Parkinson's Disease

Question 1

What is Parkinson’s Disease?

Answer 1

is the 2 most common neurodegenerative disease (after Alzheimer’s disease). Parkinson’s disease is IDIOPATHIC, usually occurs late in life, and is characterized by a variable combo of:
- resting tremor
- rigidity
- slow movements (& difficulty initiating movements)
- shuffling, slow gait
- masked facial expressions

Question 2

Parkinson’s disease is…

Answer 2

CHRONIC & PROGRESSIVE disorder produced by loss of dopaminergic neurons within the basal ganglia (in partic. the substantia nigra!)

Question 3

What is Parkinsonism?

Answer 3

a syndrome of symptoms comparable to Parkinson’s disease (variable
the basal ganglia.
combination of: tremor, rigidity, bradykinesia, gait disturbances) that are caused by loss of dopaminergic neurons due to toxins, vascular damage or inflammatory changes. May occur earlier in life.

Question 4

What are PD’s symptoms?

Answer 4

• RESTING tremor
• rigidity (‘cogwheel rigidity’)
• slow movements & difficulty initiating movements (“bradykinesia”)
• shuffling, slow gait, stooped unsteady posture
• masked facial expressions

also often:
- depressed mood
- cognitive impairment

Question 5

Symptoms may have…

Answer 5

have “ON” and “OFF” periods where a patient fluctuates
* cognitive impairment
Also often:
between relatively symptom free (= on) vs. incapacitated (=off).

Question 6

What is the prevalence & impact of PD?

Answer 6

• majority are >65
• & in long-term care
• symptoms at younger age –> increased delay for diagnosis
• MALES are more likely

Question 7

Parkinson’s disease is:

Answer 7

a CHRONIC and PROGRESSIVE produced by loss of:
DOPAMINERGIC NEURONS within the basal ganglia.

Question 8

What are apart of the Basal Ganglia?

Answer 8

• Caudate Nucleus
• Putamen
  Globus pallidus:
• External segment
• Internal segment

Subthalamic nucleus

Substantia nigra

Question 9

What is the loop?

Answer 9

Cortex –> Basal Ganglia –> Thalamus –> Cortex

Question 10

What is Voluntary Movements?

Answer 10

are produced by the corticospinal tract (=corticobulbospinal tract)

Frontal cortex areas important in motor planning project to and activate the “primary motor cortex” which elicits movement on the CONTRAlateral side of the body

Question 11

Where does the Basal Ganglia receive input from?

Answer 11

the motor cortex, and project (via the thalamus) back to influence and alter activity in areas of motor plan, and initiating the cortex producing the
the movement.

Question 12

What are Basal Ganglia imp. for?

Answer 12

for the PLANNING, INITIATION, & SMOOTH EXECUTION of movements accomplished by the cortiospinal tract

Question 13

What are Basal Ganglia?

Answer 13

several interconnected nuclei located at the “base” of the cerebral cortices.

Question 14

What is Basal Ganglia comprised of?

Answer 14

Caudate nucleus
Putamen
Globus Pallidus
Subthalamic nucleus
*Substantia Nigra (imp. for PD)

Question 15

Where does the Basal Ganglia receive input from?

Answer 15

areas of motor cortex

Question 16

Where does the Basal Ganglia project back to?

Answer 16

motor cortex via the thalamus

Question 17

What is Basal Ganglia imp. for?

Answer 17

smooth initiation & execution of motor programs

Question 18

What are 3 Basal Ganglia dyfunctions?

Answer 18

1. HYPOkinetic movement disorders (ex: PD)
2. HYPERkinetic movement disorders (ex: Huntington’s disease, maybe Tourette’s)
3. Dystonia (like a hyperkinetic, but is muscle contraction that may produce an altered posture, or altered head or limb position)

Question 19

What is PD treated with?

Answer 19

drugs aimed at increasing dopaminergic activity
- sometimes effectiveness decreases over time b/c of postsynaptic changes (ex: receptor desensitization/internalization)

Question 20

What connects the substantia nigra dopaminergic neurons to other basal ganglia nuclei?

Answer 20

nigrostriatal tract

Question 21

There are many ______ interconnections?

Answer 21

basal ganglia

Question 22

What is the “direct pathway”?

