PH2113 - Neurodegenerative Disease and Epilepsy 4

Question 1

How does the basal ganglia regulate movement?

Answer 1

D1 and D2 receptors of striatum in balance
- excitatory vs inhibitory

Balance of inhibition going to the thalamus and excitatory going to the cortex.

Question 2

What is the role of the basal ganglia in Parkinson’s disease?

Answer 2

Basal ganglia important for motor control

Lose stimulation through direct pathway
Indirect pathway becomes MORE active
- more glutamate
More GABA acting on thalamus
More inhibition of thalamus
Inactivation of cerebral cortex
cerebral cortex responsible for language, memory, reasoning, thought, learning, decision-making, emotion, intelligence and personality

Question 3

How can Parkinson’s disease be treated?

Answer 3

Replace the dopamine
- metabolised by gut enzymes
Increase the availability of dopamine to the brain
- L-dopa
- peripheral AADC inhibitors
- COMT inhibitors
Decrease the breakdown of dopamine
- monoamine oxidase-B inhibitors
Replace the post-synaptic dopamine stimulation
- D2 agonists
- stimulate D2 received
- mimic dopamine
- not D1 as side effects and short half life

Question 4

What is the problem with using Levodopa to treat Parkinson’s disease?

Answer 4

Dopamine does not pass the Blood-Brain Barrier
- metabolised in the gut

Question 5

How effective is Levodopa as a treatment for Parkinson’s disease? (percentages)

Answer 5

20% are restored to almost normal locomotion
80% show improvement in rigidity and hypokinesia

Question 6

Why isn’t Levodopa given on its own to treat Parkinson’s disease?

Answer 6

It is metabolised in the gut
- always given with a dopadecarboxylase inhibitor

Question 7

How effective are dopamine D2 receptor agonists in treating Parkinson’s disease?

Answer 7

Proven anti-parkinsonian activity
Ergot and non-ergot derived
Differential selectivity for D1 vs D2 like receptors and D2 vs D3 receptors
Variable half lives
- often once a day administration
- much longer than levodopa
Can be used in early disease de novo
- on their own
Late disease requires supplementation with L-dopa
- keeps L-dopa levels lower
Risk of impulse control disorders
- gambling
- shopping
- sexual partners

Question 8

What is COMT?

Answer 8

Catechol-o-methyltransferase
- enzyme that degrades dopamine.

Inhibiting it increases dopamine
- effective drug for treating Parkinson’s disease

MAO-B also degrades dopamine.

Question 9

Give an example of a COMT inhibitor that can be used to treat Parkinson’s disease?

Answer 9

Stalevo
- triple fixed dose combination
- L-dopa
- benserazide
- decarboxylase inhibitor
- entacapone
- COMT inhibitor

Question 10

Why was Tolcapone withdrawn as a treatment for Parkinson’s disease?

Answer 10

Liver toxicity
- used off label where necessary and patient is undergoing regular liver monitoring

Question 11

Give an example of monoamine oxidase B inhibitors used to treat Parkinson’s disease

Answer 11

Eldepryl
- rasagiline
- selegiline

Inhibition of monoamine oxidase B
- predominantly in CNS
- inhibition of MAOA has more side effects
- lack of non-selective peripheral effects
- hypertensive response to ingesting tyramine

Question 12

What should selegiline not be used in conjunction with?

Answer 12

Antitussives
- dextromethorphan

Question 13

How does levodopa affect the basal ganglia in treating Parkinson’s disease?

Answer 13

GABA pathway to thalamus inhibited
Thalamus disinhibited
Glutamate pathway to cerebral cortex stimulated
- excessive movement

Question 14

What is continuous dopamine stimulation (CDS)?

Answer 14

Different drug formulations
- provide continuous dopamine stimulation
Aim to smooth out highs and lows
- controlled release formulations
- madopar
- sinemet
- continuous interperitoneal infusion
- duodopa
- rotigotine transdermal patch
- dopamine agonist
- continuous subcutaneous infusion
- apomorphine
- prefilled syringes
- prefilled pen
- ampoules

Question 15

What is the spread of different dementia percentages in the UK?

Answer 15

Alzheimer’s disease
- 60%
Vascular dementia
- 20%
Dementia with Lewy Bodies (DLB)
- 15%
Frontotemporal dementia (FTD)
- <5%

Question 16

What is dementia?

Answer 16

Umbrella term to define a syndrome
- loss of mental processing ability such that it affects daily living
- communication
- abstract thinking
- judgment
- physical abilities
Acquired, chronic disorder which is usually progressive
Affects multiple parts of the brain
- higher cognitive functions
- memory
- thinking
- comprehension
- learning capacity
- language
- daily living activities/emotional behaviour
- non-cognitive symptoms
- behavioural and psychological symptoms of dementia (BPDS)
- agitation
- apathy - lack of interest, enthusiasm, concern
- depression
- anxiety
- delusions
- hallucinations
- irritability
- wandering

Question 17

What is the initial presentation of dementia?

Answer 17

Poor memory

Question 18

What are the later symptoms of dementia?

Answer 18

Physical abilities
- stooped posture
- shuffling gait
- rigidity
- bradykinesia
- Tremors at rest
- pill-rolling motion of the hand

Question 19

Explain in more depth the pathology of the basal ganglia in Parkinson’s disease.

Answer 19

The striatum in the basal ganglia consists of 2 types of GABAergic medium spiny neuron, D1 and D2

In Parkinson’s disease there is less dopamine acting at the D1 and D2 receptors. This leads to less inhibition at the output nuclei through the D1 mediated pathway. Less dopamine on the D2 indirect pathway leads to increased activity of this pathway (D2 receptors are inhibitory) so therefore MORE inhibition of the GPi, less inhibition of the STN and therefore greater excitatory input to the output nuclei.

More excitation and less inhibition of the output nuclei (GPi and STN) leads to increased GABA mediated inhibition of the thalamus which is then less able to excite the cortex which reduces movement as in PD.