1. The Science and Medicine of Parkinson’s 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

2. 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 Parkinson’s 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 Parkinson’s Disease and Movement Disorders Center Disorders Center Associate Professor of Neurology University of Pennsylvania Philadelphia, PA

3. 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 Speaker’s Bureau: Allergan, Boehringer-Ingelheim, GSK, Novartis, Solstice, Teva, UCB, Valeant Andrew D. Siderowf, MD, MSCE Grant/Research Support: Boehringer-Ingelheim Consultant: Boehringer-Ingelheim, TEVA Speaker’s Bureau: Boehringer-Ingelheim, Schwarz-Pharma, Teva William G. Ondo, MD Grant/Research Support: Forrest, UCB Speaker’s 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 Speaker’s Bureau: Allergan, Boehringer-Ingelheim, GSK, Novartis, Solstice, Teva, UCB, Valeant Andrew D. Siderowf, MD, MSCE Grant/Research Support: Boehringer-Ingelheim Consultant: Boehringer-Ingelheim, TEVA Speaker’s Bureau: Boehringer-Ingelheim, Schwarz-Pharma, Teva William G. Ondo, MD Grant/Research Support: Forrest, UCB Speaker’s Bureau: Boehringer-Ingelheim, GSK, TEVA, Valeant, UCB

4. 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?

5. 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?

6. Parkinson’s 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)

7. Parkinson’s 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 Parkinson’s 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. Parkinson’s 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 Parkinson’s 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. Parkinson’s Disease Foundation, Inc. 2007

8. Parkinson’s Disease — Costs Staggering Resources Expended ► Combined direct and indirect cost of Parkinson’s, 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 Parkinson’s Disease Foundation, Inc. 2007 Staggering Resources Expended ► Combined direct and indirect cost of Parkinson’s, 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 Parkinson’s Disease Foundation, Inc. 2007

9. 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.

10. H. Braak, et al., Cell Tissue Res (2004) 318: 121–134. Progressive Parkinson’s Disease Pathology Progressive Parkinson’s Disease Pathology

11. Stages of Parkinson’s Disease ► Mild symptoms, no disability ► Non-pharmacological approaches ► Moderate symptoms with some disability ► Multiple treatments available including l-dopa ► Progression of symptoms ► Levodopa required +/- other meds Early ModerateAdvanced ► Disease progresses ► 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

12. Early Diagnosis and Intervention In Parkinson’s 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 Parkinson’s Disease The Science and Medicine of Parkinson’s Disease

13. Parkinson’s Disease: Old News ► Chronic progressive neurodegenerative disorder ► Characterized by loss of dopaminergic neurons in the substantia nigra ► Clinical features of Parkinson’s Disease ● Tremor, rigidity and bradykinesia ● Postural instability in later stages ● Autonomic failure (constipation, orthostasis, impotence) ● Neuropsychiatric dysfunction (depression, dementia) ► Chronic progressive neurodegenerative disorder ► Characterized by loss of dopaminergic neurons in the substantia nigra ► Clinical features of Parkinson’s Disease ● Tremor, rigidity and bradykinesia ● Postural instability in later stages ● Autonomic failure (constipation, orthostasis, impotence) ● 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.

14. Parkinson’s Disease: Epidemiology ► Approximately 1 million patients in US ► 40,000 to 60,000 new cases/year ► Average age of onset is 60 years, predominantly males ● Affects up to 0.3% of general population ● 1% to 3% of those older than 65 years ► Prevalence increasing as the population ages ► Approximately 1 million patients in US ► 40,000 to 60,000 new cases/year ► Average age of onset is 60 years, predominantly males ● Affects up to 0.3% of general population ● 1% to 3% of those older than 65 years ► 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.

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

16. Is the “Gold Standard” Really Golden? ► Levodopa/carbidopa: Dopamine precursor ► Most effective therapy: Gold standard? ► Early side effects: Nausea and hypotension ► Long term side effects: Dyskinesias and motor fluctuations such as “wearing off” ► Levodopa/carbidopa: Dopamine precursor ► Most effective therapy: Gold standard? ► Early side effects: Nausea and hypotension ► 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. Parkinson’s 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.

18. 2004;351 (Dec 9):2498-2508 Landmark Trials in Parkinson’s Disease Landmark Trials in Parkinson’s Disease

19. 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?

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

21. 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

22. 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

23. 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%

24. Old School Thinking

25. Does Early Diagnosis = Early Treatment? ► 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... 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 Parkinson’s Disease

27. 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

28. 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.

