Lecture neurodegenerative disorders 6: treatment for neurodegenerative disorders (therapy 1)

Question 1

What two treatments exist for neurodegenerative diseases?

Answer 1

• Symptomatic treatment (affects symptoms, but not the cause)
• Disease modifying treatment (reduce the activity and progression of a disease)

Question 2

What treatment options are there for neurodegenerative diseases mostly? Name examples of this/these treatment option(s).

Answer 2

Symptomatic treatment, for example:

• Sleep medication
• Anti-depressants
• Anti-anxiety
• Substituting lost neurotransmitter systems

Question 3

In regard to the treatment option; substituting lost neurotransmitter system, what registered treatment is there for AD?

Answer 3

Stimulation of cholinergic transmission

Question 4

Why is it needed to stimulate cholinergic transmission as a treatment for AD? What is used in this treatment?

Answer 4

Because in AD, there’s a lack of acetylcholine (ACh). Therefore, you can inhibit the enzym that breaks down acetylcholine, i.e. acetylcholine-esterase inhibitor, to increase the availability of ACh in the synaptic cleft.

Question 5

What else happens in Alzheimer’s that can be targeted for therapy?

Answer 5

Excitotoxicity. This is due to neurons that are dying/under stress and release a lot of glutamate into the synaptic cleft. Glutamate then overstimulates its (NMDA-)receptors, which results in glutamate excitotoxicity. By using a NMDA receptor blocker, excitotoxicity is halted/diminished.

Question 6

What’s the downside of the use of acetylcholine-esterase inhibitors and NMDA receptor blockers?

Answer 6

That both treatments can only be used in late stages of AD. So both treatments are only symptomatic, have small effects and only benefit a small group of patients.

Question 7

What is L-DOPA (levodopa)?

Answer 7

An anti-parkinson drug. It acts as a precursor from dopamine.

In Parkinson’s there’s a dopamine shortage due to loss of dopaminergic neurons. L-DOPA is converted to dopamine when it arrives in the brain.

Question 8

There are many side effect of L-DOPA for Parkinson’s disease. Name a few.

Answer 8

• Abnormal thinking: holding false beliefs that cannot be changed by fact
• Agitation
• Anxiety
• Clenching or grinding of teeth
• Clumsiness or unsteadiness
• Confusion
• Difficulty swallowing
• Dizziness
• Excessive watering of mouth
• False sense of wellbeing
• Feeling faint
• General feeling of discomfort or illness
• Hallucinations (seeing, hearing, or feeling things that are not there)
• Hand tremor, increased
• Nausea or vomiting
• Numbness
• Unusual and uncontrolled movements of the body, including the face, tongue, arms, hands, head, and upper body
• Unusual tiredness or weakness

Question 9

Name two non-pharmacological ways of neurotransmission restoration in Parkinson’s disease.

Answer 9

Deep brain stimulation or stem cell transplantation (already discussed in lecture about synucleopathies).

Question 10

What is seen based on epidemiological studies in regard to the development of AD and the risk for it?

Answer 10

That the risk at AD is reduced in people who take non-steroid anti-inflammatory drugs (NSAIDs)

Question 11

What is thought to be the reason behind the possible protective function of NSAIDs?

Answer 11

NSAIDs inhibit inflammatory responses, which also contribute in AD pathogenesis. NSAIDs inhibit COX1 and COX2, which are enzymes responsible for the production of prostaglandins

Question 12

Did clinical trials also show that NSAIDs were effective against AD pathogenesis?

Answer 12

No, in clinical trials there was no evidence for efficacy of NSAIDs against AD pathogenesis.

Question 13

But still it is seen that NSAIDs can target several processes important for AD pathogenesis. What are targets of NSAIDs that are important in AD pathogenesis?

Answer 13

Most importantly is that NSAIDs affect APP processing (which results in less AB, tau and oxidative stress).

Other targets can be seen in picture.

Question 14

What would be the reason why we see protective effects of NSAIDs in epidemiological studies, but not in clinical trials?

