Neurological disorders

Question 1

• Four primary symptoms of parkinsons

Answer 1

Resting tremor
• 2. Muscular rigidity, stiffness of the body
• 3. Bradykinesia - slowness of movement
• 4. Postural instability or impaired balance.

Question 2

other symptoms of parkinsons

Answer 2

• Other symptoms: loss of sense of smell, nerve pain, problems with urination, constipation, erectile dysfunction , sexual dysfunction, dizziness, blurred vision or fainting, excessive sweating, swallowing difficulties, excessive production of saliva, depression, anxiety, insomnia, mild cognitive impairment; dementia

Question 3

• PD 2nd most common neurodegenerative disorder after ….

Answer 3

• PD 2nd most common neurodegenerative disorder after Alzheimer’s disease

Question 4

parkinsons affects what % of the population

Answer 4

• Affects about 0.3% of the population

Question 5

parkinsons rates

Answer 5

• Diagnosis rates rise from about 1% in those over 60 years of age to 4% of the population over 80.

Question 6

what is parkinsons caused by

Answer 6

• Caused by degeneration of nigrostriatal DA pathway — dopamine-secreting neurons of substantia nigra (midbrain) which project to striatum and basal ganglia nuclei

Question 7

PD symptoms dont show until

Answer 7

• The symptoms typically don’t show until 80-90% of DA cells lost.

Question 8

• Nigrostriatal dopamine neurons that survive in PD express….

Answer 8

• Nigrostriatal dopamine neurons that survive in PD express Lewy Bodies

Question 9

what are lewy bodies

Answer 9

• Lewy bodies first appear brain stem when individuals are asymptomatic.
• Lewy bodies develop in the substantia nigra, brain stem and basal forebrain, and finally cortex.
• Nigrostrial cells appear particularly vulnerable to damage caused by lewy bodies.

Question 10

• 95% of PD cases sporadic,, this means what?

Answer 10

• 95% of PD cases sporadic (possible causes = environmental toxins, metabolism, infection.)

Question 11

what was found in 1976 by Barry Kidston

Answer 11

• Frozen addicts - adulteration of synthetic heroin MPPP with MPTP
• MPTP disrupts mitochondrial metabolism causing build up of free radicals and nigrostriatal apoptosis .
• First recorded by in 1976 by Barry Kidston, a 23-year-old chemistry graduate student who synthesized MPPP with MPTP impurity, and self-injected producing PD in three days.
• MPTP reinvigorated animal research on Parkinson’s by creating Parkinsonian animals to be tested.

Question 12

why is L-dopa administered

Answer 12

• L-dopa is administered because can cross the blood brain barrier dopamine cannot.

Question 13

side effects of L-dopa

Answer 13

• Side effects: ↑ dopamine in mesolimbic and mesocortical pathways produce pathological gambling and schizotypal delusions and hallucination in some patients.
• Continued L-dopa produces dyskinesia (involuntary movements). Effective but last resort due to these side effects

Question 14

standard treatment line for parkinsons

Answer 14

1. First line: MAO-B inhibitors (maximise what dopamine remains).
   Then: Dopamine agonists (e.g. apomorphine) but floods system creating side effects: hallucinations delusions and compulsive behaviour.
2. Introduce L-dopa and disease worsens, and ↑ dose as needed.
3. Combine the 3 therapies.
4. DBS.

Question 15

• PD patients show decreased ????? activity

Answer 15

• PD patients show ↓ striatal dopamine activity (b) than controls (a) in PET scan.

Question 16

two main pathways in PD

Answer 16

• Direct pathway - Activates cortex – activates wanted movement.
• Indirect pathway - Inhibits cortex – inhibits unwanted movements.

Question 17

direct pathway in PD explained

Answer 17

Direct pathway – excite cortex
•	Striatum inhibits GPint. 
•	GPint inhibits thalamus.
•	Reducing excitation of cortex.
•	Default state = inhibition of movement.
•	When cortical cells excite the direct pathway striatal cells they inhibit the GPint. 
•	Releases the thalamus from inhibition 
•	Excites the cortex.

Question 18

indirect pathway in PD explained

Answer 18

Indirect pathway – inhibit cortex
• Striatal cells inhibit globus pallidus external (GPext).
• The GPext inhibits subthalamic nucleus (STN)
• STN excits Gpint (the only excitatory pathway within the basal ganglia).
• GPint inhibits thalamus.
• Reducing excitation of cortex.
• Again default state = inhibits movement.
• Cortical excitation of striatal indirect cells results in inhibition of the thalamus, and thus motor cortex.

Question 19

Nigrostriatal pathway in PD explained

Answer 19

Nigrostriatal pathway
• Nigrostriatal dopamine projection excites striatal direct pathway neurons via D1 receptors.
• Nigrostriatal dopamine projection inhibit striatal indirect pathway neurons via D2 receptors.
• Dual effect of exciting the direct pathway while simultaneously inhibiting the indirect pathway.
• Dual effect excites raises the activation of the cortex.

• Loss of nigrostriatal path decreases cortical activation.
• And destabilises balance between direct and indirect paths, blurring wanted and unwanted movements, creating erratic firing in direct and indirect path.
• Rationale of Deep Brain Stimulation is to provide a pacemaker (steady) firing pattern within the indirect path with either stimulation of the (GPi) or the subthalamic nucleus (STN).
• Or steady stimulation of thalamus to increase cortical excitation.
• They all produce similar therapeutic outcomes, and is not often obvious why.