29. 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

30. 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

31. 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

32. 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

33. TEMPO: Study Conclusions ► In early PD patients: ● Rasagiline effectively manages symptoms over 1 year ● 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.” ► In early PD patients: ● Rasagiline effectively manages symptoms over 1 year ● 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.” Parkinson Study Group. Arch Neurol. 2004; 61:561-566

34. Old School Revisited

35. 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

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

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

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

39. Conclusions: Early Treatment ► 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 ► 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 ► 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 1 Parkinson Study Group. Arch Neurol. 2004;61:561-566 2 Lew EFNS 2005

40. Adjunctive Drug Therapy for Advanced Parkinson’s 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 Parkinson’s Disease

41. Stages of Parkinson’s Disease ► Mild symptoms, no disability ► Non-pharmacological approaches ► Moderate symptoms with some disability ► Multiple treatments available including l-dopa ► Progression of symptoms ► Levodopa required +/- other meds Early ModerateAdvanced ► Disease progresses ► 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

42. Early or Moderate Stage Management of PD ► Level A – MAO-B inhibitors – selegiline, rasagiline ► Level A – Dopamine agonists – pramipexole, ropinirole, rotigotine – caution in elderly, cognitive impairment, young males (?) ► Level A - Carbidopa/levodopa – immediate release ► Level B - Carbidopa/levodopa – controlled release Recommended Years 1-5 (possibly more?) Questionable ► Co-enzyme Q10 ► 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

43. Long-term Treatment of Parkinson’s Disease Associated with Motor Complications Adjunctive Drug Therapy for Advanced PD

44. Goals of Current Therapeutic Strategies Adjunctive Drug Therapy for Advanced PD

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

46. 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: 1990’s Adjunctive Drug Therapy for Advanced PD

47. 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

48. 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

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

50. 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 DA’s Nasal sprays Other transdermal MAO-B Extended levodopa delivery systems

51. Advanced Management of PD Treating Motor Fluctuations ► Level A – entacapone, rasagiline ► Level B – pramipexole, ropinirole, tolcapone - caution hepatotoxicity ► Level C – apomorphine, cabergoline, and selegiline ► Level C (surgical) – STN deep brain stimulation ► Level C (dyskinesias) - amantadine ► 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

52. 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)

53. Goals of Current Therapeutic Strategies Adjunctive Drug Therapy for Advanced PD

54. Plasma Levels – Rotigitine CDS Adjunctive Drug Therapy for Advanced PD

55. Adjunctive Transdermal System Adjunctive Drug Therapy for Advanced PD

56. 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).

57. 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

58. 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

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

60. ► Entacapone prolongs the half-life of levodopa by  85%, with no change in C max or T max ► Increases levodopa exposure by  35% Effect of Entacapone on Levodopa Pharmacokinetics Buottinen HM, et al. J Neurol Neurosurg Psychiatry. 1996. Diagnosis and Treatment of Parkinson’s Disease: Update 2004

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

62. 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

63. 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

64. 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)

65. 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

66. 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

67. Adjunctive Drug Therapy for Advanced PD Heinz Reichmann, Wolfgang Jost World Congress on Parkinson’s 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

68. 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

69. 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 *** *

70. 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 ***

71. Cognitive and Behavioral Adverse Events Comparison of Rasagiline with Other Agents % Incidence of CBAE’s above placebo (from package inserts) % Incidence of CBAE’s 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.

72. Deep Brain Stimulation: Reduction in “Off” Time The Deep-Brain Stimulation for Parkinson’s 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

73. Conclusions: Advanced Treatment ► 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 ► 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 Parkinson’s disease. ► 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 ► 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 Parkinson’s disease.

74. Andrew Siderowf, MD, MSCE Parkinson’s Disease and Movement Disorders Center Disorders Center Associate Professor of Neurology University of Pennsylvania Philadelphia, PA Andrew Siderowf, MD, MSCE Parkinson’s 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 Parkinson’s Disease

75. Physiological Background ► Monoamine oxidase (MAO) ● Enzyme responsible for degradation of catecholamines (dopamine, noradrenaline) and serotonin ► Two isoforms ● MAO-A: Primarily in the liver and GI tract ● MAO-B: Primarily in the brain ► The selectivity of MAO-B inhibition is dose-related ● At low doses, only MAO-B is inhibited ● At higher doses, MAO-A is also inhibited ► Monoamine oxidase (MAO) ● Enzyme responsible for degradation of catecholamines (dopamine, noradrenaline) and serotonin ► Two isoforms ● MAO-A: Primarily in the liver and GI tract ● MAO-B: Primarily in the brain ► The selectivity of MAO-B inhibition is dose-related ● At low doses, only MAO-B is 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.

