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 diseases
Prevalence in US
# per 100,000
Alzheimer’s disease
4,000,000
1,450
Parkinson’s disease
1,000,000
360
40,000
14
5,000
2
Progressive supranuclear palsy
15,000
5
Amyotrophic lateral sclerosis
20,000
7
Huntington’s disease
30,000
11
400
<1
Frontotemporal dementia
Pick’s disease
Prion disease
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

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Age
High Body Mass Index
Male gender
Family history
Depression
Environment factors

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

rural living
well-water drinking
welding
head injury
Decreased risk

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Caffeine intake
Smoking cigarettes
Anti-oxidants in diet
Motor Symptoms

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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.
“…the hand failing to answer with
exactness to the dictates of the will.”
Manifestations of PD
Nutt JG, Wooten GF. N Engl J Med. 2005;353:1021-1027.
Parkinson’s Disease Foundation Web site. www.pdf.org.
Additional Features
 Cognitive, mood, and
behavioral dysfunction
 Olfactory disturbance
 Sleep disturbance
 Constipation
 Seborrheic dermatitis
 Pain
 Autonomic
disturbances
Diagnosing PD

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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
Prefrontal
premotoric cortex
Parietal
cortex
Striatum:
N caudatus
Putamen
Thalamus
Temporal
cortex
Substantia
nigra
Damier P et al. Brain. 1999;122:1437-1448.
Dopamine deficiency in PD
PET scan
Treatment Based on Replacing Dopamine
% Remaining
Dopaminergic Neurons
Onset
Diagnosis
Dopaminergic neuron loss in PD
Nonmotor
Motor
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.
Braak Staging of PD
Olanow, C. W. et al. Neurology 2009;72:S1-S136
Alpha-Synuclein Pathology in the
Substantia Nigra and Neocortex
Substantia nigra
Cerebral cortex
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
Mechanisms of Neurodegeneration
ENVIRONMENTAL FACTORS
Oxidative stress
MPTP
Pesticides
Herbicides
Bacterial toxins
Mitochondria
Complex I
ROS
GENETIC FACTORS
PARK1 (α-synuclein)
PARK2 (Parkin)
PARK5 (UCH-L1)
PARK6 (PINK1)
PARK7 (DJ-1)
PARK8 (LRRK2, dardarin)
Other genes
a-Synuclein
Related proteins?
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.
Neurons & synapses
Sites of Action of PD Drugs
Periphery
Blood-brain barrier
Brain
Neuron
COMT 3-OMD
inhibitors
L-DOPA
L-DOPA
MAO-B
inhibitors DOPAC
AADC
Carbidopa
DA
DA
DA
DA
DA
DA
*Only tolcapone inhibits
COMT in brain.
L-DOPA = levodopa
3-OMD = 3-O-methyldopa
DA = dopamine
Dopamine receptors
AADC = aromatic acid decarboxylase
DOPAC = dihydroxyphenylacetic acid
3-MT = 3-methoxytyramine
DA
COMT 3-MT
inhibitor*
Dopamine
agonists
PD: Treatment
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Amantadine
Anticholinergics
Carbidopa/Levodopa (SINEMET)

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Immediate release (IR), controlled release (CR), combined
with entacapone (COMTAN)
STALEVO
Dopamine agonists

Pramipexole (MIRAPEX)


Ropinirole (REQUIP)

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Immediate, CR release
Immediate release, CR release
MAO-B Inhibitors

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Rasagiline (AZILECT)
Selegiline (ELDEPRYL, ZELAPAR)
Pros and Cons of Available
FDA-Approved Monotherapy
AGENT
MAO B
Inhibitors
PROS
Effective
Carbidopa/
Levodopa
Highly effective
Dopamine
agonists
Effective
Delays start of L-dopa
Amantadine
Low risk of motor complications
Beneficial for tremor
Antiparkinsonian effects
Once-daily dosing
AE profile similar to that of placebo
Rapid onset of action
*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.
CONS*
Potential drug
interactions
Motor fluctuations and
dyskinesia are common
with long-term use
Neuropsychiatric AEs
Somnolence warning
Agonist-specific AEs
Cognitive AEs
Anticholinergic AEs
Withdrawal effects
Levodopa:
The Cornerstone of PD Therapy

Levodopa provides substantial antiparkinsonian symptom control,
and significantly improves patient quality of life1
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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.
Schematic of Levodopa and Dopamine Levels
as Disease Progresses
Early Disease
Advanced Disease
Levodopa
Plasma Level
Buffer Capacity
Buffer Capacity
Neuronal
Dopamine
Level
Levodopa Dosing Interval (h)
Early Disease: Fluctuating
Plasma Levodopa Levels
Levodopa Dosing Interval (h)
Buffering by Striatal DA Terminals
Advanced Disease: Fluctuating
Buffering by Striatal DA Terminals
Plasma Levodopa Levels
Relatively Constant
Striatal Dopamine Levels
Striatal Dopamine Levels
Mirror Levodopa Serum
Levels in the Periphery
Wearing Off
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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;5:677-687.
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
Absent or infrequent dyskinesia
Diminished duration
Increased incidence
Adapted from: Stocchi F, et al. Eur Neurol, 1996.
Shorter, unpredictable response
“On” time with increased dyskinesia
of dyskinesia
Duodopa

Du
Key Points: Early but No Impairment

Early patients- no functional impairment

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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
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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


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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

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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
0
1
2
3
Lead
Electrodes
3
2
1
0
off
(+) positive
off
off
(-)
off
Unipolar
3
2
1
0
Bipolar
* The negative electrode exerts the therapeutic effect
Managing Parkinson’s Disease Patients with Activa® Therapy
off
(+)
(-)
off
DBS in PD
Parkinsonian Syndromes
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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

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Manganese
Carbon monoxide
Vascular parkinsonism
Repeated head trauma

Other Parkinsonisms

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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)
Multiple Systems Atrophy
Parkinsonism
Cerebellar
dysfxn
Autonomic
dysfxn
Early CBDG
PSP

Video
Normopressure Hydrocephalus
Magnetic Gait