“It’s Not All Dopamine: Possible Mechanisms and Interventions for Falls in PD” – Symposium Lecture Notes

“It’s Not All Dopamine: Possible Mechanisms and Interventions for Falls in PD” – Symposium Lecture Notes

In August 2020, three Parkinson’s organizations hosted a virtual summer symposium.  We at Stanford Parkinson’s Community Outreach recently listened to the three talks and are sharing our notes. 

The notes here are from the “It’s Not All Dopamine: Possible Mechanisms and Interventions for Falls in PD” talk by Dr. Roger Albin of the University of Michigan Udall Center of Excellence for Parkinson’s Disease Research. He described the impact of dopamine and acetylcholine in Parkinson’s, and some animal trials that confirmed that the dopamine and acetylcholine systems were involved. The trials consisted of rats and mice going through an obstacle course with some distractions, and half had their dopamine and acetylcholine circuits disrupted.  Changes in behavior were measured. He also spoke of the human experiments he did, where a nicotine-like drug called varenicline was used to improve attention spans in Parkinson’s patients. 

The webinar was recorded and can be viewed here.

This session begins at 44:12 and ends at 1:40:26. 

See extensive notes on the August 20, 2020 webinar below.

Regards,

– Joëlle Kuehn


“It’s Not All Dopamine: Possible Mechanisms and Interventions for Falls in PD” Notes: 

Speaker: Roger Albin MD, University of Michigan Udall Center

Hosts: APDA Minnesota Chapter, Parkinson’s Foundation Minnesota and the Dakotas, Udall Center, University of Minnesota

Date: August 20th, 2020

Summary by Joëlle Kuehn, Stanford Parkinson’s Community Outreach

Problems: Falls, Walking and Balance Problems get more severe as Parkinson’s develops, as seen on the Hoehn and Yahr scale. Soon, these issues, especially balance, start to cause a decline of quality of life.

Interesting: 

  • After 5 years of Parkinson’s, about half of patients will have balance problem
  • 70% of Parkinson’s patients have at least one fall every year, and many Parkinson’s patients have frequent repeated falls. 

Walking: 

  • Walking is a cognitively demanding task, and in Parkinson’s disease some of the systems in your brain responsible for paying attention start to break down, causing you to be more likely to have falls. 
  • Even a minor disturbance and minor slip can cause hospital visits and fractures. 
  • Changes in visual environments (a cloth on the floor or a different colored or leveled floor) and changes in motor systems such as turning can create a freezing episode. 

How they Study it — Positron Emission Tomography (PET):

  • Combination of nuclear physics, chemistry and advanced imaging methods
  • Allows doctors to study specific changes in brain function in living individuals. 
  • Making signal molecules that bind to some target in the brain with very high specificity, and then can use nuclear medicine techniques (radioisotopes) to measure how much of those molecules are bound to specific parts or functions in the brain to quantify that. 
  • Allows them to study basic biochemical and brain signaling processes in living patents.

Dopamine:

  • Major Parkinson’s symptom is loss of dopamine, which is due to the degeneration of neurons in the midbrain (substantia nigra) which results in loss of dopamine being sent to a forward part of the brain called the striatum.
  • The PET method can notice that in living patients because it can measure the integrity of dopamine neurons in the brain of living people.
  • Differences between a non-Parkinson’s patient and Parkinson’s patient are able to be seen in imaging. 
  • This was usually measured postmortem but now it is possible with living individuals with considerable precision.
  • Dopamine is tied to movement

Acetylcholine (ACh)

  • It can measure not only dopamine, but also Acetylcholine (ACh), another important brain chemical messenger. 
  • All acetylcholine comes from a few small groups of nerve cells at the base of the brain which then project diffusely throughout the brain.   
  • Acetylcholine is tied to thinking and memory, especially the ability to focus and pay attention, but cholinergic reductions can also control things like gait and posture.
  • The differences between a non-Parkinson’s patient and Parkinson’s patient are able to be seen in imaging for Acetylcholine. 

Animal Model Experiments:

  • They tried to measure gait and freezing and balance in mice and rats to measure movements and fall propensity
  • Rats walk across a beam but then the test is made more complicated by tilting it, different shapes, have the beam move, and a rotating zig-zag beam. 
  • Additional conditions can be imposed such as a doorway or food as a distraction
  • He experimentally destroys dopamine circuitry and acetylcholine circuitry and sees what changes in the rats behavior from control animals, such as freezing and ability to walk and go on detours for treats.

Interesting fact: He found that using a nicotine-like drug could be useful in reducing falls, as it stimulates the cholinergic neuromodulation. Nicotine is addictive and has unfavorable side effects and only works for a short amount of time, but the pharmaceutical industry has done research on nicotine like drugs that do a similar thing. 

Human Experiments: 

It is difficult to do clinical based trials on falls because although Parkinson’s patients do fall, they don’t fall frequently enough to experiment on, as it would take hundreds of patients and several years to complete.

Before doing a clinical trial, they do a target engagement study, where they see if the drug or intervention actually affects the process that is important in the disease. Questions include: 

  • Does the drug get into the brain?
  • If it does get into the brain, does the drug do what it is supposed to do in order to produce beneficial effects?