Answer 14

This is probably due to the fact that when you give NSAIDs to AD patients, you are probably already too late.

Other reasons can be that positive effects of NSAIDs are not regulated by anti-inflammatory mechanism or that there’s inhibition of good inflammatory response.

Question 15

Why is microglial activation seen as a double edged sword?

Answer 15

Because microglia are important for repair and clear up (macrophages of the brain). But at the same time, especially when overstimulated, they produce cytokines that could induce inflammation even further and cause pathogenesis of e.g. AD.

Question 16

Name four ways to use disease modifying drugs.

Answer 16

1. Inhibition of formation of aggregating proteins
2. Inhibition of aggregation
3. Clearance of aggregates
4. Inhibiton of spreading

Question 17

Describe the four phases of a clinical trial.

Answer 17

• Phase I: study for safety and other effects in healthy volunteers
• Phase II: RCT for efficacy and tolerability on limited number of patients
• Phase III: RCT with use of two groups (experimental and placebo) to study efficacy and tolerability in larger group of patients (500-5000 patients)

If approved, medicine is now registered.

• Phase IV: everyday clinical studies to monitor the drug (observational or RCTs)

Question 18

What outcome measures are used in clinical trials?

Answer 18

Certain biomarkers (representing disease process) and clinical measures (e.g. if PD patients have improved movement after trial)

Question 19

Name examples of biomarkers that are helpful in clinical trials.

Answer 19

• Use of PET (dopamine transporter PET or plaque PET)
• Cerebro-Spinal Fluid (CSF)

Question 20

For the retrieval of cerebrospinal fluid, a lumbar puncture is performed. What is seen in the CSF of AD patients?

Answer 20

In the CSF:

• decreased Aβ (due to Aβ sequestering in plaques)
• increased tau and p-tau (due to release of (p-)tau upon neuronal death/loss)

(The cut-off values in the left column is used for diagnostic practise)

Question 21

What biomarker is used for the diagnosis of Creutzfeldt-Jacob disease? Is it a good biomarker for diagnosis of this disease (why or why not)?

Answer 21

14-3-3 is a protein that is increased in Creutzfeldt-Jacob disease and thus is used as a biomarker for the disease.

• It has high sensitivity → it is easy to measure 14-3-3.
• It has low specificity → 14-3-3 is also increased after a stroke or HSV encephalitis.

This biomarker on its own generates a lot of false positives, so it needs to be improved. For now, it can only be used in combination with clinical diagnosis.

Question 22

Patients with Creutzfeldt-Jacob disease have misfolded PrP aggregates in their CSF. How can someone be diagnosed with Creutzfeldt-Jacob disease with the help of this misfolded protein?

Answer 22

By using seeding assays: PrP aggregates are detected by measuring the capacity of the CSF to seed to aggregation of wild type proteins (or in this case recombinant proteins).

This is done by using the CSF of a patient with (possible) Creutzfeldt-Jacob disease and adding the recombinant/wild type protein to it. Thioflavin T is used to measure the amount of aggregates (since it binds to β-sheets in aggregates).

If after this more aggregates are present in the CSF:

• more aggregation of recombinant protein
• more ThioT fluorescence

Question 23

Can these seeding assays also be used for diagnosis and development of other diseases?

Answer 23

Yes, probably for AD and PD.

Question 24

The perfect outcome measures of a clinical trial would be that both the biomarker and the clinical measures show a positive results. What would it mean if the biomarker shows a different outcome than the clinical measure, as depicted in the picture?

Answer 24

• If the biomarker shows a positive result and the clinical measures show no or a negative results, it would mean that the treatment acts on the correct mechanism, but the patient doesn’t benefit from it. It could be possible that the treatment could work in a different timing (earlier, increased dosage etc.).
• If the biomarker shows no or a negative result and the clinical measures show a positive result, it’s possible that the treatment does work for the patient, but that the drug doesn’t work on the same mechanism as the biomarker does.

Question 25

What specific issue is there with targeting the brain?

Answer 25

The blood-brain-barrier: highly charged, too large or not lipid soluble molecules cannot enter the brain.