Parkinson's Disease: Pathology and Treatment

Question 1

3 features of basal ganglia?

Answer 1

Converts highly processed sensory info into motor programme
Contains many parallel circuits / loops: some motor, esp striato-nigral-striatal loop (PD).
Many non-motor functions: cognition, motivation, addiction

Question 2

What is the difference between parkinsons disease and Huntingtons disease?

Answer 2

PD (progressive neurodegenerative)
Loss of DAergic neurons in nigrostriatal tract -> hypokinesia

HD (progessive, inherited disorder)
Loss of inhibitory GABAergic neurons in striatum -> hyPERkinesia, involuntary jerky movements, dementia

Question 3

What type of scan distingushes between parkinsons disease and drug induced PD?

Answer 3

(SPECT) scan called a dopamine transporter (DAT) scan
B shows less dopamine (Parkinson’s) binding due to decreased DA neurons.

Another type is the D2 PET scan. Radioactive ligand binds to the DA transporter BUT D2 PET scan NOT to be used as diagnostic criteria!

Question 4

4 motor symptoms of PD

Answer 4

Pill rolling tremor at rest
Muscle rigidity, stiffness
Hypokinesia, motor activity difficult to initiate & stop
Micrographia- abnormally small handwriting or the progression to progressively smaller handwriting

Question 5

11 non motor symptoms of PD

Answer 5

Question 6

Describe the Braak stages of PD

Answer 6

Stages 1 & 2: early degeneration, sleep & olfaction disturbances
Stages 3 & 4: loss of 50-80% of nigrostriatal neurons, motor symptoms
Stages 5 & 6: no nigrostriatal neurons at all. Polyergic neurons degenerate–> loss of memory, dementia. Misfolding and aggregation of Alpha-synuclein protein forms Lewy bodies.

Question 7

Explain neurochemistry of PD symptoms, focusing on hypokinesia

Answer 7

Hypokinesia (loss of voluntary movements):
Loss of DAergic inhibition of GABAergic cells - therefore more GABA activity in globus pallidus -> Less activation of cortical areas (difficulty initiating movements)

Question 8

Explain the neurochemistry of PD symptoms, focusing on tremor and rigidity

Answer 8

Tremor and rigidity:
Complex disturbances of other transmitter systems: ACh, NA, 5-HT and GABA
This is as DA isn’t inhibiting ACh, so hay increased cholinergic transmission in striatum. DA/Ach imbalance
This Ach hyperactivity causes tremor, bradykinesia.

Question 9

4 causes of PD?

Answer 9

Pesticide eg rotenone inhibit mitochondria-> PD (higher incidence in rural areas)
Genetic: mutations in parkin gene or mitochondrial proteins. Mutations of a-synuclein–>Lewy bodies
Oxidative stress, neuroinflammation
Drug induced, eg Antipsychotics (D2 antagonists), Li drugs, but this is reversible

Question 10

Several heroin addicts developed PD. Explain why and what the treatment would be for this

Answer 10

Heroin was contaminated with MPTP. MPTP alone is not toxic, but it goes through the DA transporter into DA neurons

Once inside the DA neuron, MPTP is converted into MPP by MAOb. MPP is v toxic, produces ROS + nigrostriatal tract degeneration.

Treatment = blocking MAOb, stopping the conversion.

Question 11

why cant u just give dopamine in a pill? + therefore Explain 3 main treatment modalities for PD

Answer 11

DA is polar, charged, doesn’t cross the BBB. Cant just give dopamine in a pill. So you use a precursor. How treat PD:
Block DAT
Block MAOb
Inhibit COMT - increase L-dopa, so that more L-dopa makes DA

Question 12

What is the moa of levodopa? Why is it also given with a dopa decarboxylase inhibitor?
2 examples of DC
Can DC inhibitor cross BBB?

Answer 12

L-dopa: Immediate DA precursor, first line treatment if motor symptoms impact qol.
Dopa decarboxylase also found in the periphery, so if converted to DA outside the brain=useless. So a DC inhibitor is used w L-dopa
DC inhibitor (carbidopa, benserazide) cannot cross the BBB, so doesn’t get converted to DA outside the brain.

Question 13

4 groups of Short term side effects of L dopa?

Answer 13

Outside the BBB, Dopamine on D2 acts on the CTZ to trigger the vomiting centre in the medulla

Question 14

short term vs 3 groups of Long term side effects of L dopa?