76. Relative Functions of MAO-A and MAO-B ► Functions via deamination ► Type A ● 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 ● 80% located within CNS ● Dopamine in the CNS ● Inhibitors have anti-PD effects ► Functions via deamination ► Type A ● 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 ● 80% located within CNS ● Dopamine in the CNS ● Inhibitors have anti-PD effects

77. Rasagiline vs. Selegiline ► In vitro studies ● Both are selective and highly potent ● MAO-B IC 50 in human and rat brain 20-90 fold lower than for MAO-A inhibition ► In vivo studies ● Oral acute administration in rodents ● 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 Recovery of MAO activity following chronic drug administrationRecovery of MAO activity following chronic drug administration ► In vitro studies ● Both are selective and highly potent ● MAO-B IC 50 in human and rat brain 20-90 fold lower than for MAO-A inhibition ► In vivo studies ● Oral acute administration in rodents ● 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 Recovery of MAO activity following chronic drug administrationRecovery of MAO activity following chronic drug administration

78. Concurrent Antidepressant and MAOI Use ► SSRIs are commonly used antidepressants that enhance serotonin levels in the CNS ► 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 ► SSRIs are commonly used antidepressants that enhance serotonin levels in the CNS ► 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

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

80. Symptoms of Serotonin Toxicity A Life Threatening Syndrome ► Cognitive Symptoms ► Confusion ► Agitation ► Anxiety ► Confusion ► Agitation ► Anxiety ► Autonomic Symptoms ► Hyperthermia ► Diaphoresis ► Tachycardia ► Hypertension ► Hyperthermia ► Diaphoresis ► Tachycardia ► Hypertension ► Somatic Symptoms ► Myoclonus ► Hyperreflexia ► Muscle rigidity ► Tremor ► Myoclonus ► Hyperreflexia ► Muscle rigidity ► 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.

81. 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 ► TrpH= Tryptophan hydroxylase ► 5-HTP= 5-hydroxy- tryptophan ► AADC= Aromatic acid decarboxylase ► MAO-A= Monoamine oxidase type A ► 5-HIAA=5-Hydroxy- indoleacetic acid

82. Antidepressant Use (%) in Parkinson’s Patients Source: 2006 Scientific Advisory Meeting Summary. Parkinson’s Disease Stage

83. 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 † 61 (4.5%) 66.2 66.2 *Range: 1 day to 6.2 years † Other: bupropion, mianserin, mirtazapine, nefazodone, trazodone Antidepressants That Were Used in Rasagiline Clinical Trials n=1361 subjects exposed to rasagiline

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

85. 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 Parkinson’s Study Group (PSG) ► 47 (75%) of investigators responded ► 4568 patients treated with combination of Deprenyl and antidepressants Results: ► 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) ► The constellation of symptoms reported did not seem to meet Sternbach’s 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 Parkinson’s Study Group (PSG) ► 47 (75%) of investigators responded ► 4568 patients treated with combination of Deprenyl and antidepressants Results: ► 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) ► The constellation of symptoms reported did not seem to meet Sternbach’s criteria for serotonin syndrome Richard, et al. Neurology 1997; 48(4):1070-78.

86. 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 Sternbach’s 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 Sternbach’s 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 Sternbach’s 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 Sternbach’s criteria for serotonin syndrome

87. 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. ”

88. Rasagiline and Dietary Tyramine Issues, Studies, and Results Rasagiline and Dietary Tyramine Issues, Studies, and Results The Science and Medicine of Parkinson’s Disease

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

90. 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

91. 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)

92. Tyramine Interaction Studies with Rasagiline 1.Tyramine challenge in 27 healthy subjects 1 ●Rasagiline 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 HCl 3.PRESTO home BP monitoring in 443 PD patients 3 ●Rasagiline 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 HCl 5.TEMPO tyramine challenge in 55 PD patients 4 ● Rasagiline 1mg, 2mg with 75mg tyramine HCl 1.Tyramine challenge in 27 healthy subjects 1 ●Rasagiline 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 HCl 3.PRESTO home BP monitoring in 443 PD patients 3 ●Rasagiline 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 HCl 5.TEMPO tyramine challenge in 55 PD patients 4 ● 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

93. 1.Tyramine challenge in 27 healthy subjects 1 ●Rasagiline 1mg, 2mg with up to 800 mg tyramine HCl ●No 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 HCl ●No 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.

