Parkinson Disease:
Beyond Dopamine
Roger L. Albin, M.D.
Ann Arbor VAHS GRECC & Dept. of
Neurology, University of Michigan
Epidemiology of PD
• Estimated prevalence = 300-350/100,000 or 840,000
– 1,000,000 in the USA; likely an underestimate
• Estimated incidence = 10-15/100,000
• Exponential increase with age over 60
• Risk modifiers
– Occupation?
– Heavy Metal Exposure?
– Smoking is Protective?
• Genetic Component? (Twins vs Icelanders)
Parkinsonism: A Dopamine
Deficiency Syndrome
•
•
•
•
Slow voluntary movement - Bradykinesia
“Stiff” muscles - Rigidity
Falling - Postural Instability
Shaking - Resting Tremor
All above features seen in dopamine depletions,
dopamine receptor antagonist exposures and in
degenerations of the nigrostriatal dopaminergic
projections
Differential Diagnosis of
Parkinsonism
• Pharmacologically Induced
– Dopamine Antagonists; Anti-Psychotics, Anti-Emetics
– Catecholamine Depleters; Reserpine, Tetrabenazine
– False Transmitters; a-Methyl-Tyrosine
• Essential Tremor - Not Really a Mimic
• Atherosclerotic Parkinsonism
• Other Neurodegenerations Affecting the Basal Ganglia
– Progressive Supranuclear Palsy
– Multiple Systems Atrophy
– Corticobasal Degeneration Syndrome
• Idiopathic Parkinson’s Disease
United Kingdom Parkinson’s Disease
Brain Bank Diagnostic Criteria
Step 1: Diagnosis of Parkinsonism
• Bradykinesia and at least one of the
following:
Muscular rigidity
4–6 Hz resting tremor
postural instability not caused by primary
visual, vestibular, cerebellar or
proprioceptive dysfunction
Step 2: Features tending to exclude
Parkinson’s disease as the cause of
Parkinsonism
History of repeated strokes
with stepwise progression
of parkinsonian features
History of repeated head
injury
History of definite
encephalitis
Neuroleptic treatment at
onset of symptoms
>1 affected relatives
Sustained remission
Strictly unilateral features
after 3 years
Supranuclear gaze palsy
Cerebellar signs
Early severe autonomic
involvement
Early severe dementia with
disturbances of memory,
language and praxis
Babinski's sign
Presence of a cerebral
tumour or communicating
hydrocephalus on
computed tomography
scan
Negative response to large
doses of levodopa (if
malabsorption excluded)
MPTP exposure
Step 3: Features that support a
diagnosis of Parkinson’s disease
(three or more required for diagnosis
of definite Parkinson’s disease)
Unilateral onset
Rest tremor present
Progressive disorder
Persistent asymmetry affecting the side of
onset most
Excellent (70–100%) response to levodopa
Severe levodopa-induced chorea
Levodopa response for ≥ 5 years
Clinical course of ≥ 10 years
How Common and What are They?
• 90% of Parkinsonism is PD
– About 3-4% is PSP
– About 3-4% is MSA
– A Grab Bag For the Rest
• Queen Square Autopsy Series (70 Cases)
– 35 MSA
– 20 PSP
– 4 Unknown
– 3 CBD
– 3 Vascular Parkinsonism
– 2 Post-Encephalitic Parkinsonism
Diagnostic Accuracy For PD
• Historically Not Very Good – 75%.
