parkinson’s disease background best described as “shaking palsy” by james parkinson in 1817 ...

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.

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

Neurodegenerative diseasesPrevalence in US

# per 100,000

Alzheimer’s disease 4,000,000 1,450

Parkinson’s disease 1,000,000 360

Frontotemporal dementia 40,000 14

Pick’s disease 5,000 2

Progressive supranuclear palsy 15,000 5

Amyotrophic lateral sclerosis 20,000 7

Huntington’s disease 30,000 11

Prion disease 400 <1

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 DiseaseIncreased 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

Olanow CW, Watts RL, Koller WC.. . Neurology. Neurology. 2001;56 (suppl 5):S1-S88.2001;56 (suppl 5):S1-S88.Waters CH. Diagnosis and Management of Parkinson’s Disease. 3rd ed. 2002. National Parkinson Foundation. http://www.parkinson.org. National Parkinson Foundation. http://www.parkinson.org.

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

Manifestations of PDAdditional 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;353:1021-1027.

Parkinson’s Disease Foundation Web site. www.pdf.org.

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 caudatusN caudatus

PutamenPutamen

ThalamusThalamus

TemporalTemporalcortexcortex

ParietalParietalcortexcortex

PrefrontalPrefrontalpremotoric cortexpremotoric cortex

Striatum:Striatum:

Substantia Substantia nigranigra

Damier P et al. Brain. 1999;122:1437-1448.

Dopamine deficiency in PDPET scan

Presymptomatic phase

Onset

SleepOlfactory*MoodAutonomic system

Diagnosis

Early nonmotor symptoms Specific symptoms

Motor

Treatment Based on Replacing Dopamine

Dopaminergic neuron loss in PD

% R

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% R

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Do

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Neu

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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 128-140, Copyright 2009, with permission from Elsevier.

*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.

Halperin et al. Neurotherapeutics. 2009;6:128-140.Lang. Neurology. 2007;68:948-952. Ross et al. Ann Neurol. 2008;63:167-173.

Olanow, C. W. et al. Neurology 2009;72:S1-S136

Braak Staging of PD

Alpha-Synuclein Pathology in the Substantia Nigra and Neocortex

Cerebral cortex Substantia 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 stressOxidative stressMPTPMPTPPesticidesPesticidesHerbicidesHerbicidesBacterial toxinsBacterial toxins

Mechanisms of Neurodegeneration

ENVIRONMENTAL FACTORS GENETIC FACTORS

Mitochondria

Complex IROS

PARK1 (α-synuclein)PARK2 (Parkin)PARK5 (UCH-L1)PARK6 (PINK1)PARK7 (DJ-1) PARK8 (LRRK2, dardarin)Other genes

NIGRAL CELL DEATH

Toxic injuryToxic injuryApoptosisApoptosis

InflammationInflammationExcitotoxicityExcitotoxicity

-Synuclein-SynucleinRelated proteins?Related proteins?

Altered proteinAltered proteinconformationconformation

Ubiquitin systemUbiquitin systemProteasome dysfunction?Proteasome dysfunction?

Protein aggregatesProtein aggregates(Lewy bodies: (Lewy bodies: good or bad?)good or bad?)

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.

Neurons & synapses

Dopamine receptors

DADA

L-DOPAL-DOPA

3-OMD3-OMD

DADA

DopamineDopamineagonistsagonists

COMT COMT inhibitorsinhibitors

CarbidopaCarbidopa

MAO-BMAO-B inhibitorsinhibitors DOPACDOPAC

DA DA

3-MT3-MT

DADA

DA DA

AADCAADC

DADACOMTCOMT

inhibitor*inhibitor*

L-DOPAL-DOPA

DADADADA

Blood-brain barrierPeriphery BrainNeuron

Sites of Action of PD Drugs

*Only tolcapone inhibits COMT in brain.

L-DOPA = levodopa3-OMD = 3-O-methyldopaDA = dopamine

AADC = aromatic acid decarboxylase DOPAC = dihydroxyphenylacetic acid3-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)

AGENT PROS CONS*

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

Amantadine Beneficial 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 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.

Early Disease Advanced Disease

Levodopa Plasma Level

NeuronalDopamine

Level

Levodopa Dosing Interval (h) Levodopa Dosing Interval (h)

Schematic of Levodopa and Dopamine Levels as Disease Progresses

Early Disease: Fluctuating Plasma Levodopa Levels Buffering by Striatal DA TerminalsBuffering by Striatal DA Terminals

Relatively Constant Striatal Dopamine Levels

Advanced Disease: Fluctuating Plasma Levodopa Levels Buffering by Striatal DA TerminalsBuffering by Striatal DA Terminals

Striatal Dopamine Levels Mirror Levodopa Serum Levels in the Periphery

Buffer Capacity 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 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.

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

01

2

3

DBS™ Lead Electrode Selection

* The negative electrode exerts the therapeutic effect

Lead Electrodes

BipolarUnipolar

0 1 2 3

01

2

3off

off

(-)

off

(+) positive off 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)

Cerebellardysfxn

Parkinsonism

Autonomic dysfxn

Multiple Systems Atrophy

Early CBDG

PSP Video

Normopressure Hydrocephalus

Magnetic Gait