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Start Here: The Basics of
Parkinson Disease
Dean P. Sutherland, MD, PhD
Clinical Assistant Professor, Florida State University College of MedicineClinical Assistant Professor, University of Florida College of MedicineFirst Physicians Group NeurologySarasota, Florida
Overview
What is Parkinson Disease (PD)?
Who Gets PD?
Why Do People Get PD?
Can We Stop or Reverse PD?
What Is The Treatment for PD?
What is Parkinson Disease?
A “Movement Disorder”
James Parkinson - 1817
Cardinal Features
Resting tremor
Decreased balance/reflexes
Muscle rigidity/cogwheeling
Slow movement (hypokinesia/bradykinesia)
Other Motor signs/symptoms:
Soft voiceMasked faceFreezing of gaitStooped postureFallingRestricted eye movementsTenting/cramping of hands/feet(dystonia)Small handwriting
Handwriting changes over years
Non-motor symptoms and signs
Psychiatric
depression
apathy
cognitive impairment
hallucinations
memory loss
Sleep disruption – REM behavioral disorder
Sensory dysfunction – anosmia
Non-motor symptoms and signs
Autonomic
GI – constipation, gastroparesis
Cardiac – lack of variable rhythm
Cardiovascular – orthostatic hypotension
Sialorrhea (drooling)
Sweating
Erectile/sexual dysfunction
Aching muscles and joints
Parkinson subtypes
Atypical Parkinson Disease
◦ No tremor
Tremor Predominant/Flapping Tremor
◦ Can be mistaken for Essential Tremor
Akinetic-Rigid
◦ Entire body very stiff
Postural Instability/Gait Disorder
◦ Mainly lower body and legs
Parkinson Plus Syndromes
Multiple Systems Atrophy
◦ Autonomic problems – incontinence,
impotence, passing out with standing
Progressive Supranuclear Palsy
◦ Cannot look up or down, falling backwards
Corticobasal Degeneration
◦ One hand loses knowledge of what to do,
language becomes difficult
Dementia with Lewy Bodies.
Parkinson’s symptoms AND dementia
symptoms all starting within a year of
each other
Tend to get hallucinations (70%) early on
Cognitive problems outstrip the motor
problems
PARKINSONISM
DRUG-INDUCED
CEREBROVASCULAR
PARKINSONIAN
SYNDROMES
PSYCHIATRICOTHER NEURO-DEGENERATIVE
PARKINSON DISEASE
PARKINSON PLUS
SYNDROMES
DRUG INDUCED
(MPTP)
IDIOPATHIC
GENETIC
ALS
HUNTINGTON DZ
WILSON DZ
NEUROLEPTICS
GI DRUGS
DEPRESSION
CONVERSION
DISORDER
SECONDARY
GAIN
CA CH BLOCKERS
LITHIUM
VALPROATE
STROKE
LEUKOARIOSIS
ANXIETY
ANTIDEPRESSANTS
STEROIDS
AMIODARONE
MULTIPLE SYSTEMS ATROPHY
PROGRESSIVE SUPRANUCLEAR PALSY
CORTICOBASALGANGL
IONIC DEGENERATION
DIFFUSE LEWY BODY DISEASE
ALZHEIMER DZ
STRUCTURALTRAUMA
BRAIN TUMOR
NORMAL PRESSURE
HYDROCEPHALUS
OTHER
MOVEMENT
DISORDERS
DYSTONIA
ESSENTIAL
TREMOR
What is not Parkinson Disease?
What is Parkinson Disease?
A Pathological Diagnosis?Cell death in the Substantia Nigra
Pars Compacta with
loss of Dopamine Abnormal protein accumulation of
Alpha-Synuclein Clumps of protein in
Lewy Bodies
Why do brain cells die?Role of Alpha Synuclein in PD
Why do brain cells die?Role of Alpha Synuclein in PD
http://neuroscience.nih.gov/Research.asp?People_ID=1904
http://currents.ucsc.edu/04-05/12-06/antibiotic.asp
Alpha Synuclein
The role of -synuclein in Parkinson's disease: insights from animal modelsEleonora Maries, Biplob Dass, Timothy J. Collier, Jeffrey H. Kordower & Kathy Steece-CollierNature Reviews Neuroscience 4, 727-738 (September 2003)
The entire brain is affected by PD
Stages
Braak staging of PD
21
The Parkinson’s Complex
Langston JW. Ann Neurol. 2006;59:591-596.
