Parkinson's Disease and Movement Disorders

Question 1

Prognosis of Parkinson’s post-diagnosis

Answer 1

10-20 years post-diagnosis

Question 2

What does Parkinsonism mean?

Answer 2

the person has PD-like symptoms, but can be induced by other means, such as antipsychotics

Question 3

When does Parkinson’s disease usually present?

Answer 3

in the 60s-70s, but 5-10% present before age 40

Question 4

Where is the neurological deficit with Parkinson’s disease?

Answer 4

deficit in the extrapyramidal system

Question 5

Parkinson’s disease

Answer 5

chronic, progressive, irreversible disease, leading to tremor and muscular rigidity

Question 6

Parkinson’s disease symptoms

Answer 6

resting tremor; akinesia; muscular rigidity; compromised cognitive functions; comorbid depression (25% of pts)

Question 7

Describe the rigidity of Parkinson’s disease

Answer 7

flexors and extensors both contracted, so pts often quite fatigued

Question 8

Pathophysiology of PD

Answer 8

cell death in the substantia nigra; decreased DAergic innervation in the basal ganglia

Question 9

Structures in the basal ganglia (striatum)

Answer 9

caudate nucleus; putamen; globus pallidus; terminal projection fields from the SNc

Question 10

What does the striatum do?

Answer 10

striatum allows a movement to occur, so damage to normal excitation/inhibition circuitry will disturb normal execution of movements

Question 11

What kind of circuits are the direct and indirect pathways?

Answer 11

inhibitory circuits

Question 12

Reduced direct pathway activity causes

Answer 12

greater inhibition of GPe; GPe is inhibitory, so this results in less inhibition of STN

Question 13

What does increased activity of STN contribute to

Answer 13

overactivity of GPi/SNr

Question 14

Increased activity of GPi/SNr causes

Answer 14

causes increased inhibition of the thalamus

Question 15

What happens when thalamus activity is decreased/?

Answer 15

results in reduced motor commands from cortex, resulting in the motor symptoms of PD

Question 16

What does the thalamus normally do?

Answer 16

thalamus is excitatory and normally provides activation of the cortex to allow execution of motor commands from the basal ganglia

Question 17

Etiology of PD

Answer 17

1. Age/sex
2. Environmental factors (pesticide exposure)
3. Redox hypothesis
4. Genetic factors (familial, parkin, LRRK2, alpha-synuclein)

Question 18

Redox hypothesis

Answer 18

DA toxic, oxidized, creates ROS and oxidative stress to DA neurons - which may be particularly vulnerable to this stress

Question 19

What is the correlation between smoking and Parkinson’s Disease?

Answer 19

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

Question 20

Rate-limiting enzyme in DA production

Answer 20

Tyrosine hydroxylase

Question 21

What does the L-dopa approach rely on

Answer 21

relies on the remaining, live DA neurons to produce increased amounts of DA

Question 22

Non-eroglines

Answer 22

1. Pramipexole (Mirapex)
2. Ropinirole (Requip)
3. Rotigotine (NeuroPro)

Question 23

Used to mimic the action of DA in the indirect pathway

Answer 23

DA D2 and D3 agonists

Question 24

Carbidopa is an inhibitor of

Answer 24

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

Question 25

What does reducing the dose of L-dopa help with?

Answer 25

helps to reduce the onset of dyskinesias and reduces other side effects like GI problems

Question 26

What enzyme does Carbidopa inhibit?

Answer 26

L-aromatic amino acid decarboxylase

Question 27

What is Sinemet?

Answer 27

Levo-dopa + Carbidopa

Question 28

Positive aspects of Sinemet

Answer 28

better survival; bradykinesia and rigidity improved; mood improvement

Question 29

Problems with Sinemet

Answer 29

decreased prolactin; increased GH; arrhythmias; postural hypotension; nausea initially

Question 30

Gold standard for Parkinson's treatment

Answer 30

L-dopa/Carbidopa (Sinemet)

Question 31

How long until L-dopa begins to decrease in efficacy?

Answer 31

5-6 years

Question 32

Eventually develops with long-term administration of L-dopa

Answer 32

motor dyskinesias

Question 33

Chorea

Answer 33

semi-directed, non-repetitive dancelike movements

Question 34

Dystonia

Answer 34

sustained msucle contractions cuase twisting and repetitive movements or abnormal postures

Question 35

Athetosis

Answer 35

slow, involuntary, convoluted, writhing movements of the fingers, hands, toes, and feet and in some cases, arms, legs, neck and tongue

Question 36

Why is L-dopa delayed until it is absolutely necessary

Answer 36

dyskinesias

Question 37

What should you try first in a parkinson's patient

Answer 37

try non-erogoline DA agonists; Requip is anecdotally slightly better than Mirapex

Question 38

Amantadine

Answer 38

DA releasing agent, not much better than l-dopa

Question 39

MAO-B inhibitors are specific for

Answer 39

DA (MAO-A more on 5HT and NE)

Question 40

COMT inhibitors prevent

Answer 40

methylation in the liver, allows L-dopa doses to last longer (though they don't allow you to reduce the dose)

Question 41

Inheritance of Huntington's disease

Answer 41

autosomal dominant (complete penetrance); CAG repeats in huntington gene

Question 42

What determines the disease course of Huntington's?

Answer 42

the number of CAG-repeats in the huntington gene

Question 43

Symptoms of Huntington's

Answer 43

choreiform movements, cognitive impairment, behavioral changes

Question 44

What do abnormal huntington proteins do?

Answer 44

aggregate and form inclusions

Question 45

What part of the brain is preferentially affected in Huntington's disease?

Answer 45

spiny neurons of the striatum

Question 46

Prognosis of huntington's after diagnosis

Answer 46

20 years after diagnosis; death occurs from pneumonia, suicide, heart disease, aspiration of food, falls

Question 47

Mechanism of HD pathology

Answer 47

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)

Question 48

How are PD and HD different?

Answer 48

HD is the opposite of PD: inhibition of GPi, STN, and dis-inhibition of thalamus and cortex

Question 49

Treatment of HD

Answer 49

1. Antidepressants (w/o anti-Ach effects) 2. Carbemazepine for depression 3. low-dose antipsychotics 4. Tetrabenazine 5. Benzodiazepines

Question 50

What is tetrabenazine?

Answer 50

reversible type of reserpine (which is irreversible), used to deplete monamines such as DA

Question 51

What kind of Huntington's patients get benzos?

Answer 51

for severely agitated, anxious, stressed patients

Question 52

Spasticity

Answer 52

muscle stiffness or tightness

Question 53

What does spasticity result from

Answer 53

results from imbalance in excitation/inhibition to alpha motor neuron

Question 54

Damage to upper motor neurons causes

Answer 54

reduced activity of inhibitory interneurons, overactivity of motor neurons and hyperreflexia

Question 55

Tizanidine

Answer 55

alpha2 agonist; acts via presynaptic mechanism to reduce activity of motor neuron

Question 56

Baclofen

Answer 56

GABAb agonist that can act directly on the motor neuron and presynaptically on excitatory corticospinal glutamate fiber

Question 57

Dantrolene

Answer 57

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

Question 58

Clinical use of Tizanidine

Answer 58

stroke, MS, ALS

Question 59

Clinical use of Baclofen

Answer 59

ALS

Question 60

Problems with Baclofen

Answer 60

serious, life-threatening side effects possible

Question 61

Cyclobenzaprine

Answer 61

mechanism of action unclear, may involve norepinephrine or serotonin in spinal cord, ultimately leads to decreased firing of motor neurons