Parkinson’s Disease Background

1. Parkinson’s Disease Background • Best described as “shaking palsy” by James Parkinson in 1817 • “Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace: the senses and intellects being uninjured.” Olanow CW et al. Neurology. 2001;56 (suppl 5):S1-S88. National Parkinson Foundation Web site. www.parkinson.org. Marttila RJ, Rinne UK. Acta Neurol Scand. 1991;84(suppl 136):24-28. DeStefano AL et al. Am J Hum Genet. 2002;70:1089-1095.

2. “As the disease proceeds towards its last stage, the trunk is almost permanently bowed…”

3. Neurodegenerative diseasesPrevalence in US

4. Fast Facts about PD • Annual incidence: 60,000 new cases/yr • Increase with age (3% population >65 years old) • Slightly more common in men • Mean age at onset: 60 years old • 85% of patients are over 65 years old

5. Increased risk Age High Body Mass Index Male gender Family history Depression Environment factors rural living well-water drinking welding head injury Decreased risk Caffeine intake Smoking cigarettes Anti-oxidants in diet Risk of Parkinson’s Disease

6. Motor Symptoms • Tremor at rest • Bradykinesia • Rigidity • Postural instability • Decreased arm swing when walking • Micrographia • Hypophonia • Masked face • Slow, shuffling gait • Stooped posture Olanow CW, Watts RL, Koller WC.. Neurology. 2001;56 (suppl 5):S1-S88. Waters CH. Diagnosis and Management of Parkinson’s Disease. 3rd ed. 2002. National Parkinson Foundation. http://www.parkinson.org.

7. “…the hand failing to answer with exactness to the dictates of the will.”

8. Additional Features Cognitive, mood, and behavioral dysfunction Olfactory disturbance Sleep disturbance Constipation Seborrheic dermatitis Pain Autonomic disturbances Manifestations of PD Nutt JG, Wooten GF. N Engl J Med. 2005;353:1021-1027. Parkinson’s Disease Foundation Web site. www.pdf.org.

9. Diagnosing PD • United Kingdom Brain Bank Criteria • Stage I Hoehn and Yahr (H&Y)- unilateral • Stage II H&Y – bilateral • Stage III H&Y – bilateral with loss of balance/falls • Stage IV H&Y – all above and significant disability • Stage V H&Y- bedbound

10. Parkinson’s Disease Pathology Lewy body

11. Pyramidal system Weakness Extrapyramidal system Modulator of pyramidal system Symptoms involuntary movement slow, interrupted movement  posture/tone CNS Motor Organization

12. Parkinson’s Disease Prefrontal premotoric cortex Parietal cortex Striatum: N caudatus Putamen Thalamus Temporal cortex Substantia nigra Damier P et al. Brain. 1999;122:1437-1448.

13. Dopamine deficiency in PDPET scan

14. Treatment Based on Replacing Dopamine Onset Diagnosis Dopaminergic neuron loss in PD Nonmotor Motor % Remaining Dopaminergic Neurons Sleep Olfactory* Mood Autonomic system Presymptomatic phase Early nonmotor symptoms Specific symptoms Time (years) *Olfactory dysfunction may predate clinical PD by at least 4 years. Halperin et al. Neurotherapeutics. 2009;6:128-140. Lang. Neurology. 2007;68:948-952. Ross et al. Ann Neurol. 2008;63:167-173. Adapted image reprinted from Neurotherapeutics, Vol. 6, Halperin I, Morelli M, Korczyn AD, Youdim MB, Mandel SA. Biomarkers for evaluation of clinical efficacy of multipotential neuroprotective drugs for Alzheimer's and Parkinson's diseases, pages 128-140, Copyright 2009, with permission from Elsevier.

