parkinson’s disease background best described as “shaking palsy” by james parkinson in 1817 ...
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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
emai
nin
g
% R
emai
nin
g
Do
pam
ine
rgic
Neu
ron
sD
op
amin
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ic N
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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