Parkinson's Disease and Movement Disorders Flashcards
Prognosis of Parkinson’s post-diagnosis
10-20 years post-diagnosis
What does Parkinsonism mean?
the person has PD-like symptoms, but can be induced by other means, such as antipsychotics
When does Parkinson’s disease usually present?
in the 60s-70s, but 5-10% present before age 40
Where is the neurological deficit with Parkinson’s disease?
deficit in the extrapyramidal system
Parkinson’s disease
chronic, progressive, irreversible disease, leading to tremor and muscular rigidity
Parkinson’s disease symptoms
resting tremor; akinesia; muscular rigidity; compromised cognitive functions; comorbid depression (25% of pts)
Describe the rigidity of Parkinson’s disease
flexors and extensors both contracted, so pts often quite fatigued
Pathophysiology of PD
cell death in the substantia nigra; decreased DAergic innervation in the basal ganglia
Structures in the basal ganglia (striatum)
caudate nucleus; putamen; globus pallidus; terminal projection fields from the SNc
What does the striatum do?
striatum allows a movement to occur, so damage to normal excitation/inhibition circuitry will disturb normal execution of movements
What kind of circuits are the direct and indirect pathways?
inhibitory circuits
Reduced direct pathway activity causes
greater inhibition of GPe; GPe is inhibitory, so this results in less inhibition of STN
What does increased activity of STN contribute to
overactivity of GPi/SNr
Increased activity of GPi/SNr causes
causes increased inhibition of the thalamus
What happens when thalamus activity is decreased/?
results in reduced motor commands from cortex, resulting in the motor symptoms of PD
What does the thalamus normally do?
thalamus is excitatory and normally provides activation of the cortex to allow execution of motor commands from the basal ganglia
Etiology of PD
- Age/sex
- Environmental factors (pesticide exposure)
- Redox hypothesis
- Genetic factors (familial, parkin, LRRK2, alpha-synuclein)
Redox hypothesis
DA toxic, oxidized, creates ROS and oxidative stress to DA neurons - which may be particularly vulnerable to this stress
What is the correlation between smoking and Parkinson’s Disease?
inverse correlation between smoking and PD, which has been theorized to result from nicotine in cigarettes; independent of smoking’s harmful health effects and dose-dependent
Rate-limiting enzyme in DA production
Tyrosine hydroxylase
What does the L-dopa approach rely on
relies on the remaining, live DA neurons to produce increased amounts of DA
Non-eroglines
- Pramipexole (Mirapex)
- Ropinirole (Requip)
- Rotigotine (NeuroPro)
Used to mimic the action of DA in the indirect pathway
DA D2 and D3 agonists
Carbidopa is an inhibitor of
peripheral L-dopa metabolism, which helps to direct a greater percentage of the L-dopa to the CNS and allows the dose of L-dopa to be reduced
What does reducing the dose of L-dopa help with?
helps to reduce the onset of dyskinesias and reduces other side effects like GI problems
What enzyme does Carbidopa inhibit?
L-aromatic amino acid decarboxylase
What is Sinemet?
Levo-dopa + Carbidopa
Positive aspects of Sinemet
better survival; bradykinesia and rigidity improved; mood improvement
Problems with Sinemet
decreased prolactin; increased GH; arrhythmias; postural hypotension; nausea initially
Gold standard for Parkinson’s treatment
L-dopa/Carbidopa (Sinemet)
How long until L-dopa begins to decrease in efficacy?
5-6 years
Eventually develops with long-term administration of L-dopa
motor dyskinesias
Chorea
semi-directed, non-repetitive dancelike movements
Dystonia
sustained msucle contractions cuase twisting and repetitive movements or abnormal postures
Athetosis
slow, involuntary, convoluted, writhing movements of the fingers, hands, toes, and feet and in some cases, arms, legs, neck and tongue
Why is L-dopa delayed until it is absolutely necessary
dyskinesias
What should you try first in a parkinson’s patient
try non-erogoline DA agonists; Requip is anecdotally slightly better than Mirapex
Amantadine
DA releasing agent, not much better than l-dopa
MAO-B inhibitors are specific for
DA (MAO-A more on 5HT and NE)
COMT inhibitors prevent
methylation in the liver, allows L-dopa doses to last longer (though they don’t allow you to reduce the dose)
Inheritance of Huntington’s disease
autosomal dominant (complete penetrance); CAG repeats in huntington gene
What determines the disease course of Huntington’s?
the number of CAG-repeats in the huntington gene
Symptoms of Huntington’s
choreiform movements, cognitive impairment, behavioral changes
What do abnormal huntington proteins do?
aggregate and form inclusions
What part of the brain is preferentially affected in Huntington’s disease?
spiny neurons of the striatum
Prognosis of huntington’s after diagnosis
20 years after diagnosis; death occurs from pneumonia, suicide, heart disease, aspiration of food, falls
Mechanism of HD pathology
selective destruction of medium spiny neurons of the neostriatum, particularly those that project from the striatum to the Gpe (earlier than those that proejct to Gpi)
How are PD and HD different?
HD is the opposite of PD: inhibition of GPi, STN, and dis-inhibition of thalamus and cortex
Treatment of HD
- Antidepressants (w/o anti-Ach effects)
- Carbemazepine for depression
- low-dose antipsychotics
- Tetrabenazine
- Benzodiazepines
What is tetrabenazine?
reversible type of reserpine (which is irreversible), used to deplete monamines such as DA
What kind of Huntington’s patients get benzos?
for severely agitated, anxious, stressed patients
Spasticity
muscle stiffness or tightness
What does spasticity result from
results from imbalance in excitation/inhibition to alpha motor neuron
Damage to upper motor neurons causes
reduced activity of inhibitory interneurons, overactivity of motor neurons and hyperreflexia
Tizanidine
alpha2 agonist; acts via presynaptic mechanism to reduce activity of motor neuron
Baclofen
GABAb agonist that can act directly on the motor neuron and presynaptically on excitatory corticospinal glutamate fiber
Dantrolene
block Ca2+ release in muscle; interferes with excitation contraction coupling in muscle fiber by blocking release of CA2+ from sarcoplasmic reticulum via inhibition of ryanodine receptors
Clinical use of Tizanidine
stroke, MS, ALS
Clinical use of Baclofen
ALS
Problems with Baclofen
serious, life-threatening side effects possible
Cyclobenzaprine
mechanism of action unclear, may involve norepinephrine or serotonin in spinal cord, ultimately leads to decreased firing of motor neurons