Adapted with permission of John Wiley & Sons, Inc. from Langston JW. The Parkinson’s complex:
Parkinsonism is just the tip of the iceberg. Ann Neurol. 2006;59(4):591-596. © 2006 American
Neurological Association.
Who Gets PD?
23
Epidemiology of PD
PD is the second most common
neurodegenerative disorder
after Alzheimer’s disease
Over 1 million people in the
United States (US) have PD
Prevalence in US by 2030
predicted to be 2 million cases
in people aged >50 years
de Lau LM et al. Lancet Neurol. 2006;5:525-535.
Dorsey ER et al. Neurology. 2007;68:384-386.
Nussbaum RL et al. N Engl J Med. 2003;348:1356-1364.
Olanow CW et al. Neurology. 2009;72(21 suppl 4):S1-S136.
Van Den Eeden SK et al. Am J Epidemiol. 2003;157:1015-1022.
Demographics of Parkinson Disease
About 1.5 percent of population
1.5-2.0 million Americans
Twice as prevalent in U.S. as in World
Average age 62 y.o.
Males:Females 2:1
Lifespan normal nowdays, but significant disability
In Sarasota/Manatee 5000+
Significant Economic Impact
Impact of PD
Cognitive and Emotional
Dementia 20 – 60% after 10 years
Risk of Car Accident 4 times higher
Depression 30 – 50%
Depressed spouse 20 – 30%
26
People At Risk for PD
Male:Female 2:1
Older people
Agent Orange Exposure (VA)
Pesticides
Herbicides
Fungicides
Dry Cleaning Industry (CCL4)
Industrial Cleaning Solutions (TCE)
Jewish/Berber/Basque Heritage (LRRK2)
Parkinson Disease: A Normal
Consequence of Growing Old?
28
Incidence of PD
Incidence of PD Increases
With Aging
de Lau LM et al. Lancet Neurol. 2006;5:525-535.
Dorsey ER et al. Neurology. 2007;68:384-386.
Nussbaum RL et al. N Engl J Med. 2003;348:1356-1364.
Olanow CW et al. Neurology. 2009;72(21 suppl 4):S1-S136.
Van Den Eeden SK et al. Am J Epidemiol. 2003;157:1015-1022.
0
50
100
150
200
250
300
30-39 40-49 50-59 60-69 70-79
N=588
Age, y
No
. PD
Case
s
Ott A et al. BMJ 1995;310:970-973
©1995 by British Medical Journal Publishing Group
Prevalence of Dementias
Incidence of Parkinson’s disease by age and gender, Kaiser Permanente, 1994–1995.
Van Den Eeden S K et al. Am. J. Epidemiol. 2003;157:1015-
1022
©2003 by Oxford University Press
31
Pathologic Hallmarks of PD PD is a progressive, neurodegenerative disorder involving
the dopaminergic nigrostriatal system
Nigrostriatal degeneration and Lewy Bodies (α-synuclein
aggregates) are pathologic hallmarks of PD
At the time of diagnosis, PD patients have lost 30% of
nigral cell bodies and 60% of nigral axon terminals and
dopamine content
As PD progresses, loss of dopaminergic neurons continues
Boska MD et al. J Neurosci. 2005;25:1691-1700.
Cheng HC et al. Ann Neurol. 2010;67:715-725.
Farrer MJ. Nat Rev Genetics. 2006;7:306-318.
Langston JW. Ann Neurol. 2006;59:591-596.
Olanow CW et al. Neurology. 2009;72(21 suppl 4):S1-S136.
Schapira AH. Arch Neurol. 2007;64:1083-1088.