94. 1.Tyramine challenge in 27 healthy subjects 1 2.Tyramine challenge in 20 PD patients 2 ●Chronic levodopa usage ●Rasagiline 1mg, 2mg ●Fasting (which increases tyramine bioavailability) ●75-225 mg tyramine ●At 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 usage ●Rasagiline 1mg, 2mg ●Fasting (which increases tyramine bioavailability) ●75-225 mg tyramine ●At 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.

95. 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 diet ●No 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 diet ●No 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.

96. 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 ● Substudy of pivotal trial ● Following six months therapy to demonstrate selectivity was maintained LT ● Tyramine given with light meal ● 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 ● Substudy of pivotal trial ● Following six months therapy to demonstrate selectivity was maintained LT ● Tyramine given with light meal ● 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.

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

98. Summary: MAO-B Inhibition Tyramine reaction: A theoretical risk ● No potential for “cheese reaction” at defined low doses of selective MAO-B inhibitors ● 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 Tyramine reaction: A theoretical risk ● No potential for “cheese reaction” at defined low doses of selective MAO-B inhibitors ● 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

99. Non-Motor Aspects of Parkinson’s 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 Parkinson’s Disease

100. Parkinson’s Disease Cardinal Motor Features ► Bradykinesia and hypokinesia ● Slow and small ► Rigidity ► Tremor ● Rest>action ► +/- Postural instability ► Bradykinesia and hypokinesia ● Slow and small ► Rigidity ► Tremor ● Rest>action ► +/- Postural instability

101. 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 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 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.”

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

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

104. Spectrum of Neuropsychiatric and Cognitive Symptoms ► Depression ► Anxiety ► Psychosis ► Dementia ► Apathy ► Fatigue ► Depression ► Anxiety ► Psychosis ► Dementia ► Apathy ► Fatigue

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

106. Sensory Symptoms in PD ► Pain ► Numbness ► Tingling ► Burning ► Smell loss ► Discriminant Vision ► Diplopia ► Pain ► Numbness ► Tingling ► Burning ► Smell loss ► Discriminant Vision ► Diplopia

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

108. 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

109. 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

110. 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

111. 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

112. Sleep Disorders In Parkinson’s Disease The Science and Medicine of Parkinson’s Disease

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

114. Excessive Daytime Sleepiness (EDS) and “Sleep Attacks” ► First reported with pramipexole ► Subsequent reports with other agonists and other PD medications ► Numerous studies demonstrate EDS ► First reported with pramipexole ► Subsequent reports with other agonists and other PD medications ► Numerous studies demonstrate EDS

115. Daytime Sleepiness in PD ► Poor Nocturnal Sleep ● Disease ● Medications ► Direct Daytime Somnolence ● Disease ● Medications ► Poor Nocturnal Sleep ● Disease ● Medications ► Direct Daytime Somnolence ● Disease ● Medications

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

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

118. Daytime Sleepiness in PD ► Epworth Score: 11.1 ± 5.9, 43% > 10 ► Daytime sleepiness correlates with: ● Duration of PD ● Severity of PD ● Male Gender ● 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 ► Daytime sleepiness correlates with: ● Duration of PD ● Severity of PD ● Male Gender ● 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

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

120. 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

121. Sleep Studies in PD ► Two trials have failed to correlate nocturnal sleep problems with EDS ● Apnea ● Total sleep time ● Awakenings ► One showed that more nocturnal total sleep correlated with EDS ► Two trials have failed to correlate nocturnal sleep problems with EDS ● Apnea ● Total sleep time ● Awakenings ► 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.

122. 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

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

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

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

126. Rapid Eye Movement Behavioral Disorder (RBD) Parasomnia: Vigorous movements /w dream content associated with loss of REM atonia The Science and Medicine of Parkinson’s Disease

127. Sleep Hypnogram

128. REM Behavioral Disorder ► Lack of REM sleep atonia ► Dream behavior ► Lack of REM sleep atonia ► Dream behavior

129. Male > Female Prevalence ► Not predicted by testosterone ► May result from dream content ► Not predicted by testosterone ► 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.

