of investigators responded 4568 patients treated with combination of Deprenyl and antidepressants 4568 patients treated with combination of Deprenyl and antidepressantsResults: 11 patients (0.24%) reported to have experienced symptoms possibly consistent with serotonin syndrome 11 patients (0.24%) reported to have experienced symptoms possibly consistent with serotonin syndrome 2 patients (0.04%) experienced symptoms considered to be serious (no deaths) 2 patients (0.04%) experienced symptoms considered to be serious (no deaths) The constellation of symptoms reported did not seem to meet Sternbachs criteria for serotonin syndrome The constellation of symptoms reported did not seem to meet Sternbachs criteria for serotonin syndrome Aim: To better estimate the frequency of serotonin syndrome in patients with PD treated with deprenyl and an antidepressant Surveyed all investigators in Parkinsons Study Group (PSG) Surveyed all investigators in Parkinsons Study Group (PSG) 47 (75%) of investigators responded 47 (75%) of investigators responded 4568 patients treated with combination of Deprenyl and antidepressants 4568 patients treated with combination of Deprenyl and antidepressantsResults: 11 patients (0.24%) reported to have experienced symptoms possibly consistent with serotonin syndrome 11 patients (0.24%) reported to have experienced symptoms possibly consistent with serotonin syndrome 2 patients (0.04%) experienced symptoms considered to be serious (no deaths) 2 patients (0.04%) experienced symptoms considered to be serious (no deaths) The constellation of symptoms reported did not seem to meet Sternbachs criteria for serotonin syndrome The constellation of symptoms reported did not seem to meet Sternbachs criteria for serotonin syndrome Richard, et al. Neurology 1997; 48(4):1070-78.

89 Serotonin Syndrome and the Combined Use of Selegiline and an Antidepressant Richard, et al. Neurology 1997; 48(4):1070-78. Also analyzed all published case reports and FDA data regarding possible serotonin syndrome in patients treated with Deprenyl and antidepressants Results Case Reports: 5 separate published cases from PSG survey Only 1 case met Sternbachs criteria for serotonin syndrome, though had atypical aspects associated too All cases associated with fluoxetine but one (marprotiline) Results FDA: Only 2 of 48 potential cases appeared to satisfy Sternbachs criteria for serotonin syndrome Also analyzed all published case reports and FDA data regarding possible serotonin syndrome in patients treated with Deprenyl and antidepressants Results Case Reports: 5 separate published cases from PSG survey Only 1 case met Sternbachs criteria for serotonin syndrome, though had atypical aspects associated too All cases associated with fluoxetine but one (marprotiline) Results FDA: Only 2 of 48 potential cases appeared to satisfy Sternbachs criteria for serotonin syndrome

90 Schwid, et al. American Academy of Neurology National Meeting 2005. Safety of Rasagiline in Combination with Serotonin Reuptake Inhibitors Results from PRESTO adjunct study in 472 subjects with advanced PD 77 patients treated with SSRIs No adverse events differed significantly between SSRI + and SSRI – patients other than vomiting (5% vs 1%) SSRI patients with greater impairment at baseline, however Among SSRI receiving patients, no difference in adverse events between those taking rasagiline vs. placebo Conclusions : This study showed no deleterious interactions between SSRIs and rasagiline in patients with advanced PD. Rasagiline was safe and effective. Results from PRESTO adjunct study in 472 subjects with advanced PD 77 patients treated with SSRIs No adverse events differed significantly between SSRI + and SSRI – patients other than vomiting (5% vs 1%) SSRI patients with greater impairment at baseline, however Among SSRI receiving patients, no difference in adverse events between those taking rasagiline vs. placebo Conclusions : This study showed no deleterious interactions between SSRIs and rasagiline in patients with advanced PD. Rasagiline was safe and effective.

91 Rasagiline and Dietary Tyramine Issues, Studies, and Results Rasagiline and Dietary Tyramine Issues, Studies, and Results The Science and Medicine of Parkinsons Disease

92 Tyramine Interaction Non-selective MAOI Non-selective MAOI Well recognized Well recognized Potentiated in patients taking LD Potentiated in patients taking LD Reversible MAOIs Reversible MAOIs Does not occur at clinically relevant dosages Does not occur at clinically relevant dosages High dosage or high tyramine High dosage or high tyramine Irreversible MAOIs Irreversible MAOIs Theoretical risk Theoretical risk Exceptional dosage or high tyramine Exceptional dosage or high tyramine Non-selective MAOI Non-selective MAOI Well recognized Well recognized Potentiated in patients taking LD Potentiated in patients taking LD Reversible MAOIs Reversible MAOIs Does not occur at clinically relevant dosages Does not occur at clinically relevant dosages High dosage or high tyramine High dosage or high tyramine Irreversible MAOIs Irreversible MAOIs Theoretical risk Theoretical risk Exceptional dosage or high tyramine Exceptional dosage or high tyramine

93 Pharmacology of theTyramine Reaction TyramineTyramine Hydroxyphenylacetic acid (inactive) MAO-A Sympathomimetic Response Response ( Blood Pressure) Norepinephrine (NE) displacement TyramineTyramine Non-Selective MAO Inhibitor MAO-A NE X

94 A Tyramine-Rich Meal Da Prada M et al. J Neural Transm 1988:(Suppl)26;31-56. 2.513 Parma ham 14.13 Soup, minestrone 5.30.6 Spinach 10.69 Filet of beef 5.33 Pepper sauce 3.57 Cheese, Gorgonzola 3.50.4 Dessert, Tiramisu 11.80.1 Red wine, Brunello Total Tyramine:36.1 Portion size (oz) Tyramine (mg)

95 Tyramine Interaction Studies with Rasagiline 1.Tyramine challenge in 27 healthy subjects 1 Rasagiline 1mg, 2mg with up to 800 mg tyramine HClRasagiline 1mg, 2mg with up to 800 mg tyramine HCl 2.Tyramine challenge in 20 PD patients 2 Rasagiline 1mg, 2mg with up to 75 mg tyramine HClRasagiline 1mg, 2mg with up to 75 mg tyramine HCl 3.PRESTO home BP monitoring in 443 PD patients 3 Rasagiline 0.5mg, 1.0mg + CD/LD with usual dietRasagiline 0.5mg, 1.0mg + CD/LD with usual diet 4.PRESTO tyramine challenge in 55 PD patients 4 Rasagiline 0.5mg, 1mg + CD/LD with 50 mg tyramine HClRasagiline 0.5mg, 1mg + CD/LD with 50 mg tyramine HCl 5.TEMPO tyramine challenge in 55 PD patients 4 Rasagiline 1mg, 2mg with 75mg tyramine HCl Rasagiline 1mg, 2mg with 75mg tyramine HCl 1.Tyramine challenge in 27 healthy subjects 1 Rasagiline 1mg, 2mg with up to 800 mg tyramine HClRasagiline 1mg, 2mg with up to 800 mg tyramine HCl 2.Tyramine challenge in 20 PD patients 2 Rasagiline 1mg, 2mg with up to 75 mg tyramine HClRasagiline 1mg, 2mg with up to 75 mg tyramine HCl 3.PRESTO home BP monitoring in 443 PD patients 3 Rasagiline 0.5mg, 1.0mg + CD/LD with usual dietRasagiline 0.5mg, 1.0mg + CD/LD with usual diet 4.PRESTO tyramine challenge in 55 PD patients 4 Rasagiline 0.5mg, 1mg + CD/LD with 50 mg tyramine HClRasagiline 0.5mg, 1mg + CD/LD with 50 mg tyramine HCl 5.TEMPO tyramine challenge in 55 PD patients 4 Rasagiline 1mg, 2mg with 75mg tyramine HCl Rasagiline 1mg, 2mg with 75mg tyramine HCl 1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594. 2. Data on file. TVP 1012/132. Manuscript in preparation. 3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721. TEVA has conducted 5 tyramine studies showing no interaction at approved dosesTEVA has conducted 5 tyramine studies showing no interaction at approved doses – Two possible cases on 2mg during development