• Greater Awareness of PD Mimics Has
Improved Accuracy
• UK PD Brain Bank Study – 90% for PD
– Involved general neurologists, subspecialty
neurologists, geriatric specialists, GPs
• Queen Square Study of Movement
Disorder Specialists – PPV of 98.6%
Twin Concordance Rates
Relative Type
No. of
Relatives
No. Affected
(%)
RR (95%
CI)
p
Relatives of PD
2,865
71 (2.5)
2.7 (1.74.4)
<0.00
01
Relatives of controls
2,446
25 (1.0)
1.0
(reference)
Relatives of early-onset
PD
1,172
27 (2.3)
2.9 (1.65.0)
0.000
2
Relatives of late-onset
PD
1,693
44 (2.6)
2.7 (1.64.4)
0.000
2
Relatives of controls
2,446
25 (1.0)
1.0
(reference)
Siblings of early-onset
PD
482
8 (1.7)
7.9 (2.525.5)
0.000
5
Siblings of late-onset PD
587
14 (2.4)
3.6 (1.310.3)
0.02
Siblings of controls
889
5 (0.6)
1.0
(reference)
Parents of early-onset
PD
426
17 (4.0)
1.7 (0.93.3)
0.2
Parents of late-onset PD
505
29 (5.7)
2.5 (1.44.6)
0.003
Parents of controls
789
19 (2.4)
1.0
(reference)
Relatives of tremordominant PD
989
27 (2.7)
2.6 (1.44.6)
0.002
Relatives of PIGD PD
1,460
36 (2.5)
2.9 (1.75.0)
<0.00
01
Relatives of controls
2,446
25 (1.0)
1
(reference)
PD Risk in Icelanders
Park1
(aSynuclein)
4q421
AD
Late Onset
Lewy Bodies
Park2
(Parkin)
6q25
AR (AD)
Early Onset
No Lewy
Bodies
Park5 (UCHL1)
4p14
AD
Late Onset
?
Park3
2p13
AD
Late Onset
Lewy Bodies
Park4
4p14-16.3
AD
Late Onset
Lewy Bodies
Park6 (PINK1) 1p35-36
AR
Late Onset
?
Park7 (DJ-1)
1p36
AR
Early Onset
?
Park8
(LRRK2)
12p11.2-q13
AD
Late Onset
Variable Lewy
Bodies
Park9
(ATP13A2)
1p36
AR
Early Onset
?
Park 10
1p32
?
Late Onset
?
NR4A2
(NURR1)
2a22-23
AD
Late Onset
?
Park1 - aSynuclein
• First Locus Identified
• Widely Expressed Synaptic Protein – Normal
Function Unknown
• Primary Constituent of Lewy Bodies
• Contursi Kindred and Other Pedigrees
– Many Typical Clinical Features with Somewhat
Earlier Age of Onset
• A53T Mutation
• A30P Mutation – German Pedigree
• E46K Mutation – Spanish Pedigree; Lewy Body
Dementia
• Iowa (Spellman-Muenter) Kindred – Triplication
• Recent Description of Duplication Pedigrees
Park8 – LRRK2
• Function Unknown – GTP binding and
Kinase domains
• Relatively Common – 1-2% of
apparently sporadic PD in some
studies
• Founder Effects
• Incomplete Penetrance
• Royal Road to Mechanisms of
Pathogenesis?
Fig. 2. A model of mitochondria and PD pathogenesis
Li, Chenjian and Beal, M. Flint (2005) Proc. Natl. Acad. Sci. USA 102, 16535-16536
Copyright ©2005 by the National Academy of Sciences
Initial Treatment Options
• No Treatment - No Functional
Disability
• Anti-Cholinergics - Tremor
• Amantadine - Mild Disability
• L-Dopa/Carbidopa
• Dopamine Agonists
• Selegiline
Dopaminergic Synapse
L-DOPA
AADC
Dopamine
VMAT2
D2 Receptor
DAT
PD Therapy: L-DOPA
• Advantages: Provides “natural”/”regulated” effect
in early PD.
• Mechanisms: Increased quantal size (low-dose,
mild PD), increased dopamine release, reduced
clearance.
• Preparations: Regular vs. Continuous Release.
• Disadvantages: Dietary Interactions, complex
pharmacokinetics and pharmacodynamics.
Parkinson’s Disease: Natural
History in the Post-L-DOPA Era
Dopamine/L-Dopa Toxicity?