32
Classic Neuronal Pathology of PD
32
Nigrostriatal degeneration, primarily in the substantia nigra pars compacta (SNpc) and striatum, and α-synuclein aggregates are
pathologic hallmarks of PD
Significant nigral dopaminergic neuronal loss is marked by a
reduction in neuromelanin pigment in the SNpc
Intraneuronal cytoplasmic inclusions, or “Lewy Bodies”
Normal
Patient with PD
33
Conceptual Diagram of the Phases
of PD
Schapira AH et al. Nat Rev Neurol. 2010;6:309-317.
DiseaseOnset
NonmotorSymptoms
MotorSymptoms
DopaminergicNeurons
Diagnosis
Time (y)
Premotor Phase Motor PhasePremotor Phase
Increase
Decrease
34
Genetics Environment
Cause of PD Still Unknown
Coppedè F. Sci World J. 2012;2012:1-12. Article 489830.National Human Genome Research Institute. Learning About Parkinson’s Disease. Available at: http://www.genome.gov/10001217/
Noyce AJ et al. Ann Neurol. 2012;72:893-901.
Tanner CM. Mov Disord. 2010;25(suppl 1):S58-S62.
Experts believe PD is the result of interaction
between genetic and environmental causes• Several genes and
specific mutations
associated with PD
have been identified
• Approximately 20%
of patients have a
family history of PD
• Only 5% of PD
patients have a
monogenic form
• Majority of PD cases
are sporadic (also
known as idiopathic)
in nature
• Rural living, and exposure
to environmental toxins,
such as pesticides, may
contribute to the
development of PD
• No single environmental
cause of PD has been
determined
• Personal habits, including
smoking cigarettes and
drinking coffee, appear to
be associated with a
lower risk of PD
35
Coppedè F. Sci World J. 2012. Article ID 489830, 12 pages. doi:10.1100/2012/489830.
Nussbaum RL et al. N Engl J Med. 2003;348:1356-1364.Nicoletti A et al. Neurol Sci. 2010;31:47-52.Wider C et al. Mov Disord. 2010;25:S15-S20.
PD is primarily a sporadic or idiopathic disorder
Most PD does not have a genetic component
Primary genes associated with familial and sporadic PD include: ◦ LRRK2
◦ GBA
◦ PRKN
◦ SNCA
Genetic testing is available for certain genes ◦ Clinical recommendations for management of PD remain
unchanged, regardless of genetic mutation status
PD Pathogenesis: Genetics
36
Tofaris GK. Mov Disord. 2012;27:1364-1369.
Wider C et al. Mov Disord. 2010;25(suppl 1):S15–S20.
Associated with familial and idiopathic PD
Large, multidomain protein
Autosomal dominant
Most prevalent gene associated with PD◦ Among Caucasian patients Up to 5% of familial cases
1%-2% of idiopathic cases
Its physiologic function and its role in PD etiology are unclear◦ May have a role in lysosomal pathways
LRRK2 Gene
37
At present, there is no drug or supplement
which will will stop or reverse PD.
There is good evidence that regular
exercise seems to slow down the disease.
Good cardiovascular health is associated
with lower risk of PD
Can We Stop Or Reverse PD?
38
Medication
Exercise
Rehabilitation
Information
Support Groups
What Is The Treatment For PD?
39
Classic Neuronal Pathology of PD
39
Nigrostriatal degeneration, primarily in the substantia nigra pars compacta (SNpc) and striatum, and α-synuclein aggregates are
pathologic hallmarks of PD
Significant nigral dopaminergic neuronal loss is marked by a
reduction in neuromelanin pigment in the SNpc
Intraneuronal cytoplasmic inclusions, or “Lewy Bodies”
Normal
Patient with PD
40
Treatment OptionsReplace Dopamine - Levodopa
Simulate Dopamine – Dopamine Agonists
Block Dopamine Breakdown – Entacapone
Enhance Dopamine Release – Amantadine
Reprogram the brain – Deep Brain Stimulation
Treat Other Symptoms
Dementia
Hallucinations
Constipation
Drooling
Dyskinesia
Depression
Sleep Problems
Melanoma
Dopamine receptors
DA
L-DOPA
3-OMD
DA
Dopamine
agonists
COMT
inhibitors
Carbidopa
MAO-B
inhibitors DOPAC
DA
3-MT
DA
DA
AADC
DACOMT
inhibitor*
L-DOPA
DADA
Blood-brain barrierPeriphery BrainNeuron
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
42
Wearing off and dyskinesia both increase over time
Adapted by permission from Macmillan Publishers Ltd: Nat Clin Pract Neurol., Olanow CW, Obeso JA, Stocchi F. Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson's disease. Nat Clin Pract Neurol. 2006;2:382-392. copyright 2006.