96 1.Tyramine challenge in 27 healthy subjects 1 Rasagiline 1mg, 2mg with up to 800 mg tyramine HClRasagiline 1mg, 2mg with up to 800 mg tyramine HCl No significant differences between selegiline and rasagiline in the studyNo significant differences between selegiline and rasagiline in the study 2.Tyramine challenge in 20 PD patients 2 3.PRESTO home BP monitoring in 443 PD patients 3 4.PRESTO tyramine challenge in 55 PD patients 4 5.TEMPO tyramine challenge in 55 PD patients 4 1.Tyramine challenge in 27 healthy subjects 1 Rasagiline 1mg, 2mg with up to 800 mg tyramine HClRasagiline 1mg, 2mg with up to 800 mg tyramine HCl No significant differences between selegiline and rasagiline in the studyNo significant differences between selegiline and rasagiline in the study 2.Tyramine challenge in 20 PD patients 2 3.PRESTO home BP monitoring in 443 PD patients 3 4.PRESTO tyramine challenge in 55 PD patients 4 5.TEMPO tyramine challenge in 55 PD patients 4 Tyramine Interaction Studies 1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594. 2. Data on file. TVP 1012/132. Manuscript in preparation. 3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.

97 1.Tyramine challenge in 27 healthy subjects 1 2.Tyramine challenge in 20 PD patients 2 Chronic levodopa usageChronic levodopa usage Rasagiline 1mg, 2mgRasagiline 1mg, 2mg Fasting (which increases tyramine bioavailability)Fasting (which increases tyramine bioavailability) 75-225 mg tyramine75-225 mg tyramine At 2 mg, two patients demonstrated increased BP based on these unrealistic conditionsAt 2 mg, two patients demonstrated increased BP based on these unrealistic conditions 3.PRESTO home BP monitoring in 443 PD patients 3 4.PRESTO tyramine challenge in 55 PD patients 4 5.TEMPO tyramine challenge in 55 PD patients 4 1.Tyramine challenge in 27 healthy subjects 1 2.Tyramine challenge in 20 PD patients 2 Chronic levodopa usageChronic levodopa usage Rasagiline 1mg, 2mgRasagiline 1mg, 2mg Fasting (which increases tyramine bioavailability)Fasting (which increases tyramine bioavailability) 75-225 mg tyramine75-225 mg tyramine At 2 mg, two patients demonstrated increased BP based on these unrealistic conditionsAt 2 mg, two patients demonstrated increased BP based on these unrealistic conditions 3.PRESTO home BP monitoring in 443 PD patients 3 4.PRESTO tyramine challenge in 55 PD patients 4 5.TEMPO tyramine challenge in 55 PD patients 4 Tyramine Interaction Studies 1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594. 2. Data on file. TVP 1012/132. Manuscript in preparation. 3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.

98 1.Tyramine challenge in 27 healthy subjects 1 2.Tyramine challenge in 20 PD patients 2 3.PRESTO home BP monitoring in 443 PD patients 3 Rasagiline 0.5mg, 1.0mg + CD/LD with usual dietRasagiline 0.5mg, 1.0mg + CD/LD with usual diet No pressor effectsNo pressor effects 4.PRESTO tyramine challenge in 55 PD patients 4 5.TEMPO tyramine challenge in 55 PD patients 4 1.Tyramine challenge in 27 healthy subjects 1 2.Tyramine challenge in 20 PD patients 2 3.PRESTO home BP monitoring in 443 PD patients 3 Rasagiline 0.5mg, 1.0mg + CD/LD with usual dietRasagiline 0.5mg, 1.0mg + CD/LD with usual diet No pressor effectsNo pressor effects 4.PRESTO tyramine challenge in 55 PD patients 4 5.TEMPO tyramine challenge in 55 PD patients 4 Tyramine Interaction Studies 1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594. 2. Data on file. TVP 1012/132. Manuscript in preparation. 3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.

99 1.Tyramine challenge in 27 healthy subjects 1 2.Tyramine challenge in 20 PD patients 2 3.PRESTO home BP monitoring in 443 PD patients 3 4.PRESTO tyramine challenge in 55 PD patients 4 AND AND 5.TEMPO tyramine challenge in 55 PD patients 4 Rasagiline 1mg, 2mg with 75mg tyramine HCl Rasagiline 1mg, 2mg with 75mg tyramine HCl Substudy of pivotal trial Substudy of pivotal trial Following six months therapy to demonstrate selectivity was maintained LT Following six months therapy to demonstrate selectivity was maintained LT Tyramine given with light meal Tyramine given with light meal No pressor effects No pressor effects 1.Tyramine challenge in 27 healthy subjects 1 2.Tyramine challenge in 20 PD patients 2 3.PRESTO home BP monitoring in 443 PD patients 3 4.PRESTO tyramine challenge in 55 PD patients 4 AND AND 5.TEMPO tyramine challenge in 55 PD patients 4 Rasagiline 1mg, 2mg with 75mg tyramine HCl Rasagiline 1mg, 2mg with 75mg tyramine HCl Substudy of pivotal trial Substudy of pivotal trial Following six months therapy to demonstrate selectivity was maintained LT Following six months therapy to demonstrate selectivity was maintained LT Tyramine given with light meal Tyramine given with light meal No pressor effects No pressor effects Tyramine Interaction Studies 1. Guillaume JJ, et al. Mov Disord. 2006;21(Suppl 15):S594. 2. Data on file. TVP 1012/132. Manuscript in preparation. 3. White WB, et al. Neurology. 2006; 66 (Suppl 2): A314-A315. 4. deMarcaida, JA. et al. Movement Disord. 2006;21(10):1716-1721.

100 Summary: Serotonin Syndrome and Cheese Effect Both related to excess catecholamines Both related to excess catecholamines May be precipitated by non-selective MAO inhibition May be precipitated by non-selective MAO inhibition Selectivity for MAO-B Selectivity for MAO-B Not absolute; may diminish at higher doses Not absolute; may diminish at higher doses Studies ongoing to establish, characterize in humans Studies ongoing to establish, characterize in humans Both related to excess catecholamines Both related to excess catecholamines May be precipitated by non-selective MAO inhibition May be precipitated by non-selective MAO inhibition Selectivity for MAO-B Selectivity for MAO-B Not absolute; may diminish at higher doses Not absolute; may diminish at higher doses Studies ongoing to establish, characterize in humans Studies ongoing to establish, characterize in humans

101 Summary: MAO-B Inhibition Tyramine reaction: A theoretical risk No potential for cheese reaction at defined low doses of selective MAO-B inhibitors No potential for cheese reaction at defined low doses of selective MAO-B inhibitors At recommended doses, no confirmed tyramine reactions to date At recommended doses, no confirmed tyramine reactions to date More than 30,000 patients treatedMore than 30,000 patients treated No tyramine restriction in 3 pivotal studies or ADAGIO trialNo tyramine restriction in 3 pivotal studies or ADAGIO trial Five tyramine challenge studiesFive tyramine challenge studies Relatively easy to avoid foods/beverages high in tyramine, per label Relatively easy to avoid foods/beverages high in tyramine, per label Tyramine reaction: A theoretical risk No potential for cheese reaction at defined low doses of selective MAO-B inhibitors No potential for cheese reaction at defined low doses of selective MAO-B inhibitors At recommended doses, no confirmed tyramine reactions to date At recommended doses, no confirmed tyramine reactions to date More than 30,000 patients treatedMore than 30,000 patients treated No tyramine restriction in 3 pivotal studies or ADAGIO trialNo tyramine restriction in 3 pivotal studies or ADAGIO trial Five tyramine challenge studiesFive tyramine challenge studies Relatively easy to avoid foods/beverages high in tyramine, per label Relatively easy to avoid foods/beverages high in tyramine, per label