15. Braak Staging of PD Olanow, C. W. et al. Neurology 2009;72:S1-S136

16. Cerebral cortex Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex Substantia nigra

17. Alpha Synuclein

18. Toxic Alpha-synuclein • Chaperones prevent toxic alpha-synuclein from forming • Develop antibodies that keep alpha-synuclein from forming aggregates • Find small molecules that can prevent misfolding

19. Mechanisms of Neurodegeneration ENVIRONMENTAL FACTORS GENETIC FACTORS PARK1 (α-synuclein) PARK2 (Parkin) PARK5 (UCH-L1) PARK6 (PINK1) PARK7 (DJ-1) PARK8 (LRRK2, dardarin) Other genes a-Synuclein Related proteins? Oxidative stress MPTP Pesticides Herbicides Bacterial toxins Mitochondria Complex I ROS Altered protein conformation Ubiquitin system Proteasome dysfunction? Toxic injury Apoptosis Protein aggregates (Lewy bodies: good or bad?) Inflammation Excitotoxicity NIGRAL CELL DEATH BenMoyal-Segal L, Soreq H. J Neurochem. 2006;97:1740-1755. Dawson TM, Dawson VL. J Clin Invest. 2003;111:145-151. Mouradian MM. Neurology. 2002;58:179-185.

20. Neurons & synapses

21. Sites of Action of PD Drugs DA DA Periphery Brain Neuron Blood-brain barrier 3-OMD COMT inhibitors L-DOPA L-DOPA MAO-B inhibitors AADC DOPAC Carbidopa DA DA DA DA DA DA 3-MT COMT inhibitor* *Only tolcapone inhibits COMT in brain. Dopamine receptors Dopamine agonists L-DOPA = levodopa 3-OMD = 3-O-methyldopa DA = dopamine AADC = aromatic acid decarboxylase DOPAC = dihydroxyphenylacetic acid 3-MT = 3-methoxytyramine

22. PD: Treatment • Amantadine • Anticholinergics • Carbidopa/Levodopa (SINEMET) • Immediate release (IR), controlled release (CR), combined with entacapone (COMTAN) • STALEVO • Dopamine agonists • Pramipexole (MIRAPEX) • Immediate, CR release • Ropinirole (REQUIP) • Immediate release, CR release • MAO-B Inhibitors • Rasagiline (AZILECT) • Selegiline (ELDEPRYL, ZELAPAR)

23. Pros and Cons of Available FDA-Approved Monotherapy *This does not represent a complete listing of safety information. Please see product prescribing information. FDA = Food and Drug Administration; L-dopa = levodopa. AZILECT Prescribing Information. 05/09. Olanow et al. Neurology. 2001;56(11 suppl 5):S1-S88. Jankovic. Neurology. 2002;58(4 suppl 1):S19-S32.

24. Levodopa: The Cornerstone of PD Therapy • Levodopa provides substantial antiparkinsonian symptom control, and significantly improves patient quality of life1 • Levodopa is the most efficacious antiparkinsonian medication in moderate and advanced disease • Levodopa provides relatively rapid symptomatic benefits2,3 • Levodopa is generally well tolerated with few initial side effects • Levodopa continues to provide antiparkinsonian benefits through the course of the illness • All PD patients eventually require levodopa therapy 1. Louis ED, et al. Arch Neurol. 1997;54:260-264. 2. Olanow CW, et al. Neurology. 2001;56:S1-S86. 3. Agidy et al. Lancet. 2002;360:575.

25. Early Disease Advanced Disease Levodopa Plasma Level NeuronalDopamineLevel Levodopa Dosing Interval (h) Levodopa Dosing Interval (h) Schematic of Levodopa and Dopamine Levels as Disease Progresses Buffer Capacity Buffer Capacity Early Disease: Fluctuating Plasma Levodopa Levels Relatively Constant Striatal Dopamine Levels Buffering by Striatal DA Terminals Striatal Dopamine Levels Mirror Levodopa Serum Levels in the Periphery Advanced Disease: Fluctuating Plasma Levodopa Levels Buffering by Striatal DA Terminals

26. Wearing Off • Most common motor fluctuation • Occurs toward end of dose • “wear down” • Regular and predictable • Adjust dose

27. On-Off Response • Sudden and unpredictable • Dose failure • Late afternoon, probably related to poor gastric emptying or absorption • Hardest feature • Dose adjustments, add-ons

28. Dyskinesia

29. Off Freezing

30. Continuous Delivery Theory • Pulsatile stimulation causes levodopa-associated motor complications • Stable plasma levels may prevent priming for motor fluctuationsand dyskinesia • Continuous delivery systems in development Stocchi F, Olanow CW. Neurology. 2004;62:S56-S63. Olanow CW et al. Lancet Neurol. 2006;5:677-687.

