RESEARCH UPDATE STEM CELLS NEUROPROTECTION
Transcript of RESEARCH UPDATE STEM CELLS NEUROPROTECTION
PARKINSON DISEASE
Scott J Sherman MD, PhDThe University of Arizona
LEARNING OBJECTIVES
The Course Participant will:1. Be familiar with the pathogenesis of
Parkinson’s Disease (PD)
2. Understand clinical and neuroimaging criteria
for the diagnosis of PD
3. Be proficient in choosing medications for
symptomatic treatment of PD
4. Understand the role of surgical treatment for
PD
Parkinson’s disease
Movement symptoms-
Tremor
Bradykinesia
Rigidity
Balance
Etiology of Parkinson disease
Pathogenesis
free mitochondrial oxidative protein radicals dysfunction stress aggregation
Parkinson's disease(s)
Environmentalor endogenous
toxins
Single or multiple
genes
etiology
Environmental influences PD
Most PD cases are not inherited
Risk factors
Pesticide exposure
Rural area
Protective factors
Gender (Female hormones)
Caffeine intake
Nicotine
Monogenic causes of PD are rare but
scientifically important
• Protein Aggregation
• α-synuclein
• Mitochondrial maintenance
• Parkin, PINK-1
• LRRK2
• 5% Ashkenazi Jews with
PD
What causes typical PD?
Damaged protein α-synuclein
forms clumps
May spread from cell to cell
via “exosomes”
Impairs cellular function- esp.
mitochondria
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Environmental
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Normal aging
Other process
Parkinsonian Symptoms
Age: a PD risk factor
Environmental factors
Age, smoking, gender
Caffeine reduces risk of PDBoth caffeine and nicotine interact within dopamine system
Drug develop opportunities:
Adenosine receptor antagonists, under development
Nicotinic Acetylcholine Receptor agonists
New drug class: Adenosine antagonists
(still investigational)
Istradefylline is approved in Japan
More of these drugs are in testing
Related to caffeine
Reduces dyskinesia
Spread of Lewy bodies: PD
progression
Manifestations at PD Onset Tremor at rest
Bradykinesia
Rigidity
Micrographia
Hypophonia
Masked face
Stooped, shuffling gait
Slowing of activities of daily living
Decreased arm swing when walking
Barbosa et al. Psychiatr Clin North Am. 1997;20:769-90.
Playfer. Postgrad Med. 1997;73:257-64.
Parkinson’s disease
Non-movement symptoms- less response
Dizziness/ hypotension
Postural instability-balance
Swallowing problems
Soft voice-speech
Depression–Anxiety-Apathy
Memory problems
Difficulty with mental concentration
Shulman et al. Mov Disord. 2001;16:507-10.
Exercise-Phys Ther.
MAO Inhibitor
Dopamine agonist
Levodopa
Ancillary medications
Deep Brain Stimulation
The continuum of
treatment in PD
Dopamine
replacement
MAO-B inhibitors
Selegeline
Generic available
Rasagaline (Azilect)
Better evidence for neuroprotection
Not converted to amphetamine
Safinamide (Xadago)
Warnings about drug interactions
Dopamine Agonists
Oral
Pramipexole (Mirapex)
Ropinirole (Requip)
Injectable
Apomorphine (Apokyn)
Transdermal
Rotigotine – (Neupro)
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Ropinirole
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P < 0.0001
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L-dopa
Ropinirole
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P < 0.0001
Dopamine agonists reduce dyskinesia: either as monotherapy or in combination with
levodopa
Intention to TreatMonotherapy
Dopamine Agonists
Advantages
Long duration of effect
Do not cause dyskinesia
Allow reduction of
levodopa and smooth out
fluctuations
Can improve
sleep/depression/sensory
sx’s
Disdavantages
Numerous side effects
Drowsiness
Sleep attacks (rare)
Low blood pressure
Leg swelling
Visual illusions
Compulsive behavior
Gambling
Sex addiction
Eating
Levodopa
DOPAMINELEVODOPA
CARBIDOPA
COMT-inhibition
Entacapone
Stages of levodopa effect
Stage 1: “Honeymoon”-works great
Stage 2: “Wearing off” –end of dose
Stage 3: Dyskinesia- at peak dose
Stage 4: Motor fluctuations- Effects become erratic and unpredictable
Dyskinesia
Normal
PD Symptoms8 AM 12 2PM 4PM
L-D
OP
A l
evel
Dyskinesia
Normal
PD Symptoms8 AM 12 2PM 4PM
L-D
OP
A l
evelDyskinesia
8 AM 12 2PM 4PM
L-D
OP
A l
evel
PD Symptoms
Normal
Dyskinesia
8 AM 12 2PM 4PM
L-D
OP
A l
evel
PD Symptoms
Normal
Pharmocokinetic strategies
Rytary
Pharmacokinteic strategies
Duopa: continuous enteral delivery
Carbidopa/Levodopa
Advantages
Most potent
Few side effects
Almost always
necessary
Inexpensive
Disadvantages
Short duration/frequent
dosing needed
Poor absorption by gut
Interference by food
Erratic effects
Stored and converted
by brain cells
Causes dyskinesia
When to start levodopa?
Advantages to early start:
Most efficacious
Few side effects in early stages
Advantages to delayed start
Ultimately require polypharmacy for optimum
treatment
Levodopa have smoother action when added later
Ancillary medications
Movement symptoms
Amantadine 100-300 mg daily
Anticholinergic medications
Trihexyphenidyl (artane) 2-4 mg tid
Benztropine (Cogentin) 1-2 mg daily
Ancillary medications
Non-Movement symptoms
Hypotension
Midodrine
Fludrocortisone
Droxidopa (Northera)
Cognition
Memantine
Cholinesterase Inhibitors
Okay to use these, paradoxically they do not
worsen tremor
What is DBS-how does it work?
Deep Brain Stimulation (DBS)
uses high frequency (HF)
electrical stimulation to mask
abnormal neuronal activity
leading to symptomatic benefit
Benefits of DBS
Increase Periods of Good Mobility*
27% Good
Mobility
73% Poor
Mobility
74% Good
Mobility 26% Poor
Mobility
*Source: The Deep-Brain Stimulation for Parkinson’s Disease Study Group. Deep-brain stimulation of
the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson’s disease. N Engl J Med. 2001;345:956-
963.
Good mobility: “on” time without dyskinesia
Poor mobility: “off ” time and “on” time with dyskinesia
Before DBS After DBS
DBS can effectively control tremor
Tremor can be relatively
resistant to medical
treatment compared to
other PD symptoms
STN STIMULATION
Psychosis and Hallucinations
• “Atypical”
Antipsychotics
• Ideally no dopamine
receptor activity
• Quetiapine
• 25-100 mg daily
• Clozapine
• Requires frequent
labs
• Pimavanserin
• “Nuplazid”
• FDA approved
Summary
PD diagnosis can be aided by DAT scans
Carbidopa/levodopa remains the most potent
medical treatment
Ancillary medications are important therapies
Surgical treatment DBS can be treatment of
choice in carefully selected patients