102 Non-Motor Aspects of Parkinsons Disease Assessment and Management Sleep, Depression, and Dementia William G. Ondo, MD Associate Professor of Neurology Baylor College of Medicine Houston, Texas William G. Ondo, MD Associate Professor of Neurology Baylor College of Medicine Houston, Texas The Science and Medicine of Parkinsons Disease

103 Parkinsons Disease Cardinal Motor Features Bradykinesia and hypokinesia Bradykinesia and hypokinesia Slow and small Slow and small Rigidity Rigidity Tremor Tremor Rest>action Rest>action +/- Postural instability +/- Postural instability Bradykinesia and hypokinesia Bradykinesia and hypokinesia Slow and small Slow and small Rigidity Rigidity Tremor Tremor Rest>action Rest>action +/- Postural instability +/- Postural instability

104 Non-Motor Complications of PD In his original essay, James Parkinson alluded to the non-motor problems in advancing disease in the following terms: In his original essay, James Parkinson alluded to the non-motor problems in advancing disease in the following terms: In this stage, the sleep becomes much disturbed. The bowels, which had been all along torpid,now in most cases, demand stimulating medicines of considerable power: the expulsion of faeces from the rectum sometimes requiring mechanical aid. In this stage, the sleep becomes much disturbed. The bowels, which had been all along torpid,now in most cases, demand stimulating medicines of considerable power: the expulsion of faeces from the rectum sometimes requiring mechanical aid. In his original essay, James Parkinson alluded to the non-motor problems in advancing disease in the following terms: In his original essay, James Parkinson alluded to the non-motor problems in advancing disease in the following terms: In this stage, the sleep becomes much disturbed. The bowels, which had been all along torpid,now in most cases, demand stimulating medicines of considerable power: the expulsion of faeces from the rectum sometimes requiring mechanical aid. In this stage, the sleep becomes much disturbed. The bowels, which had been all along torpid,now in most cases, demand stimulating medicines of considerable power: the expulsion of faeces from the rectum sometimes requiring mechanical aid.

105 Non-Motor Features in PD Sleep disruption Sleep disruption Psychiatric and/or cognitive disturbances Psychiatric and/or cognitive disturbances Autonomic dysfunction and related findings Autonomic dysfunction and related findings Sensory symptoms Sensory symptoms Sleep disruption Sleep disruption Psychiatric and/or cognitive disturbances Psychiatric and/or cognitive disturbances Autonomic dysfunction and related findings Autonomic dysfunction and related findings Sensory symptoms Sensory symptoms

106 Spectrum of Sleep Disturbances Excessive Daytime Sleepiness Excessive Daytime Sleepiness Fractionate Nocturnal Sleep Fractionate Nocturnal Sleep REM Behavioral Disorder REM Behavioral Disorder Periodic Limb Movements of Sleep Periodic Limb Movements of Sleep Restless Legs Syndrome Restless Legs Syndrome Sleep Apnea Sleep Apnea Excessive Daytime Sleepiness Excessive Daytime Sleepiness Fractionate Nocturnal Sleep Fractionate Nocturnal Sleep REM Behavioral Disorder REM Behavioral Disorder Periodic Limb Movements of Sleep Periodic Limb Movements of Sleep Restless Legs Syndrome Restless Legs Syndrome Sleep Apnea Sleep Apnea

107 Spectrum of Neuropsychiatric and Cognitive Symptoms Depression Depression Anxiety Anxiety Psychosis Psychosis Dementia Dementia Apathy Apathy Fatigue Fatigue Depression Depression Anxiety Anxiety Psychosis Psychosis Dementia Dementia Apathy Apathy Fatigue Fatigue

108 Autonomic Symptoms in PD Constipation Constipation Hyperhidrosis (sweating dysfunction) Hyperhidrosis (sweating dysfunction) Urinary dysfunction (urgency, frequency incontinence) Urinary dysfunction (urgency, frequency incontinence) Sexual dysfunction Sexual dysfunction Sialorrhea Sialorrhea Constipation Constipation Hyperhidrosis (sweating dysfunction) Hyperhidrosis (sweating dysfunction) Urinary dysfunction (urgency, frequency incontinence) Urinary dysfunction (urgency, frequency incontinence) Sexual dysfunction Sexual dysfunction Sialorrhea Sialorrhea

109 Sensory Symptoms in PD Pain Pain Numbness Numbness Tingling Tingling Burning Burning Smell loss Smell loss Discriminant Vision Discriminant Vision Diplopia Diplopia Pain Pain Numbness Numbness Tingling Tingling Burning Burning Smell loss Smell loss Discriminant Vision Discriminant Vision Diplopia Diplopia

110 PD NMS: Patient Questionnaire Pilot Study (UK, USA, Germany, Spain) Parkinsons Disease Parkinsons Disease N = 123 N = 123 Age: 68.1 ± 10.3 yrs (41-87) Age: 68.1 ± 10.3 yrs (41-87) 59.3% Male 59.3% Male 51% mixed, 28% AD,, 20% TD 51% mixed, 28% AD,, 20% TD PD Duration: 6.4 ± 4.3 y (0.5-22 yrs) PD Duration: 6.4 ± 4.3 y (0.5-22 yrs) 84% levodopa, 60% DA 84% levodopa, 60% DA Controls Controls N = 89 N = 89 Age: 62.7 ± 12.8 yrs (27-81) Age: 62.7 ± 12.8 yrs (27-81) 42.7% Male 42.7% Male Parkinsons Disease Parkinsons Disease N = 123 N = 123 Age: 68.1 ± 10.3 yrs (41-87) Age: 68.1 ± 10.3 yrs (41-87) 59.3% Male 59.3% Male 51% mixed, 28% AD,, 20% TD 51% mixed, 28% AD,, 20% TD PD Duration: 6.4 ± 4.3 y (0.5-22 yrs) PD Duration: 6.4 ± 4.3 y (0.5-22 yrs) 84% levodopa, 60% DA 84% levodopa, 60% DA Controls Controls N = 89 N = 89 Age: 62.7 ± 12.8 yrs (27-81) Age: 62.7 ± 12.8 yrs (27-81) 42.7% Male 42.7% Male Chaudhuri R, et al. The NMSQuest study (p NA) Mov Disord 2006:21(7):916-923.

111 PD NMS Patient Questionnaire Study GU/GI Tract Symptoms p = 0.000 p = 0.0001 p = 0.0007 p = 0.0000 p = 0.3 p = 0.2 p = 0.001 p = 0.01 Vomiting, fecal incontinence, incomplete bowel emptying not significantly different from controls Vomiting, fecal incontinence, incomplete bowel emptying not significantly different from controls

112 PD NMS Patient Questionnaire Study Cognition/Neuropsychiatric Features p = 0.9 p = 0.001 p = 0.06 p = 0.0001 p = 0.01 p = 0.004 p = 0.01 p = 0.0000 Cognition + Neuropsychiatry p = 0.006 Pain and memory problems were not significantly different from controls

113 PD NMS Patient Questionnaire Study Autonomic Features p = 0.1 p = 0.05 p = 0.0007 p = 0.25 p = 0.0000 p = 0.003 p = 0.0000 Autonomic Ankle swelling and sex drive not significantly different from controls

114 PD NMS Patient Questionnaire Study Sleep Disturbances p = 0.001 p = 0.2 p = 0.04 p = 0.003 p = 0.0005 Sleep + Somnolence Insomnia not significantly different from controls