Answer 22

removes inhibition from the thalamus –> ENHANCED activity in the motor cortices

Question 23

What is the “indirect pathway?”

Answer 23

ends up inhibiting the thalamus –> DECREASED activity in the motor cortices

Question 24

What pathway is PD?

Answer 24

reduced activity in the direct pathway, and
increased activity in the indirect pathway
(–> slow movements = “bradykinesia”)

INDIRECT

Question 25

What pathway is Huntington's disease?

Answer 25

reduced activity in the indirect pathway, and increased activity in the direct pathway (-->excessive movements = “hyperkinesia”)

Question 26

What causes the loss of dopaminergic neurons?

Answer 26

Parkinson’s disease is most often IDIOPATHIC (=cause unknown). -denoted idiopathic Parkinson’s disease (IPD)

Question 27

There are known causes of Parkinsonism, such as:

Answer 27

1. Drugs (partic. antipsychotics) - largely dopamine antagonists (that --> Parkinsonism) - usually resolves after drug use stopped 2. Toxins (ex: MPTP, & pesticide "rotenone") - impurity in synthetic opioid production --> caused Parkinsonism in drug users - has been used as a tool for research - IRREVERSIBLE damage to dopaminergic neurons - one mech is known to be due to --> mitochondrial dysfunction & free radical production 3. Infections - post-encephalic syndrom - viral illness that causes degeneration of substantial nigria neurons 4. Injury/trauma - substantia nigra neurons may be particularly susceptible to trauma - boxers are ~4x more likely to develop Parkinsonism!

Question 28

Loss of dopaminergic neurons is...

Answer 28

PROGRESSIVE & largely SUB-CLINICAL (meaning we're not gonna know) *Symptoms don't show up until SN cells are ~80% gone! (only 20% present)

Question 29

What is the treatment of PD?

Answer 29

- There is NO CURE for Parkinson’s disease. - Treatment goal is to MINIMIZE the symptoms (i.e. facilitate function). 1. Pharmacological 2. Deep Brain Stimulation 3. Therapy

Question 30

What is the Pharmacological Treatment Strategies for PD?

Answer 30

* Increase dopamine: ‐ L‐DOPA (levodopa) ‐crosses the blood brain barrier (dopamine does not) ‐increases dopamine release at remaining synapses ‐given in conjunction with DOPA Decarboxylase Inhibitor (ex: Carbidopa) * Decrease dopamine breakdown: - monoamine oxidase inhibitors * Dopamine agonists (more SE'S) - do not rely on release from dopaminergic neurons (activate postsynaptic receptors directly) - can --> more prolonged stimulation of dopaminergic receptors * Anticholinergics - may be beneficial (alter balance of activity in basal ganglia, & also in cortex) - may not be tolerated well in the elderly (various side effects, & exacerbates memory loss & confusion that might already be present - like Dementia)

Question 31

Why would you want to increase dopamine by L-DOPA?

Answer 31

‐because DOPA Decarboxylase is also in the peripheral nervous system (and levodopa would get converted to dopamine there) --> side effects! ‐CARBIDOPA doesn’t cross BBB, so reduces conversion in the PNS ‐COMT INHIBITORS (catechol‐O‐methyl transferase) also decrease levodopa breakdown in the periphery ‐ L‐DOPA (levodopa) (cont’d) ‐ usually provides a FEW YEARS of therapeutic efficacy.

Question 32

Why isn't L-DOPA a cure?

Answer 32

- relies on DOPAMINERGIC neurons (that continue to degenerate) - high dopamine release from the synapses that are left may stimulate mech's to turn down those synapses (ex: receptor internalization, desensitization etc.) ALSO, L-DOPA treatment can --> DYSKINESIA (unwanted dysfunctional movements: tic's, chorea, etc.)

Question 33

What is the Deep Brain Stimulation for PD?

Answer 33

* Implanted electrodes in thalamus or basal ganglia * Electrical stimulation using an implanted stimulator can be very effective for relieving some symptoms * May require bilateral electrodes & stimulation (uni or bilateral)

Question 34

What is the Therapy for PD?

Answer 34

* Physical therapy, Occupational therapy * Musical gait therapy - auditory rhythm may help activate the basal ganglia rhythmically