ELLDOPA
Basic Principles of Using LDopa
• Give enough Carbidopa - Start with 25/100
tid with meals.
• Use immediate release initially.
• “Enough is as good as a feast” – titrate to
clinical effect.
• Almost no drug interactions.
• Almost no medical contraindications.
• Provide adequate time to assess
response.
Adapted from Obeso, et al, 1997
Clinical Effect
Dyskinesia Threshold
Response Threshold
Time (Hrs)
Time (Hrs)
Time (Hrs)
•Early PD
Moderate PD
Advanced PD
•Long-duration
response
•Short-duration
response
•Short-duration
response
•Low incidence
of dyskinesia
•Increased
dyskinesias
•Narrow window
Year 0-5
Year 610
Year >11
PD Therapy: Dopamine
Agonists
• Advantages: Sustained, steady-state plasma
levels; No dietary effects on CNS availability;
Convenient dosing regimens
• Mechanism: Stimulation of D2-type receptors
• Disadvantages: Unregulated effect on all D2
receptors; More frequent side-effects
• Use non-ergot agents because of fibrotic
complications.
• Speculative long term benefits.
CALM-PD Design
• Subjects
– Early PD requiring Dopaminergic
Treatment
– No L-dopa or pramipexole x 2 months
– No motor complications
• Intervention
– Ascending Pramipexole; 4.5 mg/day
max
– Ascending L-dopa; 150-600/day max
– Open label additional L-dopa allowed
Symptomatic vs Protective Effects
Impulse Control Disorders
• Pathologic Gambling, Sexual
Behavior, Compulsive Shopping
• Strongly Associated with Dopamine
Agonists
• Not Uncommon: 4% - 8% in some
good clinic series
• Rare with L-dopa Monotherapy
• Reversible
CALM-PD Summary
• No Evidence for Neuroprotection
• Effect on Wearing Off?
– Use of Long Acting Agents
– Inappropriate Design
• Effect on Dyskinesias?
– Lack of Therapeutic Equivalence
• Generalizability of Trial
– Age of Subjects
– Health of Subjects
– Cognitive Status
The Bottom Line
• Dopamine agonists and L-Dopa are
both reasonable choices for initial
therapy.
• L-Dopa possesses advantages for
symptomatic treatment.
• The long-term benefits of dopamine
agonists are hypothetical.
What to Do?
• Experts Differ Somewhat.
• <60 years – Tendency to use agonist initial
therapy
• 60 – 65 and healthy – Consider agonist
initial therapy
• > 65 years and anyone with hint of
cognitive impairment, other medical
problems, or complex medical regimens –
L-dopa
• Financial Issues – L-dopa
Important Later Clinical Features
• Major Contributors to Disability
• Refractory Speech and Swallowing
Problems
• Marked Postural Instability - Falls
• Refractory Gait Problems
• Autonomic Insufficiency
• Dementia: 30% - 50%
• Hallucinations and Psychosis
• Sleep Disorders
• Constipation
Hallucinations
Very Common
Characteristic Features
Not necessarily psychosis
Insight preserved often
Often medication related
If infrequent or not bothersome; reassure
If treatment needed – quetiapine preferred
Harbinger of dementia
Dementia
• Very Common: 40% - 50% in some
estimates. 70% in one recent community
survey.
• Lewy Body Type Features
– Parkinsonism
– Hallucinations
– Fluctuations
• Benefit with Cholinesterase Inhibitors?
• Bad Prognostic Predictor
Sleep Disorders
• Sleep Disruption and Daytime
Somnolence Very Common
• Many Problems with Sleep
• REM Sleep Behavior Disorder
– History from sleep partners
– May herald PD
• Obstructive Sleep Apnea
Contact Information
Roger L. Albin, MD
Rm 202, Bldg 31
Ann Arbor VA
2215 Fuller Road
Ann Arbor, MI, 48105-2399
734-845-5466
ralbin@umich.edu