115 Sleep Disorders In Parkinsons Disease The Science and Medicine of Parkinsons Disease

116 Sleep Disorders in PD Excessive Daytime Somnolence Excessive Daytime Somnolence Insomnia/Fractionated Sleep Insomnia/Fractionated Sleep Daytime soporific drive Daytime soporific drive REM Behavioral Disorder REM Behavioral Disorder Restless Legs Syndrome (RLS) Restless Legs Syndrome (RLS) Sleep Apnea Sleep Apnea 20% 20% Not associated with weight Not associated with weight Excessive Daytime Somnolence Excessive Daytime Somnolence Insomnia/Fractionated Sleep Insomnia/Fractionated Sleep Daytime soporific drive Daytime soporific drive REM Behavioral Disorder REM Behavioral Disorder Restless Legs Syndrome (RLS) Restless Legs Syndrome (RLS) Sleep Apnea Sleep Apnea 20% 20% Not associated with weight Not associated with weight

117 Excessive Daytime Sleepiness (EDS) and Sleep Attacks First reported with pramipexole First reported with pramipexole Subsequent reports with other agonists and other PD medications Subsequent reports with other agonists and other PD medications Numerous studies demonstrate EDS Numerous studies demonstrate EDS First reported with pramipexole First reported with pramipexole Subsequent reports with other agonists and other PD medications Subsequent reports with other agonists and other PD medications Numerous studies demonstrate EDS Numerous studies demonstrate EDS

118 Daytime Sleepiness in PD Poor Nocturnal Sleep Poor Nocturnal Sleep Disease Disease Medications Medications Direct Daytime Somnolence Direct Daytime Somnolence Disease Disease Medications Medications Poor Nocturnal Sleep Poor Nocturnal Sleep Disease Disease Medications Medications Direct Daytime Somnolence Direct Daytime Somnolence Disease Disease Medications Medications

119 Baylor PD Sleep Survey 303/320 consecutive patients included 303/320 consecutive patients included 11 (Not PD), 4 (unknown drugs), 2 (incomplete data) 11 (Not PD), 4 (unknown drugs), 2 (incomplete data) Age: 67.1 ± 10.7 Age: 67.1 ± 10.7 Duration: 9.1 ± 5.7 years Duration: 9.1 ± 5.7 years Gender: 60.4 % male Gender: 60.4 % male Hoehn and Yahr: 2.5 ± 0.9 Hoehn and Yahr: 2.5 ± 0.9 303/320 consecutive patients included 303/320 consecutive patients included 11 (Not PD), 4 (unknown drugs), 2 (incomplete data) 11 (Not PD), 4 (unknown drugs), 2 (incomplete data) Age: 67.1 ± 10.7 Age: 67.1 ± 10.7 Duration: 9.1 ± 5.7 years Duration: 9.1 ± 5.7 years Gender: 60.4 % male Gender: 60.4 % male Hoehn and Yahr: 2.5 ± 0.9 Hoehn and Yahr: 2.5 ± 0.9 Neurology, 2001 Oct 23;57(8):1392-6

120 Nocturnal Sleep Problems REM Behavioral Disorder 42.8 % REM Behavioral Disorder 42.8 % Somniloquism 50.8 % Somniloquism 50.8 % Somnambulism 5.3 % Somnambulism 5.3 % Snoring 38.8 % Snoring 38.8 % RLS 19.5 % RLS 19.5 % Number of Awakenings 2.7 ± 2.5 Number of Awakenings 2.7 ± 2.5 REM Behavioral Disorder 42.8 % REM Behavioral Disorder 42.8 % Somniloquism 50.8 % Somniloquism 50.8 % Somnambulism 5.3 % Somnambulism 5.3 % Snoring 38.8 % Snoring 38.8 % RLS 19.5 % RLS 19.5 % Number of Awakenings 2.7 ± 2.5 Number of Awakenings 2.7 ± 2.5 Neurology, 2001 Oct 23;57(8):1392-6

121 Daytime Sleepiness in PD Epworth Score: 11.1 ± 5.9, 43% > 10 Epworth Score: 11.1 ± 5.9, 43% > 10 Daytime sleepiness correlates with: Daytime sleepiness correlates with: Duration of PD Duration of PD Severity of PD Severity of PD Male Gender Male Gender All dopamine agonists All dopamine agonists Pergolide 12.5 ± 5.4Pergolide 12.5 ± 5.4 Ropinirole 12.1 ± 5.7Ropinirole 12.1 ± 5.7 Pramipexole11.7 ± 5.4Pramipexole11.7 ± 5.4 Epworth Score: 11.1 ± 5.9, 43% > 10 Epworth Score: 11.1 ± 5.9, 43% > 10 Daytime sleepiness correlates with: Daytime sleepiness correlates with: Duration of PD Duration of PD Severity of PD Severity of PD Male Gender Male Gender All dopamine agonists All dopamine agonists Pergolide 12.5 ± 5.4Pergolide 12.5 ± 5.4 Ropinirole 12.1 ± 5.7Ropinirole 12.1 ± 5.7 Pramipexole11.7 ± 5.4Pramipexole11.7 ± 5.4 Neurology, 2001 Oct 23;57(8):1392-6

122 Falling Asleep While Driving Falling Asleep: 63/279 (20.8 %) Falling Asleep: 63/279 (20.8 %) Correlates with: Correlates with: Age Age Dopamine agonists Dopamine agonists Levodopa Levodopa Independently correlates only with levodopa Independently correlates only with levodopa All DA had similar % of falling asleep All DA had similar % of falling asleep Falling Asleep: 63/279 (20.8 %) Falling Asleep: 63/279 (20.8 %) Correlates with: Correlates with: Age Age Dopamine agonists Dopamine agonists Levodopa Levodopa Independently correlates only with levodopa Independently correlates only with levodopa All DA had similar % of falling asleep All DA had similar % of falling asleep Neurology, 2001 Oct 23;57(8):1392-6

123 Adjusted Mean (95% CI) Epworth Score Mean (SD) Epworth Score 0 4 8 12 16 20 24 0 4 8 12 16 20 24 Levodopa Monotherapy(N = 100) Pramipexole and Levodopa(N =85) Pergolide and Levodopa(N = 32) Ropinirole and Levodopa(N =22) Dopamine Agonist Monotherapy(N = 34) No Dopaminergic Therapy(N = 18) PD Therapy and Sleep Disturbances

124 Sleep Studies in PD Two trials have failed to correlate nocturnal sleep problems with EDS Two trials have failed to correlate nocturnal sleep problems with EDS Apnea Apnea Total sleep time Total sleep time Awakenings Awakenings One showed that more nocturnal total sleep correlated with EDS One showed that more nocturnal total sleep correlated with EDS Two trials have failed to correlate nocturnal sleep problems with EDS Two trials have failed to correlate nocturnal sleep problems with EDS Apnea Apnea Total sleep time Total sleep time Awakenings Awakenings One showed that more nocturnal total sleep correlated with EDS One showed that more nocturnal total sleep correlated with EDS Rye et al. J Sleep Res. 2000;9:63 Arnulf et al. Neurology 2002;58:1019.

125 CSF Orexin-A Lower levels correlated with disease severity. Drouot, 03 Lower levels correlated with disease severity. Drouot, 03 Normal levels in small sample. Overeem, 02 Normal levels in small sample. Overeem, 02

126 Thannickal, T. C. et al. Brain 2007 130:1586-1595. Distribution of Hcrt Cells in Normal and Across PD Stages

127 Management of Daytime Sleepiness Optimize nocturnal sleep Optimize nocturnal sleep Minimize offending agents Minimize offending agents Stimulant medications? Stimulant medications? Modafinil? Modafinil? Sodium Oxybate? Sodium Oxybate? Optimize nocturnal sleep Optimize nocturnal sleep Minimize offending agents Minimize offending agents Stimulant medications? Stimulant medications? Modafinil? Modafinil? Sodium Oxybate? Sodium Oxybate?

