Module 3 Section 5 (Neurodegenerative Diseases)

Question 1

What are neurodegenerative diseases?

Answer 1

These diseases are characterised by progressive and irreversible loss of neurons from selected regions of the brain and spinal cord.

Question 2

What are the common features amongst neurodegenerative diseases?

Answer 2

1) Selective Areas Affected: for each neurodegenerative disease, the area of the brain where neuronal loss occurs is selective or specific for that disease, while other areas of the brain are often unaffected.

2) Distinct Genetic Forms: each neurodegenerative disease has distinct genetic forms of the condition, and the interaction between genetic and environmental factors are important for the determination of some of the features of these diseases.
- For instance, the age of onset can be affected by the interaction of genetics and environmental factors.

3) Inappropriate Protein: a common feature of neurodegenerative diseases is the presence of an inappropriate protein, or the deposition of a protein in a specific region of the brain.
- Ex: the presence of β-amyloid protein in Alzheimer’s disease.

4) Increased Likelihood with Age: the neurodegenerative diseases are primarily a disorder of age, although recognised forms in childhood do exist.
5) Treatment Controls the Symptoms: currently available treatments for neurodegenerative diseases control symptoms but do not alter the neurodegenerative process.

Question 3

What is Parkinson’s disease?

Answer 3

Parkinson’s disease is a neurodegenerative disease that affects movement.

Question 4

What is Parkinson’s disease categorized by?

Answer 4

It develops gradually and is characterised by 4 main clinical features:

• Bradykinesia (slow and poor movement)
• Muscle rigidity
• Tremor at rest
• Poor postural balance and a shuffling/impaired gait.

Question 5

What is the most common form of PD?

Answer 5

The most common form of Parkinson’s disease is called idiopathic Parkinson’s disease, as it has no known or confirmed cause.

Question 6

What causes PD?

Answer 6

Other forms of the disease can result from stroke or drugs, such as the phenothiazine antipsychotics.

Question 7

What occurs during PD?

Answer 7

There is a loss of dopaminergic neurons in the region of the brain called the substantia nigra pars.

These dopaminergic neurons provide input into the striatum, an area of the brain involved in motor coordination and movement.

Question 8

How much dopaminergic function loss is needed for PD?

Answer 8

70% to 80% of dopaminergic function loss is required for symptomatic Parkinson’s disease.

Question 9

While dopaminergic neurons are the main deficit in Parkinson’s disease, as the disease progresses other brain structures are affected. What are those brain structures?

Answer 9

The brain stem, hippocampus, and cerebral cortex.

Deficits in these other brain structures are responsible for the sleep disorders and memory loss associated with advanced Parkinson’s disease.

Question 10

What treatment strategies are used for PD?

Answer 10

Treatment strategies for Parkinson’s disease are aimed at enhancing the function of the remaining dopaminergic neurons by increasing the amount of dopamine, inhibiting the breakdown of dopamine, and/or administering dopamine agonists.

Many of the drugs used in the treatment of Parkinson’s disease alter the dopamine synthesis pathway.

Question 11

How is dopamine made in the body?

Answer 11

Dopamine is synthesised in the brain from dietary phenylalanine after conversion to tyrosine. Tyrosine is taken up into the neuron, where the enzyme tyrosine hydroxylase converts it into DOPA.

DOPA is then converted into dopamine and packaged into vesicles for subsequent release.

The enzymes monoamine oxidaseand catechol-o-methyltransferase break down and inactivate dopamine.

Question 12

True or false: Dopamine does not cross the blood brain barrier, thus administering dopamine has no effect in Parkinson’s disease.

Answer 12

True

Question 13

Why is levodopa used to treat PD?

Answer 13

Levodopa, which is a manufactured form of DOPA (the immediate precursor to dopamine), does cross the blood brain barrier and reaches the brain in sufficient concentrations to increase dopamine levels.

It essentially bypasses the blood brain barrier (BBB) to increase dopamine levels in th

Question 14

What is the downside of using levodopa ?

Answer 14

Unfortunately, levodopa is rapidly metabolised in peripheral tissues to dopamine. Using levodopa alone, only 1-3% of the administered dose gets passed the blood brain barrier and reaches the brain.

Question 15

Why is carbidopa odten added with levodopa for the treatment of PD?

Answer 15

To bypass some of this conversion of levodopa to dopamine peripherally, carbidopa is often added.

Question 16

How does Carbidopa work?

Answer 16

Carbidopa is an inhibitor of the enzyme L-amino acid decarboxylase (AAD), which converts levodopa into dopamine. As a result, this decreases the amount of levodopa that is metabolized peripherally, increasing the concentration of levodopa that has the potential to cross the blood brain barrier.

Question 17

What is the advantage of combinding levodopa and carbidopa?

Answer 17

The combination of levodopa and carbidopa allows approximately 10% of a dose of levodopa to reach the brain.

The combination of drugs is the most effective treatment for Parkinson’s disease, resulting in a dramatic improvement in tremor, rigidity, and movement. With long term use, this effect is reduced, and the motor symptoms begin to fluctuate.

