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

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 TypeNo. of

RelativesNo. Affected

(%)RR (95%

CI) p

Relatives of PD 2,865 71 (2.5) 2.7 (1.7-4.4)

<0.0001

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)

0.0002

Relatives of late-onset PD

1,693 44 (2.6) 2.7 (1.6-4.4)

0.0002

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)

0.0005

Siblings of late-onset PD 587 14 (2.4) 3.6 (1.3-10.3)

0.02

Siblings of controls 889 5 (0.6) 1.0 (reference)

Parents of early-onset PD

426 17 (4.0) 1.7 (0.9-3.3)

0.2

Parents of late-onset PD 505 29 (5.7) 2.5 (1.4-4.6)

0.003

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)

0.002

Relatives of PIGD PD 1,460 36 (2.5) 2.9 (1.7-5.0)

<0.0001

Relatives of controls 2,446 25 (1.0) 1 (reference)

PD Risk in Icelanders

Park1 (Synuclein)

4q421 AD Late Onset Lewy Bodies

Park2 (Parkin)

6q25 AR (AD) Early Onset No Lewy Bodies

Park5 (UCH-L1)

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 - 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

Pathogenesis?

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

• L-Dopa/Carbidopa

• Dopamine Agonists

• Selegiline

VMAT2

D2 Receptor

Dopaminergic Synapse

DAT

AADC

L-DOPA

Dopamine

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 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

response.

Clin

ica

l Effe

ct

Response Threshold

Dyskinesia Threshold

Time (Hrs) Time (Hrs) Time (Hrs)

•Early PD

•Long-duration response

•Low incidence of dyskinesia

Moderate PD

•Short-duration response

•Increased dyskinesias

Advanced PD

•Short-duration response

•Narrow window

Year 0-5 Year 6-10

Year >11

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.

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, MDRm 202, Bldg 31

Ann Arbor VA2215 Fuller Road

Ann Arbor, MI, 48105-2399734-845-5466

ralbin@umich.edu