31. As the Disease Progresses, the Therapeutic Window Narrows* Symptoms and side effects occur as the levodopa therapeutic window diminishes* Plasma Levodopa Concentrations Smooth, extended response Diminished duration Shorter, unpredictable response Absent or infrequent dyskinesia Increased incidence “On” time with increased dyskinesia of dyskinesia Adapted from: Stocchi F, et al. Eur Neurol, 1996.

32. Duodopa • Du

34. Key Points: Early but No Impairment • Early patients- no functional impairment • Easiest treatment category • ADAGIO, TEMPO (rasagiline) and ELLDOPA trial indicate earlier treatment may be better • Consider rasagiline (Azilect), selegiline (Eldepryl,Zelapar) • Refer for potential neuroprotective trials • Coenzyme Q10, selegiline, rasagiline, creatine

35. Key Points: Early with Impairment • Early patient-functional impairment • Bothersome tremor, stiffness, slowness, decrease in dexterity interfering with ADLs or job • AAN guidelines 2002 • MAO B inhibitors provide some benefit • Dopamine agonists • Levodopa • If the patient is chronologically or physiologically young (<70) try a dopamine agonist as the first robust treatment • If older, or cognitively impaired, use levodopa first

36. Key Points: Middle Stage Patients • Starting to have wearing off of drug benefit prior to next dose • Goal is to enhance dopamine system in the brain, since these medications have different mechanisms of action=Polypharmacy is expected! • Layer on medications and adjust to best benefit

37. Key Points: Later Mid-Stage Patient • Experiencing fluctuation in motor control to include significant wearing off with poor mobility and dyskinesias • Have patients keep diaries of motor control • Add additional medications • Consider smaller, more frequent doses of medications to minimize “off” time and dyskinesia • Onset or worsening of many non-levodopa responsive symptoms, such as falling, worsening cognition, dysphagia, autonomic dysfunction

38. Key Points: Advanced Parkinson’s Disease • Treatment is made difficult by the worsening of motor complications, cognitive, psychiatric and autonomic disturbances • Medications may need to be streamlined (reduced or eliminated) because of confusion or psychosis

39. Surgical Treatment for PD • Patient selection is KEY • Patients who are very sensitive to levodopa are the best candidates • Patients should have motor fluctuations including dyskinesias • Patients must be free of significant cognitive disease • Usually, consideration after 10 years of disease, but trend toward earlier use in several trials

40. Deep Brain Surgery • Most commonly done is deep brain stimulation of the STN, bilateral • Best patient is fluctuating, still responsive to levodopa, good cognitive skills

41. DBS™ Lead Electrode Selection 0 1 2 3 Lead Electrodes off (+) positive 3 3 off off 2 2 off (+) 1 1 (-) (-) 0 0 off off Unipolar Bipolar * The negative electrode exerts the therapeutic effect Managing Parkinson’s Disease Patients with Activa® Therapy

42. DBS in PD

44. Parkinsonian Syndromes • Patient has bilateral onset of a gait disorder • Patient has early falling • Patient does not respond well to L-Dopa • Patient has prominent dementia or autonomic nervous system dysfunction

45. Drug induced parkinsonism Normal Pressure Hydrocephalus Toxin exposure Manganese Carbon monoxide Vascular parkinsonism Repeated head trauma Other Parkinsonisms Progressive Supranuclear Palsy CBGD Multiple Systems Atrophy DLBD Differential Diagnosis of PD

46. Vascular PD

47. Multiple Systems Atrophy • Combination disorder with parkinsonism, ataxia and signs of autonomic nervous system dysfunction • Pathologically distinct from Parkinson’s disease • Three types • MSA-P (SND), MSA-C (OPCA), PAF (SDS)

48. Multiple Systems Atrophy Parkinsonism Cerebellar dysfxn Autonomic dysfxn

50. Early CBDG