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; -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
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)
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 TypeNo. of
Relatives of PD 2,865 71 (2.5) 2.7 (1.7-4.4)
Relatives of controls 2,446 25 (1.0) 1.0 (reference)
Relatives of early-onset PD
1,172 27 (2.3) 2.9 (1.6-5.0)
Relatives of late-onset PD
1,693 44 (2.6) 2.7 (1.6-4.4)
Relatives of controls 2,446 25 (1.0) 1.0 (reference)
Siblings of early-onset PD
482 8 (1.7) 7.9 (2.5-25.5)
Siblings of late-onset PD 587 14 (2.4) 3.6 (1.3-10.3)
Siblings of controls 889 5 (0.6) 1.0 (reference)
Parents of early-onset PD
426 17 (4.0) 1.7 (0.9-3.3)
Parents of late-onset PD 505 29 (5.7) 2.5 (1.4-4.6)
Parents of controls 789 19 (2.4) 1.0 (reference)
Relatives of tremor-dominant PD
989 27 (2.7) 2.6 (1.4-4.6)
Relatives of PIGD PD 1,460 36 (2.5) 2.9 (1.7-5.0)
Relatives of controls 2,446 25 (1.0) 1 (reference)
PD Risk in Icelanders
4q421 AD Late Onset Lewy Bodies
6q25 AR (AD) Early Onset No Lewy Bodies
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 ?
12p11.2-q13 AD Late Onset Variable Lewy Bodies
1p36 AR Early Onset ?
Park 10 1p32 ? Late Onset ?
2a22-23 AD Late Onset ?
Park1 - Synuclein
• 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
Copyright ©2005 by the National Academy of Sciences
Li, Chenjian and Beal, M. Flint (2005) Proc. Natl. Acad. Sci. USA 102, 16535-16536
Fig. 2. A model of mitochondria and PD pathogenesis
Initial Treatment Options
• No Treatment - No Functional Disability
• Anti-Cholinergics - Tremor
• Amantadine - Mild Disability
• Dopamine Agonists
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
Basic Principles of Using L-Dopa
• 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
Time (Hrs) Time (Hrs) Time (Hrs)
•Low incidence of dyskinesia
Year 0-5 Year 6-10
Adapted from Obeso, et al, 1997
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.
• 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
• 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
Not necessarily psychosis
Insight preserved often
Often medication related
If infrequent or not bothersome; reassure
If treatment needed – quetiapine preferred
Harbinger of 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 Disruption and Daytime Somnolence Very Common
• Many Problems with Sleep
• REM Sleep Behavior Disorder– History from sleep partners– May herald PD
• Obstructive Sleep Apnea
Roger L. Albin, MDRm 202, Bldg 31
Ann Arbor VA2215 Fuller Road
Ann Arbor, MI, 48105-2399734-845-5466