128 EDS Conclusions Caused by PD and dopaminergic medications Caused by PD and dopaminergic medications Role of dopamine on sleep poorly understood Role of dopamine on sleep poorly understood Not associated with nocturnal sleep problems Not associated with nocturnal sleep problems Some physiologic similarities to narcolepsy Some physiologic similarities to narcolepsy Treatments often not satisfactory Treatments often not satisfactory Caused by PD and dopaminergic medications Caused by PD and dopaminergic medications Role of dopamine on sleep poorly understood Role of dopamine on sleep poorly understood Not associated with nocturnal sleep problems Not associated with nocturnal sleep problems Some physiologic similarities to narcolepsy Some physiologic similarities to narcolepsy Treatments often not satisfactory Treatments often not satisfactory

129 Rapid Eye Movement Behavioral Disorder (RBD) Parasomnia: Vigorous movements /w dream content associated with loss of REM atonia The Science and Medicine of Parkinsons Disease

130 Sleep Hypnogram

131 REM Behavioral Disorder Lack of REM sleep atonia Lack of REM sleep atonia Dream behavior Dream behavior Lack of REM sleep atonia Lack of REM sleep atonia Dream behavior Dream behavior

132 Male > Female Prevalence Not predicted by testosterone Not predicted by testosterone May result from dream content May result from dream content Not predicted by testosterone Not predicted by testosterone May result from dream content May result from dream content Male(n=75)Female(n=45) Defense from attack 18.7%0.0% Aggression9.3%0.0% Work Related 32.0%6.3% Sports/Adventure17.3%4.4% Domestic32.0%66.7% Borek, 2006.

133 RBD and Synucleinopathies Synucleinopathies Synucleinopathies PD, MSA, DLB PD, MSA, DLB Schenck et al 1996 Schenck et al 1996 38% of 29 RBD patients developed AS 38% of 29 RBD patients developed AS 3.7 years after RBD Dx3.7 years after RBD Dx 65% of 26 RBD patients developed AS 65% of 26 RBD patients developed AS 13.3 years after RBD Dx13.3 years after RBD Dx RBD seen in PD, MSA, DLB in 30-70% of cases RBD seen in PD, MSA, DLB in 30-70% of cases RBD preceded parkinsonism RBD preceded parkinsonism MSA: 1-2 years MSA: 1-2 years PD: 3-4 years PD: 3-4 years DLB: 9 years DLB: 9 years Synucleinopathies Synucleinopathies PD, MSA, DLB PD, MSA, DLB Schenck et al 1996 Schenck et al 1996 38% of 29 RBD patients developed AS 38% of 29 RBD patients developed AS 3.7 years after RBD Dx3.7 years after RBD Dx 65% of 26 RBD patients developed AS 65% of 26 RBD patients developed AS 13.3 years after RBD Dx13.3 years after RBD Dx RBD seen in PD, MSA, DLB in 30-70% of cases RBD seen in PD, MSA, DLB in 30-70% of cases RBD preceded parkinsonism RBD preceded parkinsonism MSA: 1-2 years MSA: 1-2 years PD: 3-4 years PD: 3-4 years DLB: 9 years DLB: 9 years

134 Eisensehr, I. et al. Brain 2000 123:1155-1160. The [123I]IPT-SPECT of One Patient With RBD, One Patient with Parkinson's Disease (H&Y I) and One Control Subject

135 RBD Pathophysiology Brainstem involvement Brainstem involvement Pons: Locus coeruleus, laterodoasal and pedunculopontine tegmental nuclei Pons: Locus coeruleus, laterodoasal and pedunculopontine tegmental nuclei Medulla: Magnocellularis, gigantocellularis, paramedianus nuclei Medulla: Magnocellularis, gigantocellularis, paramedianus nuclei Dorsal pontine lesions results in RBD Dorsal pontine lesions results in RBD Animal models Animal models Human lesions Human lesions Single autopsy: Lewy bodies in pons and medulla Single autopsy: Lewy bodies in pons and medulla Brainstem involvement Brainstem involvement Pons: Locus coeruleus, laterodoasal and pedunculopontine tegmental nuclei Pons: Locus coeruleus, laterodoasal and pedunculopontine tegmental nuclei Medulla: Magnocellularis, gigantocellularis, paramedianus nuclei Medulla: Magnocellularis, gigantocellularis, paramedianus nuclei Dorsal pontine lesions results in RBD Dorsal pontine lesions results in RBD Animal models Animal models Human lesions Human lesions Single autopsy: Lewy bodies in pons and medulla Single autopsy: Lewy bodies in pons and medulla

136 REM Sleep

137 Braak PD Pathology Staging

138 Pre-Motor Features of PD RBD RBD Olfaction loss Olfaction loss Autonomic Dysfunction Autonomic Dysfunction Cardiac, constipation Cardiac, constipation RBD RBD Olfaction loss Olfaction loss Autonomic Dysfunction Autonomic Dysfunction Cardiac, constipation Cardiac, constipation

139 RBD: Conclusions This is probably a form fruste of PD and other synucleinopathies This is probably a form fruste of PD and other synucleinopathies No overt pathological or physiological difference No overt pathological or physiological difference Sex difference may reflect dream content Sex difference may reflect dream content No treatment trials in PD but benzodiazepines, melatonin, or cholinesterase inhibitors may help No treatment trials in PD but benzodiazepines, melatonin, or cholinesterase inhibitors may help This is probably a form fruste of PD and other synucleinopathies This is probably a form fruste of PD and other synucleinopathies No overt pathological or physiological difference No overt pathological or physiological difference Sex difference may reflect dream content Sex difference may reflect dream content No treatment trials in PD but benzodiazepines, melatonin, or cholinesterase inhibitors may help No treatment trials in PD but benzodiazepines, melatonin, or cholinesterase inhibitors may help

140 Restless Legs Syndrome (RLS) and Parkinsons Disease The Science and Medicine of Parkinsons Disease

141 Restless Leg Syndrome Urge to move the legs Urge to move the legs Improves during movement Improves during movement Worsens with inactivity Worsens with inactivity Worse in evening/night Worse in evening/night Urge to move the legs Urge to move the legs Improves during movement Improves during movement Worsens with inactivity Worsens with inactivity Worse in evening/night Worse in evening/night

142 Restless Leg Syndrome Original PD/No RLS (n=240) Original PD/RLS (n=63) Total PD/RLS (n=109) Total RLS Only (n=146) RLS Only (+) Fam. Hist. of RLS (n=96) RLS Only (-) Fam. Hist. of RLS (n=50) Age 67.5 ± 11 67.0 ± 10 67.9 ± 10 59.8 ± 15 59.3 ± 15 60.9 ± 16 Age Onset of RLS N/A 62.5 ± 12.8 56.6 ± 18.6 35.6 ± 19.8 29.8 ± 17.5 46.5 ± 19.5 % with (+) Fam. History of RLS --17.520.265.81000 % Male 62.552.448.637.035.440.0 Ferritin (Mg/ml) 88.4 ± 68 (n=32) 50.7 ± 47 (n=25) 58.8 ± 51 (n=46) 86.3 ± 63 (n=90) 96.4 ± 65 (n=64) 61.5 ± 51 (n=26) Ondo WG, at al. Arch Neurol 2002:59:421-424.