Pla
sm
a L
D C
oncentr
ations
Dyskinesiathreshold
Efficacythreshold
Time (y)
Early disease Moderate disease Advanced disease
Therapeutic
window
“on” “on” “off”“off” “on” “off”
43
Goals of Add-on Therapy to LD Are to Reduce “Off”
Time and Improve Symptoms and Functionality
Throughout the Patient’s Day
Pahwa R et al. Curr Med Res Opin. 2009;25:841-849.
Improved
Worsened
Sym
pto
m C
on
tro
l
LD + Add-on
LD + placebo
“Off” time
“O
n”
“O
ff”
Improve severity
during “on”
Less
“off” time
LD + Add-on
dose
LD doses
Improve severity
during “off”
Carbidopa/Levodopa
Approved for 42 years
Best response
Short half-life (2 hours)
May induce dyskinesias after 5-8 years
Generic
Dosing 3-4 times per day
As disease progresses, must be dosed more and more frequently per day
Levodopa plus Carbidopa = “Sin emet”
Can use extra dose of carbidopa (Lodosyn)
Sinemet CR - questionable
Dopamine receptors
DA
L-DOPA
3-OMD
DA
Dopamine
agonists
COMT
inhibitors
Carbidopa
MAO-B
inhibitors DOPAC
DA
3-MT
DA
DA
AADC
DACOMT
inhibitor*
L-DOPA
DADA
Blood-brain barrierPeriphery BrainNeuron
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
Forms of carbidopa/levodopa
25/100 Immediate release pill
25/100 Oral Dissolving Tablet
25/100 Extended Release pill
50/200 Controlled Release Pill
25/250 Pill
Extended Release Capsules (Rytary)
Levodopa Inhaler (Inbrija)
Levodopa intestinal gel (Duopa pump)
Dopamine Agonists
Pramipexole (Mirapex)
Ropinerole (Requip)
Rotigotine Patch (Neupro)
Stimulates Dopamine receptors
Much more potent than dopamine
Longer half-life
Dosing 3-4 times per day
May delay dyskinesia (relative to Sinemet)
There are in generic forms
Dopamine receptors
DA
L-DOPA
3-OMD
DA
Dopamine
agonists
COMT
inhibitors
Carbidopa
MAO-B
inhibitors DOPAC
DA
3-MT
DA
DA
AADC
DACOMT
inhibitor*
L-DOPA
DADA
Blood-brain barrierPeriphery BrainNeuron
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
Enzyme Inhibitors – keep dopamine
around longer COMT inhibitor
◦ Entacapone (Comtan)
MAO-B inhibitors
◦ Rasagiline (Azilect)
◦ Safinamide (Xadago)
MAO inhibitor
◦ Selegiline
Dopamine receptors
DA
L-DOPA
3-OMD
DA
Dopamine
agonists
COMT
inhibitors
Carbidopa
MAO-B
inhibitors DOPAC
DA
3-MT
DA
DA
AADC
DACOMT
inhibitor*
L-DOPA
DADA
Blood-brain barrierPeriphery BrainNeuron
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
51
Istradefylline (Nourianz)Recently FDA Approved
Novel mechanism – increases the
amount of GABA in the nervous
system by binding to Adenosine A2a
receptors
Helps with OFF periods between
medication doses
NO drug interactions
LSVT BIG
Lee Silverman Voice Training – created LOUD therapy in 1987 by Dr. Lorraine Ramig
BIG therapy created later
Incorporates large movements
Improves walking, balance, reaching
Reduces falls
2018 study with 114 patients – 40-50% improvement in Timed Up and Go, Cognition and Motor scores
Isaacson, et al, Journal of Physical Therapy Science, 2018, April 30(4), 636-641.
LSVT BIG Homework DVD
LSVT LOUD Homeword DVD
61
Thank You