Question 18

What is the “wearing off” phenomenon surrounding the carbidopa/levodopa combination?

Answer 18

There appears to be a “wearing off” phenomenon with the carbidopa/levodopa combination, where each dose of the drugs improves walking and balance for one to two hours, and then the symptoms return.

Question 19

What are some adverse effects of levodopa?

Answer 19

Nausea and dopamine-induced hallucinations.

Question 20

What do selective MAO-B inhibitors do?

Answer 20

The enzyme monoamine oxidase metabolizes dopamine.

MAO-B is responsible for most of the oxidative metabolism of dopamine in the brain. MAO-B inhibitors, such as selegiline, inhibit the breakdown of dopamine to 3, 4-dihydroxyphenylacetic acid (DOPAC).

MAO inhibitors prevent the inactivation of tyramine. However, MAO-B selective inhibitors do not interact with the tyramine in cheeses like non-selective MAO inhibitors do.

Question 21

What are Catechol-o-Methyltransferase Inhibitors?

Answer 21

They break down dopamine.

Administration of levodopa with carbidopa decreases the fraction of levodopa converted to dopamine peripherally, but increases the amount converted to another metabolite (3-OMD) by COMT.

This class of drugs inhibit the peripheral COMT, reducing the peripheral metabolism of levodopa and increasing levels of levodopa reaching the critical areas of the brain.

Question 22

What are the adverse effects of COMT?

Answer 22

Adverse effects of COMT inhibitors are mainly due to the resulting increased levels of dopamine in the brain, and include nausea, vivid dreams, confusion, and hallucinations.

Question 23

What are dopamine receptor agonists?

Answer 23

An alternate approach to increasing dopaminergic activity in the substantia nigra is to administer synthetic dopamine agonists to supplement the decreased endogenous dopamine.

Drugs of this class are useful in patients who are not adequately controlled with levodopa. Adverse effects include hallucinations and confusion. One adverse effect often not recognised is that patients receiving dopamine agonists may engage in reward seeking behavi

Question 24

What are some adverse effects of dopamine receptor agonists?

Answer 24

Adverse effects include hallucinations and confusion. One adverse effect often not recognised is that patients receiving dopamine agonists may engage in reward seeking behaviour.

Question 25

What is Alzheimer’s disease?

Answer 25

Alzheimer’s disease is characterised by progressive loss of memory and cognitive function.

Question 26

What occurs during the early stages compared to the progressive stages of AD?

Answer 26

In the early stages of Alzheimer’s disease, the person may be forgetful, but as the disease progresses, there is a loss of cognitive function that affects daily activities and can result in a vegetative state.

During the progression of the disease, patients can become anxious, depressed, and irritable.

Question 27

What are the 2 pathological features of Alzheimer’s disease?

Answer 27

1) Amyloid Plaques: in a patient with Alzheimer’s, there is deposition of proteins, specifically β-amyloid proteins, into certain regions of the cerebral cortex. These depositions are called amyloid plaques. These plaques collect between neurons in the brain and disrupt cell function.

2) Neurofibrillary Tangles: they occur later in the disease progression than amyloid plaques, and are more closely associated with cognitive impairment.
- These tangles are the result of aggregated tau protein within the neuron. The tau protein normally supports microtubules within the cell, however in Alzheimer’s, the tau proteins dissociate and stick together instead, forming threads that eventually join to form tangles within the neuron.

As a result of the two pathological features of Alzheimer’s, amyloid plaques and neurofibrillary tangles, there is a progressive loss of neurons within the brain, especially cholinergic neurons.

Question 28

How is AD treated?

Answer 28

No disease modifying drugs are available for Alzheimer’s disease.

Current therapy is aimed at symptom control. However, most drugs used to treat the condition by modifying cholinergic transmission, or attempting to enhance transmission in the remaining cholinergic neurons.

Question 29

What drugs are used to treat AD?

Answer 29

• Cholinesterase inhibitors
• Memantine
• Other drugs

Question 30

What are cholinesterase inhibitors?

Answer 30

They block the enzyme acetylcholinesterase, reducing the rate of breakdown of acetylcholine. This enhances the activity of acetylcholine at the receptors and potentially improves memory and cognition.

The response is a modest improvement in symptoms, including a decreased rate in the decline of memory and cognitive function.

Question 31

What are the adverse effects?

Answer 31

Adverse effects of include gastrointestinal effects, muscle cramping, and abnormal dreams.

Question 32

What are memantines and how do they work?

Answer 32

This drug is an antagonist for a specific glutamate receptor, called the NMDA receptor.

This drug may slow the rate of destruction of neurons by inhibiting the excitatory responses to glutamate, preventing glutamate-induced excitatory neuronal death.

Glutamate can cause excitotoxic death of neurons if glutamate excitation is above normal. This is mediated by a subset of glutamate receptors, NMDA type. By inhibiting glutamate from binding to NMDA receptors, neurons can be protected.