143 PD/RLS Conclusions Symptoms of RLS are common in PD (20%) Symptoms of RLS are common in PD (20%) RLS does not contribute to PD sleepiness RLS does not contribute to PD sleepiness RLS/PD: associated with lower serum ferritins RLS/PD: associated with lower serum ferritins PD symptoms precede RLS symptoms unless there is a (+) family history of RLS PD symptoms precede RLS symptoms unless there is a (+) family history of RLS RLS is not a form fruste of PD RLS is not a form fruste of PD RLS pathology much different than PD RLS pathology much different than PD Symptoms of RLS are common in PD (20%) Symptoms of RLS are common in PD (20%) RLS does not contribute to PD sleepiness RLS does not contribute to PD sleepiness RLS/PD: associated with lower serum ferritins RLS/PD: associated with lower serum ferritins PD symptoms precede RLS symptoms unless there is a (+) family history of RLS PD symptoms precede RLS symptoms unless there is a (+) family history of RLS RLS is not a form fruste of PD RLS is not a form fruste of PD RLS pathology much different than PD RLS pathology much different than PD

144 Depression The Science and Medicine of Parkinsons Disease

145 Depression Screening and Assessment Assessment tools Assessment tools 1-question screen 1-question screen Geriatric Depression Scale (GDS-15) Geriatric Depression Scale (GDS-15) Hamilton Depression Scale (HDRS) Hamilton Depression Scale (HDRS) SCID depression module (DSM-IV diagnosis) SCID depression module (DSM-IV diagnosis) 42% patients GDS-15 + (5) 42% patients GDS-15 + (5) but... but... 26% reported depression on 1-question screen 26% reported depression on 1-question screen Problem with perception or instrument? Problem with perception or instrument? Assessment tools Assessment tools 1-question screen 1-question screen Geriatric Depression Scale (GDS-15) Geriatric Depression Scale (GDS-15) Hamilton Depression Scale (HDRS) Hamilton Depression Scale (HDRS) SCID depression module (DSM-IV diagnosis) SCID depression module (DSM-IV diagnosis) 42% patients GDS-15 + (5) 42% patients GDS-15 + (5) but... but... 26% reported depression on 1-question screen 26% reported depression on 1-question screen Problem with perception or instrument? Problem with perception or instrument? Shulman LM, at al. Mvmt Disord 2001;16(3):507-510

146 Nonrecognition of Depression and Other Non-motor Symptoms in PD Results of validated screening instruments The physicians impression following a routine office visit Results of validated screening instruments The physicians impression following a routine office visit Patients (%) Shulman LM, at al. Mvmt Disord 2001;16(3):507-510

147 Impact of Depression on Function (Schwab and England Score) Explained 54% of variance Variable Coefficient b Standard error se (b) tP Constant56.017.13.3.002 Hoehn and Yahr -11.01.9-5.8<.001 HDRS-0.70.2-4.0<.001 MMSE1.90.53.6.001 Shulman LM, at al. Mvmt Disord 2001;16(3):507-510

148 Impact of Depression on Function (UPDRS ADL Score) Explained 37% of variance Variable Coefficient b Standard error se (b) tP Constant47.59.15.2<.001 HDRS0.50.14.4<.001 MMSE-1.40.3-4.2<.001 Shulman LM, at al. Mvmt Disord 2001;16(3):507-510

149 Frequency 34% with DSM-IV depression 34% with DSM-IV depression 21% with major depression 21% with major depression 13% with minor depression or dysthymia 13% with minor depression or dysthymia Caveat is using inclusive criteria Caveat is using inclusive criteria GDS-15 good screening instrument for DSM- IV diagnosis of depression at cutoff of 5 GDS-15 good screening instrument for DSM- IV diagnosis of depression at cutoff of 5 Sensitivity = 89% Sensitivity = 89% Specificity = 80% Specificity = 80% 34% with DSM-IV depression 34% with DSM-IV depression 21% with major depression 21% with major depression 13% with minor depression or dysthymia 13% with minor depression or dysthymia Caveat is using inclusive criteria Caveat is using inclusive criteria GDS-15 good screening instrument for DSM- IV diagnosis of depression at cutoff of 5 GDS-15 good screening instrument for DSM- IV diagnosis of depression at cutoff of 5 Sensitivity = 89% Sensitivity = 89% Specificity = 80% Specificity = 80%

150 Treatment of Depression Antidepressant properties Antidepressant properties Serotonergic Serotonergic Adrenergic Adrenergic Anticholinergic Anticholinergic Dopamine re-uptake Dopamine re-uptake Histaminic Histaminic Antidepressant properties Antidepressant properties Serotonergic Serotonergic Adrenergic Adrenergic Anticholinergic Anticholinergic Dopamine re-uptake Dopamine re-uptake Histaminic Histaminic

151 Treatment of Depression in PD Antidepressant medications Antidepressant medications 4 small controlled trials 4 small controlled trials Large NIH trial ongoing Large NIH trial ongoing MAO-B inhibitors? MAO-B inhibitors? Dopamine agonists? Dopamine agonists? Antidepressant medications Antidepressant medications 4 small controlled trials 4 small controlled trials Large NIH trial ongoing Large NIH trial ongoing MAO-B inhibitors? MAO-B inhibitors? Dopamine agonists? Dopamine agonists?

152 Dementia Lewy Body Dementia (LBD) Parkinsons Disease with Dementia (PDD) Lewy Body Dementia (LBD) Parkinsons Disease with Dementia (PDD) The Science and Medicine of Parkinsons Disease

153 Dementia in PD Prevalence of PDD Prevalence of PDD Cross-sectional prevalence of dementia is 40% in patients with PD 1 Cross-sectional prevalence of dementia is 40% in patients with PD 1 78% of a population-based, representative cohort of patients with PD developed dementia during an 8-year study period 2 78% of a population-based, representative cohort of patients with PD developed dementia during an 8-year study period 2 Best predictor of mortality Best predictor of mortality Prevalence of PDD Prevalence of PDD Cross-sectional prevalence of dementia is 40% in patients with PD 1 Cross-sectional prevalence of dementia is 40% in patients with PD 1 78% of a population-based, representative cohort of patients with PD developed dementia during an 8-year study period 2 78% of a population-based, representative cohort of patients with PD developed dementia during an 8-year study period 2 Best predictor of mortality Best predictor of mortality Cummings JL. J Geriatr Psychiatry Neurol. 1988;1:24-36. Hughes TA, et al. Neurology. 2000;54:1596-1602.

154 Dementia in PD Emre M. Lancet Neurol. 2003;2:229-237. Impaired memory (retrieval > amnestic pattern) Impaired memory (retrieval > amnestic pattern) Benefit from external cues Benefit from external cues Preserved recognition Preserved recognition Executive dysfunction Executive dysfunction Concepts, problem solving, set shifting Concepts, problem solving, set shifting Internally cued behavior Internally cued behavior Tasks that require planning and sequencing Tasks that require planning and sequencing Attentional impairment Attentional impairment Reaction times and vigilance Reaction times and vigilance Fluctuations Fluctuations Hallucinations Hallucinations Impaired memory (retrieval > amnestic pattern) Impaired memory (retrieval > amnestic pattern) Benefit from external cues Benefit from external cues Preserved recognition Preserved recognition Executive dysfunction Executive dysfunction Concepts, problem solving, set shifting Concepts, problem solving, set shifting Internally cued behavior Internally cued behavior Tasks that require planning and sequencing Tasks that require planning and sequencing Attentional impairment Attentional impairment Reaction times and vigilance Reaction times and vigilance Fluctuations Fluctuations Hallucinations Hallucinations

155 Clinical Symptoms of PDD vs AD Parkinsons Disease Dementia (N=34) Alzheimers Disease (N=92) Major Depression FluctuationFalls Visual Hallucinations Parkinsonism Ballard C, et al. Am J Psych. 1999;156:1039-1045. Ballard C, et al. J Clin Psych. 2001;62:46-49.