Answer 14

Taking drug for 5/6 years continuously leads to long term effects

Question 15

Which PD patients are likely to experience Impulse Control Disorder? + What is this?
2 risk factors, mechanism

Answer 15

13% of PD patients given DA agonists experience Impulse Control Disorder inc pathological gambling, hypersexuality, punding

Risk factors: Earlier onset, personal/family Hx of substance abuse
Reduce dose and monitor
DA agonists hyperstimulate the mesolimbic pathway, which leads to psychiatric symptoms

Question 16

Link dopamine drugs with schizophrenia and psychotic symptoms

Answer 16

Amph enhances DA release in schizophrenics more which makes the disease worse
D2 agonists produce stereotyped behaviour (not D1), whereas blocking D2= antipsychotic action
Reserpine depletes DA, which controls positive symptoms
DA release only in mesolimbic, mesocortical, NOT nigrostriatal

Question 17

What is the on/off effect? What are the other long term side effects of Ldopa?

Answer 17

Rapid oscillations in mobility (on-off effect, see below) due to fluctuating Ldopa levels in plasma
Increased akinesia (can’t initiate movement)
End of dose deterioration- long term-narrow therapeutic window

Question 18

Compare old D2/3 agonists vs New ones - side effects,
What can ergot derivatives cause?
Extra positive effects of a new D2/3 agonist

Answer 18

D2/D3 agonists, eg bromocriptine spares L-dopa, delaying ‘on-off’ effects
Side effects: nausea, vomiting, psych symptoms
Ergot derivatives can cause valvular heart disease

Newer DA agonists (ropinirole, pramipexole), longer action -> lower tendency for dyskinesia
Side effects: confusion, delusion, disturbs sleep, compulsive behaviours
Pramipexole also has antioxidant effects & protective effect on mitochondria

Question 19

Explain how antivirals are used in treatment of early PD if quality of life not impaired or ad hoc in later PD
3 mechanisms, compare it to levodopa

Answer 19

Amantadine (antiviral drug)
decreases amine uptake, direct DA agonist, antimuscarinic
Less effective than levodopa, efficacy reduces over time
Also treats PD associated sleepiness and dyskinesias
However Side effects are less severe!

Question 20

Compare & contrast how MOAb + COMT inhibitors are used in treatment of early PD if quality of life not impaired or ad hoc in later PD
compare & contrast their side effects

Answer 20

Selegiline: selective MAOBi (no peripheral effect unlike non selective, cheese effect MAOa inhibitors)
Used w Ldopa, decreased L-dopa and DA metabolism,
Fewer adverse effects, potentiates effect

Entacapone: COMT inhibitor
Slows elimination of levodopa, potentiates effect, reduces dyskinesias
More adverse effects, but low hallucination risk

Question 21

How are antimuscarinics used to treat PD?
2 examples, who r they useful in & not to be used in,
mechanism, 3 side effects + what else can they be used for

Answer 21

Antimuscarinics – benzatropine, procyclidine
Useful in early stages in young to decrease tremor, rigidity
Not to be used on old ppl (memory issues, confusion)
Corrects Ach overactivity from reduced inhibitory DA activity
Reduces sialorrhoea
Side effects (dry mouth, blurred vision, urinary retention)
Used for antipsychotic drug-induced PD

Question 22

What are the surgical PD interventions? Who are they aimed towards?

Answer 22

Implanting electrodes in Bilateral subthalamic stimulation –deep brain stimulation
Implanting foetal nigral tissue into striatum to form synaptic connections, but limited clinical benefit. Side effects: severe dyskinesias
For advanced PD whose symptoms are not controlled w meds

Question 23

Early PD Treatment?

Answer 23

DA Agonists – mild effect: Ropinorole, Pramipexole, Rotigotine, Cabergoline
MAOB-Inhibitors – mild effect: Selegiline, Rasagiline
Ldopa – moderate/good effect: Co-careldopa, Co-beneldopa
COMT inhibitors- mild effect: entacapone
Antivirals- mild effect: amantadine
also, no treatment

Question 24

Advanced PD Treatment? - 2 extra things u can give

Answer 24

Adding extra drugs to prolong QOL, inc:
DA agonists (adverse effects, hallucination)
MAOB-inhibitors (less adverse effects)
COMT inhibitors (adverse effects)

Apomorphine (non selective DA agonist) injection or s/c infusion
Levodopa gel infusion (jejunal)

Question 25

Treatment of Non-Motor
Symptoms?

Answer 25