Question 33

What are some other drugs used to treat AD?

Answer 33

Antipsychotics and mood stabilizers are used to control the behavioural symptoms of Alzheimer’s disease.

Question 34

Whay is Huntington’s disease?

Answer 34

Huntington’s disease is an inherited neurodegenerative disease characterized by a loss of neurons in the striatum of the brain.

Specifically, there is a loss of nerve projections from the striatum, leading to a decrease in GABA concentrations.

Question 35

Discuss the symptoms of HD.

Answer 35

It presents as a gradual onset of motor incoordination, impairment of balance, and a decline in cognitive function that usually appears in midlife.

Memory is impaired, making some daily tasks difficult to complete, but affected individuals do not lose their memory of family and friends. Depression is often associated with Huntington’s disease.

Question 36

What is the treatment for HD?

Answer 36

Treatment for Huntington’s disease is targeted to relieve symptoms.

Antidepressants are used to treat depression, and antipsychotics are used to treat any paranoia, psychosis, or delusional states associated with Huntington’s disease.

Question 37

There are numerous antidepressants and antipsychotics available to treat depression and bipolar disorder, respectively. Many of these pharmacological drugs are also commonly employed to treat patients who suffer from Huntington’s Disease. Using previous knowledge, specify whether each drug type is an antidepressant or an antipsychotic:

a) Serotonin-norepinephrine reuptake inhibitors (SSRIs)
b) Haloperidol
c) Presynaptic autoreceptor antagonists
d) Monoamine oxidase inhibitors (MAOis)
e) Phenothiazine

Answer 37

a) Serotonin-norepinephrine reuptake inhibitors (SSRIs) = antidepressant
b) Haloperidol = antipsychoticc
c) Presynaptic autoreceptor antagonists = Antidepressant
d) Monoamine oxidase inhibitors (MAOis) = Antidepressant
e) Phenothiazine = Antipsychotic

Question 38

What is Amyotrophic Lateral Sclerosis (ALS)?

Answer 38

Also known as Lou Gehrig’s disease, ALS is a disorder of the motor neurons in the spinal cord, brain stem, and brain.

Question 39

The somatic nervous system controls voluntary movement. The somatic nervous system requires just one neuron, called a motor neuron, to reach the skeletal muscle and exert its effect. How does this relate to ALS?

Answer 39

ALS targets these motor neurons, limiting their ability to carry signals from the CNS to the skeletal muscles. The motor neurons in both the brain and spinal begin to degenerate and eventually die.

Question 40

Briefly give an overview on motor neurons.

Answer 40

Messages from the CNS are carried to the spinal cord via upper motor neurons. The upper motor neuron then synapses with an interneuron. The interneuron then directs the message to the lower motor neurons, which transmits the message to the skeletal muscle via acetylcholine and causes contraction.

Question 41

What occurs to motor neurons during ALS?

Answer 41

In ALS there is a loss of motor neurons and hence motor function, leading initially to muscle twitching, cramps, weakness of an arm or leg, or difficulty in swallowing.

However, there is rapid progression of muscle atrophy, leading to increased weakness, spasticity, and inability to swallow, associated with behavioural changes and cognitive dysfunction.

Death results from compromised respiration, or other complications due to the loss of motor function.

Question 42

Is there a cure for ALS?

Answer 42

There is no cure for ALS.

Question 43

What is the treatment fir ALS?

Answer 43

Riluzole, a glutamate receptor (kainate and NMDA) blocker, is thought to decrease the rate of excitotoxic cell death induced by glutamate.

This drug increases survival by several months. Other therapeutic intervention is aimed at symptom control of muscle spasticity and respiratory assistance.

Question 44

A common symptom of ALS is muscle spasticity. Using the repertoire of drugs you were introduced to over the course of this module, select the drugs listed below that would be effective for treating muscle spasticity. Select all drugs that apply.

a) Diazepam (benzodiazepine)
b) Imipramine (TCA)
c) Zopiclone (“Z” drug)
d) Fluoxetine (SSRI)

Answer 44

a) Diazepam (benzodiazepine)
c) Zopiclone (“Z” drug)

Benzodiazepines cause muscle relaxation by increasing GABA-mediated CNS inhibition.

Zopiclone, a “Z’’ drug, binds to a subset of GABA receptors and has a sedative effect.

Question 45

Alzheimer’s disease is characterized by a loss of?

a) Cholinergic neurons from the brain stem.
b) Dopaminergic neurons from the cerebellum.
c) Dopaminergic neurons from the spinal cord.
d) Cholinergic neurons from the cerebral cortex.

Answer 45

d) Cholinergic neurons from the cerebral cortex.

Question 46

Parkinson’s Disease is characterized by?

a) The loss of adrenergic neurons from the substantia nigra.
b) The gain of cholinergic neurons in the substantia nigra.
c) The deposition of amyloid protein into the substantia nigra.
d) The loss of dopaminergic neurons from the substantia nigra.

Answer 46

d) The loss of dopaminergic neurons from the substantia nigra.