156 PD Dementia Diffuse loss of Cholinergic function (imaging and pathology) Diffuse loss of Cholinergic function (imaging and pathology) Worse than Alzheimers disease Worse than Alzheimers disease Marked reduction in Nucleus Basalis of Meynert (basal forebrain) Marked reduction in Nucleus Basalis of Meynert (basal forebrain) Pathology is mostly Lewy bodies Pathology is mostly Lewy bodies Responds to cholinesterase inhibitors Responds to cholinesterase inhibitors Diffuse loss of Cholinergic function (imaging and pathology) Diffuse loss of Cholinergic function (imaging and pathology) Worse than Alzheimers disease Worse than Alzheimers disease Marked reduction in Nucleus Basalis of Meynert (basal forebrain) Marked reduction in Nucleus Basalis of Meynert (basal forebrain) Pathology is mostly Lewy bodies Pathology is mostly Lewy bodies Responds to cholinesterase inhibitors Responds to cholinesterase inhibitors

157 Treatment of Dementia Acetylcholinesterase inhibitors Acetylcholinesterase inhibitors Rivastigmine (Exelon)* Rivastigmine (Exelon)* Galantamine (Razadyne) Galantamine (Razadyne) Donepezil (Aricept) Donepezil (Aricept) Memantine (Namenda) Memantine (Namenda) Acetylcholinesterase inhibitors Acetylcholinesterase inhibitors Rivastigmine (Exelon)* Rivastigmine (Exelon)* Galantamine (Razadyne) Galantamine (Razadyne) Donepezil (Aricept) Donepezil (Aricept) Memantine (Namenda) Memantine (Namenda)

158 177 (83.9%) completed 96 (78.0%) completed 211 to Riv-Rivastigmine123 to Plc-Rivastigmine Rivastigmine PD Study Extension study 334 patients entered O-L study 263 (72.7%) completed 147 (82.1%) completed 99 (27.3%) discontinued 32 (17.9%) discontinued 362 Rivastigmine179 placebo Core study 24 weeks 541 randomized to core study 650 screened

159 ADAS-Cog Results 2 1 0 -2 -3 -4 -5 Placebo Rivastigmine n=284 P<0.001 n=256 P<0.001 n=150 n=139 16240 Weeks During Treatment Improvement Decline Mean (± SEM) Change From Baseline ADAS-Cog Rating * OC analysis

160 Adverse Events Core and Extension Studies Core Rivastig N=362 n (%) Placebo N=179 n (%) Total patients with AE(s) 303 (83.7) 127 (70.9) Nausea 105 (29.0) 20 (11.2) Vomiting 60 (16.6) 3 (1.7) Tremor 37 (10.2) 7 (3.9) Diarrhea 26 (7.2) 8 (4.5) Anorexia 22 (6.1) 5 (2.8) Fall 21 (5.8) 11 (6.1) Dizziness 21 (5.8) 2 (1.1) Hypotension 19 (5.2) 14 (7.8) Hallucination 17 (4.7) 17 (9.5) Constipation 17 (4.7) 12 (6.7) Confusional state 13 (3.6) 10 (5.6) Orthostatic Hyp 6 (1.7) 9 (5.0) Extension Riv-Rivastig N=211 n (%) Pl-Rivastig N=123 n (%) 159 (75.4)93 (75.6) 29 (13.7)33 (26.8) 17 (8.1)20 (16.3) 8 (3.8)15 (12.2) 4 (1.9)4 (3.3) 6 (2.8)6 (4.9) 7 (3.3)9 (7.3) 5 (2.4)3 (2.4) 8 (3.8)5 (4.1) 9 (4.3)7 (5.7) 4 (1.9)2 (1.6) 10 (4.7)7 (5.7) 5 (2.4)4 (3.3)

161 Psychosis in PD Visual hallucinations Visual hallucinations Paranoid delusions Paranoid delusions Main risk factor for NHP Main risk factor for NHP Risk factors Risk factors Age, dementia, multiple medications, vision loss, Apo E, reduced occipitotemporoparietal activity Age, dementia, multiple medications, vision loss, Apo E, reduced occipitotemporoparietal activity Visual hallucinations Visual hallucinations Paranoid delusions Paranoid delusions Main risk factor for NHP Main risk factor for NHP Risk factors Risk factors Age, dementia, multiple medications, vision loss, Apo E, reduced occipitotemporoparietal activity Age, dementia, multiple medications, vision loss, Apo E, reduced occipitotemporoparietal activity

162 PET Imaging of PD Hallucination

163 Treatment of Psychosis Clozapine (12.5-100 mg) Clozapine (12.5-100 mg) Quetiapine (25 - 400 mg) Quetiapine (25 - 400 mg) Olanzapine (1.25 - 5 mg) Olanzapine (1.25 - 5 mg) Risperidone (1 - 2 mg) Risperidone (1 - 2 mg) Ziprasidone (20-80 mg) Ziprasidone (20-80 mg) Aripiprizole (?) Aripiprizole (?) Ondansetron (8 - 32 mg) Ondansetron (8 - 32 mg) Cholinesterase inhibitors Cholinesterase inhibitors Clozapine (12.5-100 mg) Clozapine (12.5-100 mg) Quetiapine (25 - 400 mg) Quetiapine (25 - 400 mg) Olanzapine (1.25 - 5 mg) Olanzapine (1.25 - 5 mg) Risperidone (1 - 2 mg) Risperidone (1 - 2 mg) Ziprasidone (20-80 mg) Ziprasidone (20-80 mg) Aripiprizole (?) Aripiprizole (?) Ondansetron (8 - 32 mg) Ondansetron (8 - 32 mg) Cholinesterase inhibitors Cholinesterase inhibitors

164 Conclusions Non-motor features are common in PD and may be more problematic than motor symptoms Non-motor features are common in PD and may be more problematic than motor symptoms Recognition historically poor, but improving Recognition historically poor, but improving Pathology is heterogeneous and variably related to dopaminergic function Pathology is heterogeneous and variably related to dopaminergic function Non-motor features are common in PD and may be more problematic than motor symptoms Non-motor features are common in PD and may be more problematic than motor symptoms Recognition historically poor, but improving Recognition historically poor, but improving Pathology is heterogeneous and variably related to dopaminergic function Pathology is heterogeneous and variably related to dopaminergic function

165 Case Studies The Science and Medicine of Parkinsons Disease

166 Case #1 A 56-year-old male in good health presents with rest tremor of the right (dominant) hand. Tremor worse with stress and when he walks. Handwriting has become slightly smaller but all words are legible. Wife has noticed decreased arm swing on the right. A 56-year-old male in good health presents with rest tremor of the right (dominant) hand. Tremor worse with stress and when he walks. Handwriting has become slightly smaller but all words are legible. Wife has noticed decreased arm swing on the right. He is complaining of severe constipation and stiffness in right side, He states that symptoms are only minimally interfering with job and home life. More importantly, the couple is troubled that condition will become apparent to coworkers and interfere with career. He is complaining of severe constipation and stiffness in right side, He states that symptoms are only minimally interfering with job and home life. More importantly, the couple is troubled that condition will become apparent to coworkers and interfere with career. A 56-year-old male in good health presents with rest tremor of the right (dominant) hand. Tremor worse with stress and when he walks. Handwriting has become slightly smaller but all words are legible. Wife has noticed decreased arm swing on the right. A 56-year-old male in good health presents with rest tremor of the right (dominant) hand. Tremor worse with stress and when he walks. Handwriting has become slightly smaller but all words are legible. Wife has noticed decreased arm swing on the right. He is complaining of severe constipation and stiffness in right side, He states that symptoms are only minimally interfering with job and home life. More importantly, the couple is troubled that condition will become apparent to coworkers and interfere with career. He is complaining of severe constipation and stiffness in right side, He states that symptoms are only minimally interfering with job and home life. More importantly, the couple is troubled that condition will become apparent to coworkers and interfere with career.