They did a target engagement study to see if boosting this particular aspect of the acetylcholine system would favorably affect attention and gait in Parkinson’s disease patients. They targeted the acetylcholine nicotine receptor, and studied that particular system and used PET imaging as a tool to see whether or not the brain will get into the brain and be as effective as they want. 

Drug they used — Varenicline.  Also known as Chantix.  It is advertised to help stop smoking.

  • It is a nicotine-like drug, and has been shown in some age groups to improve attention
  • Very few side effects
  • PET can be used to see if varenicline gets into the brain and works like they think it should. They gave Parkinson’s patients over a few days increasing amounts of varenicline (staying within the amount used for smoking cessation), and looked to see if it gets into the brain and interacts with this particular target like they suspect. 
  • Result: It does make a difference in imaging, that shows it is getting into the brain and is hitting targets that it should, at a dose below what is used for smoking cessation. 

They then did a small clinical study to see if this also helps with gait function and balance. They administered the drug and a placebo to two groups, and then stopped for 3 weeks for a washout period, and then switched which group got the drug and the placebo. They did tests on attention function and gait and balance testing through walking speed and postural stability. The balance tests were measured using sensors, which can measure gait speed and postural stability. 

Next they performed a Sustained Attention Test that focused on the acetylcholine system. A signal is presented and it tells you whether or not to respond to the second signal. Then there is a delay period and then the person gets a cue to make a response, and they have to respond whether there was a signal or not. There is also a flashing distractor. Performance on the task is difficult.

What did they learn?

  • Varenicline is very safe.
  • Well tolerated by Parkinson’s patients
  • Efficacy:
    • Surprising: walked slower.  Note: this could be because they are paying better attention to their surroundings
    • No change in ability to control upright posture
    • Change in dual task walking (walking with a distractor)
    • Better attention seen in Sustained Attention Test

Questions and Answers:

Question: General recommendations for someone who is looking to improve freezing episodes?

Answer: Work closely with movement-disorder neurologists, and be aware of things that precipitate freezing. Cues can be helpful, as well as marching instead of walking. 

Question: Are there any non-medication interventions that can be used for treating balance and falls?

Answer: General health is important, as is exercise. Maintaining fitness routines is very helpful, but it has to be done consistently. We don’t know which kind of exercise is specifically better than others. 

Question: Are there any acetylcholine nicotine-like drugs on the market right now?

Answer: Varenicline is on the market and is safe. I would not prescribe it because there isn’t enough good scientific evidence. There is a lot of interest in the pharmaceutical industry not just in nicotine type drugs, but also acetylcholine type drugs as well, and it may be that there will be some further developments there. Some drugs for dementia have also been helpful for gait problems and balance problems, but they’re not specific for targets in the brain.

Question: Recommendations for foot cramping or twisting?

Answer: It is an example of off-dose dystonia, which is similar to the motor fluctuations seen in advancing Parkinson’s disease where people’s response to medication varies. I recommend working with your treating neurologist to optimize your medical therapy. Deep brain stimulation could also be an excellent treatment. 

Question: What is the downside of increasing a drug you already on (such as carbidopa levodopa)?

Answer: There is no ceiling but it depends on how well you can tolerate it and if you have side effects. 

Question: Thoughts on research on spinal cord stimulation in Parkinson’s disease and the improvements that they’ve seen in their freezing of gait. 

Answer: There is a need for a substantial systematic study on the procedure. The animal model experiments were done very well, so it is an important line of research to pursue. But at this point the clinical data is cloudy. 

Question: Does Varenicline improve focus and cognition as well as balance?

Answer: It improves attention. It won’t improve all aspects of thinking and memory but does improve attention. 

Question: Where is Varenicline in the clinical trial process?

Answer: It is a FDA approved drug for the purpose of smoking cessation, and it’s been used by possibly millions of people world-wide. For this purpose it is nowhere, we would first have to enter the FDA process to see if we can get a clinical trial to see if we can get an approved indication for it. It’s a big undertaking but we’re going to try to pursue in the next couple of years. 

Question: How has your research been affected by the pandemic?

Answer: The primary standard is that we don’t want to expose anyone, so if you were in a therapeutic clinical trial, you would continue in that trial but there were a lot of efforts made to minimize exposure, so any evaluation that can be done remotely was done remotely. A lot of our research is imaging research, so we had to stop because we didn’t want elderly patients with Parkinson’s disease to come to our medical center where they could get infected. We don’t study anyone over 65. 

Question: Do you think that some Parkinson’s patients benefit from medical marijuana for falling and freezing incidents?

Answer: I have no idea and I don’t think anyone else does either. Marijuana does a lot of different things in the brain, including in the basal ganglia which is the part of the brain involved in Parkinson’s disease, although what it does is unknown. These are not products regulated by the FDA and you don’t know who is making them and what’s in them, which carries a risk as well. A lot of Parkinson’s features are worsened by anxiety, it’s a common problem. Anything sedating will tune down the anxiety and make it easier for them to cope but that’s a completely non-specific effect. 

Question: What is the cause and treatment for Parkinson’s related dementia?

Answer: The cause is not a single thing. It varies from different phases of the illness but there are cognitive consequences during the loss of dopamine, but not necessarily dementia. There are more cognitive problems with a loss of Acetylcholine and we have some early data that shows it causes lots of cognition problems. In later disease what appears to happen is the pathology involves more and more of the brain, and consequently there is a lot of cognitive impairment. You will need different treatments for different stages of the illness.