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. Marttila RJ, Rinne UK. Acta Neurol Scand. 1991;84(suppl 136): DeStefano AL et al. Am J Hum Genet. 2002;70:

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

Neurodegenerative diseases P revalence in US

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

Risk of Parkinson’s Disease 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

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

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

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

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

Parkinson’s Disease Pathology Lewy body

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

Parkinson’s Disease N caudatus Putamen Thalamus Temporalcortex Parietalcortex Prefrontal premotoric cortex Striatum: Substantianigra Damier P et al. Brain. 1999;122:

Dopamine deficiency in PD PET scan

Presymptomatic phase Onset Sleep Olfactory* Mood Autonomic system Diagnosis Early nonmotor symptomsSpecific symptoms Motor Treatment Based on Replacing Dopamine Dopaminergic neuron loss in PD % Remaining Dopaminergic Neurons Time (years) Nonmotor 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 , Copyright 2009, with permission from Elsevier. *Olfactory dysfunction may predate clinical PD by at least 4 years. Halperin et al. Neurotherapeutics. 2009;6: Lang. Neurology. 2007;68: Ross et al. Ann Neurol. 2008;63:

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

Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex Cerebral cortexSubstantia nigra

Alpha Synuclein

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

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

Neurons & synapses

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

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)

AGENTPROSCONS * MAO B Inhibitors Effective Once-daily dosing AE profile similar to that of placebo Potential drug interactions Carbidopa/ Levodopa Highly effective Rapid onset of action Motor fluctuations and dyskinesia are common with long-term use Dopamine agonists Effective Delays start of L-dopa Low risk of motor complications Neuropsychiatric AEs Somnolence warning Agonist-specific AEs AmantadineBeneficial for tremor Antiparkinsonian effects Cognitive AEs Anticholinergic AEs Withdrawal effects * 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. Pros and Cons of Available FDA-Approved Monotherapy

Levodopa: The Cornerstone of PD Therapy  Levodopa provides substantial antiparkinsonian symptom control, and significantly improves patient quality of life 1  Levodopa is the most efficacious antiparkinsonian medication in moderate and advanced disease  Levodopa provides relatively rapid symptomatic benefits 2,3  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: Olanow CW, et al. Neurology. 2001;56:S1-S Agidy et al. Lancet. 2002;360:575.

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

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

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

Dyskinesia

Off Freezing

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

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

Duodopa  Du

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

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

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

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

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

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

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

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

DBS in PD

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

Differential Diagnosis of PD  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

Vascular PD

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)

Cerebellar dysfxn Parkinsonism Autonomic dysfxn Multiple Systems Atrophy

Early CBDG

PSP  Video

Normopressure Hydrocephalus

Magnetic Gait