167 Case #1 Family History: No family history of Parkinsons disease Family History: No family history of Parkinsons disease Medical History/Medications: Wife noticed that for the past three years the patient thrashes around during sleep and fell out of bed twice. No current medications Medical History/Medications: Wife noticed that for the past three years the patient thrashes around during sleep and fell out of bed twice. No current medications Examination: Reveals normal mental status and eye movements. He has mild bradykinesia on repetitive alternating movements in the right hand and a rest tremor is noted. Examination: Reveals normal mental status and eye movements. He has mild bradykinesia on repetitive alternating movements in the right hand and a rest tremor is noted. Decision making: Making the diagnosis of PD; early non-motor features of PD; when to initiate therapy Decision making: Making the diagnosis of PD; early non-motor features of PD; when to initiate therapy Family History: No family history of Parkinsons disease Family History: No family history of Parkinsons disease Medical History/Medications: Wife noticed that for the past three years the patient thrashes around during sleep and fell out of bed twice. No current medications Medical History/Medications: Wife noticed that for the past three years the patient thrashes around during sleep and fell out of bed twice. No current medications Examination: Reveals normal mental status and eye movements. He has mild bradykinesia on repetitive alternating movements in the right hand and a rest tremor is noted. Examination: Reveals normal mental status and eye movements. He has mild bradykinesia on repetitive alternating movements in the right hand and a rest tremor is noted. Decision making: Making the diagnosis of PD; early non-motor features of PD; when to initiate therapy Decision making: Making the diagnosis of PD; early non-motor features of PD; when to initiate therapy

168 Case #2 58-year-old male in good health presents with resting tremor of the right (dominant) hand and difficulty with simple tasks such as brushing teeth and combing hair. He works as a desk clerk and has noticed significant problems with writing. Also has trouble buttoning and at times has trouble cutting food. 58-year-old male in good health presents with resting tremor of the right (dominant) hand and difficulty with simple tasks such as brushing teeth and combing hair. He works as a desk clerk and has noticed significant problems with writing. Also has trouble buttoning and at times has trouble cutting food. Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily during the day. Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily during the day. 58-year-old male in good health presents with resting tremor of the right (dominant) hand and difficulty with simple tasks such as brushing teeth and combing hair. He works as a desk clerk and has noticed significant problems with writing. Also has trouble buttoning and at times has trouble cutting food. 58-year-old male in good health presents with resting tremor of the right (dominant) hand and difficulty with simple tasks such as brushing teeth and combing hair. He works as a desk clerk and has noticed significant problems with writing. Also has trouble buttoning and at times has trouble cutting food. Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily during the day. Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily during the day.

169 Case #2 Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinsons disease 2 years ago is responding well to levodopa Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinsons disease 2 years ago is responding well to levodopa Medical History/Medications: No significant medical or surgical history. No current medications Medical History/Medications: No significant medical or surgical history. No current medications Examination: Bilateral bradykinesia and asymmetric rest tremor right greater than left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the examination is normal Examination: Bilateral bradykinesia and asymmetric rest tremor right greater than left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the examination is normal Decision making: Patient diagnosed with Parkinsons disease with some disability and he wishes to start treatment. Decision making: Patient diagnosed with Parkinsons disease with some disability and he wishes to start treatment. Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinsons disease 2 years ago is responding well to levodopa Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinsons disease 2 years ago is responding well to levodopa Medical History/Medications: No significant medical or surgical history. No current medications Medical History/Medications: No significant medical or surgical history. No current medications Examination: Bilateral bradykinesia and asymmetric rest tremor right greater than left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the examination is normal Examination: Bilateral bradykinesia and asymmetric rest tremor right greater than left. Gait is slow but there is no problem turning. Pull Test is negative. Rest of the examination is normal Decision making: Patient diagnosed with Parkinsons disease with some disability and he wishes to start treatment. Decision making: Patient diagnosed with Parkinsons disease with some disability and he wishes to start treatment.

170 Case #3 68-year-old woman with a 4-year history of Parkinsons disease. She initially presented with asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. Was started on levodopa 3 years ago. 68-year-old woman with a 4-year history of Parkinsons disease. She initially presented with asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. Was started on levodopa 3 years ago. Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing return of tremor and slowness and sweating and abdominal pain as the medication is wearing off. During off periods, and in the early morning hours and she has painful dystonia of the left foot. She has abnormal movements while the medication is working. Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing return of tremor and slowness and sweating and abdominal pain as the medication is wearing off. During off periods, and in the early morning hours and she has painful dystonia of the left foot. She has abnormal movements while the medication is working. 68-year-old woman with a 4-year history of Parkinsons disease. She initially presented with asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. Was started on levodopa 3 years ago. 68-year-old woman with a 4-year history of Parkinsons disease. She initially presented with asymmetric tremor involving the left hand. Subsequently, she progressed to have tremor both sides and significant slowness bilaterally. Was started on levodopa 3 years ago. Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing return of tremor and slowness and sweating and abdominal pain as the medication is wearing off. During off periods, and in the early morning hours and she has painful dystonia of the left foot. She has abnormal movements while the medication is working. Currently takes carbidopa-levodopa 25/100 one tablet 4 times per day. She is experiencing return of tremor and slowness and sweating and abdominal pain as the medication is wearing off. During off periods, and in the early morning hours and she has painful dystonia of the left foot. She has abnormal movements while the medication is working.

171 Case #3 Family History: no relatives with PD Family History: no relatives with PD Medical History: No significant medical or surgical history Medical History: No significant medical or surgical history Medications: Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa-levodopa Medications: Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa-levodopa Decision making: treatment of motor fluctuations, non-motor features of PD Decision making: treatment of motor fluctuations, non-motor features of PD Family History: no relatives with PD Family History: no relatives with PD Medical History: No significant medical or surgical history Medical History: No significant medical or surgical history Medications: Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa-levodopa Medications: Amitriptyline 50 mg. q.h.s for depression in addition to carbidopa-levodopa Decision making: treatment of motor fluctuations, non-motor features of PD Decision making: treatment of motor fluctuations, non-motor features of PD

172 Case #4 82-year-old woman has a history of Parkinsons disease for 12 years. She presented with shuffling gait, masked facies, postural instability, and a pill-rolling tremor of the right hand. 82-year-old woman has a history of Parkinsons disease for 12 years. She presented with shuffling gait, masked facies, postural instability, and a pill-rolling tremor of the right hand. Initially responded well to carbidopa-levodopa. Then she developed mild wearing off and dyskinesia. Over the past two years she has been experiencing visual hallucinations, paranoia, and vivid dreams. She has become more forgetful and gets lost easily around familiar places. She falls frequently. Initially responded well to carbidopa-levodopa. Then she developed mild wearing off and dyskinesia. Over the past two years she has been experiencing visual hallucinations, paranoia, and vivid dreams. She has become more forgetful and gets lost easily around familiar places. She falls frequently. 82-year-old woman has a history of Parkinsons disease for 12 years. She presented with shuffling gait, masked facies, postural instability, and a pill-rolling tremor of the right hand. 82-year-old woman has a history of Parkinsons disease for 12 years. She presented with shuffling gait, masked facies, postural instability, and a pill-rolling tremor of the right hand. Initially responded well to carbidopa-levodopa. Then she developed mild wearing off and dyskinesia. Over the past two years she has been experiencing visual hallucinations, paranoia, and vivid dreams. She has become more forgetful and gets lost easily around familiar places. She falls frequently. Initially responded well to carbidopa-levodopa. Then she developed mild wearing off and dyskinesia. Over the past two years she has been experiencing visual hallucinations, paranoia, and vivid dreams. She has become more forgetful and gets lost easily around familiar places. She falls frequently.

173 Case #4 Family History: 87-year-old sister diagnosed with Alzheimers disease and Pakinsons disease Family History: 87-year-old sister diagnosed with Alzheimers disease and Pakinsons disease Medical History: Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. Medical History: Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. Medications: She takes 1 aspirin daily in addition to carbidopa-levodopa Medications: She takes 1 aspirin daily in addition to carbidopa-levodopa Decision making: management of advanced PD motor and non-motor features Decision making: management of advanced PD motor and non-motor features Family History: 87-year-old sister diagnosed with Alzheimers disease and Pakinsons disease Family History: 87-year-old sister diagnosed with Alzheimers disease and Pakinsons disease Medical History: Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. Medical History: Mild stroke 3 years ago; has minimal residual effects of right-sided weakness. Medications: She takes 1 aspirin daily in addition to carbidopa-levodopa Medications: She takes 1 aspirin daily in addition to carbidopa-levodopa Decision making: management of advanced PD motor and non-motor features Decision making: management of advanced PD motor and non-motor features


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