130. RBD and Synucleinopathies ► Synucleinopathies ● PD, MSA, DLB ► Schenck et al 1996 ● 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 13.3 years after RBD Dx13.3 years after RBD Dx ► RBD seen in PD, MSA, DLB in 30-70% of cases ► RBD preceded parkinsonism ● MSA: 1-2 years ● PD: 3-4 years ● DLB: 9 years ► Synucleinopathies ● PD, MSA, DLB ► Schenck et al 1996 ● 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 13.3 years after RBD Dx13.3 years after RBD Dx ► RBD seen in PD, MSA, DLB in 30-70% of cases ► RBD preceded parkinsonism ● MSA: 1-2 years ● PD: 3-4 years ● DLB: 9 years

131. 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

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

133. REM Sleep

134. Braak PD Pathology Staging

135. Pre-Motor Features of PD ► RBD ► Olfaction loss ► Autonomic Dysfunction ● Cardiac, constipation ► RBD ► Olfaction loss ► Autonomic Dysfunction ● Cardiac, constipation

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

137. Restless Legs Syndrome (RLS) and Parkinson’s Disease The Science and Medicine of Parkinson’s Disease

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

139. 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.

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

141. Depression The Science and Medicine of Parkinson’s Disease

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

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

144. 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

145. 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

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

147. Treatment of Depression ► Antidepressant properties ● Serotonergic ● Adrenergic ● Anticholinergic ● Dopamine re-uptake ● Histaminic ► Antidepressant properties ● Serotonergic ● Adrenergic ● Anticholinergic ● Dopamine re-uptake ● Histaminic

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

149. Dementia Lewy Body Dementia (LBD) Parkinson’s Disease with Dementia (PDD) Lewy Body Dementia (LBD) Parkinson’s Disease with Dementia (PDD) The Science and Medicine of Parkinson’s Disease

150. Dementia in PD ► Prevalence of PDD ● 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 ► Best predictor of mortality ► Prevalence of PDD ● 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 ► Best predictor of mortality Cummings JL. J Geriatr Psychiatry Neurol. 1988;1:24-36. Hughes TA, et al. Neurology. 2000;54:1596-1602.

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

152. Clinical Symptoms of PDD vs AD Parkinson’s Disease Dementia (N=34) Alzheimer’s 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.

153. PD Dementia ► Diffuse loss of Cholinergic function (imaging and pathology) ● Worse than Alzheimer’s disease ► Marked reduction in Nucleus Basalis of Meynert (basal forebrain) ► Pathology is mostly Lewy bodies ► Responds to cholinesterase inhibitors ► Diffuse loss of Cholinergic function (imaging and pathology) ● Worse than Alzheimer’s disease ► Marked reduction in Nucleus Basalis of Meynert (basal forebrain) ► Pathology is mostly Lewy bodies ► Responds to cholinesterase inhibitors

154. Treatment of Dementia ► Acetylcholinesterase inhibitors ● Rivastigmine (Exelon)* ● Galantamine (Razadyne) ● Donepezil (Aricept) ► Memantine (Namenda) ► Acetylcholinesterase inhibitors ● Rivastigmine (Exelon)* ● Galantamine (Razadyne) ● Donepezil (Aricept) ► Memantine (Namenda)

155. 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

156. 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

157. 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)

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

159. PET Imaging of PD Hallucination

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

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

162. Case Studies The Science and Medicine of Parkinson’s Disease

163. 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. ► 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. ► 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.

164. Case #1 ► Family History: No family history of Parkinson’s 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 ► 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 ► Family History: No family history of Parkinson’s 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 ► 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

165. 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. ► 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. ► Complains of fatigue, lack of motivation and disinterest. He tends to fall asleep easily during the day.

166. Case #2 ► Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinson’s disease 2 years ago is responding well to levodopa ► 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 ► Decision making: Patient diagnosed with Parkinson’s disease with some disability and he wishes to start treatment. ► Family History: Father died with Parkinson Disease and a cousin diagnosed with Parkinson’s disease 2 years ago is responding well to levodopa ► 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 ► Decision making: Patient diagnosed with Parkinson’s disease with some disability and he wishes to start treatment.

167. Case #3 ► 68-year-old woman with a 4-year history of Parkinson’s 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. ► 68-year-old woman with a 4-year history of Parkinson’s 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.

168. Case #3 ► Family History: no relatives with PD ► Medical History: No significant medical or surgical history ► 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 ► Family History: no relatives with PD ► Medical History: No significant medical or surgical history ► 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

169. Case #4 ► 82-year-old woman has a history of Parkinson’s 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. ► 82-year-old woman has a history of Parkinson’s 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.

170. Case #4 ► Family History: 87-year-old sister diagnosed with Alzheimer’s disease and Pakinson’s disease ► 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 ► Decision making: management of advanced PD motor and non-motor features ► Family History: 87-year-old sister diagnosed with Alzheimer’s disease and Pakinson’s disease ► 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 ► Decision making: management of advanced PD motor and non-motor features