In January 2021, the World Parkinson Coalition (WPC) hosted a webinar on why people with REM sleep behavior disorder (RBD) are often later diagnosed with Parkinson’s disease (PD).  RBD is acting out dreams or moving a lot in the REM stage of sleep.  Normally, during the REM stage of sleep, the body is paralyzed, and with RBD, the paralysis stops working.  Note that sleep walking, talking, screaming is common in the population (one-third), and this is not RBD. 

This webinar featured movement disorder neurologist Dr. Ron Postuma.  According to the speaker, about 80% of people who have the diagnosis of RBD have synuclein-related disorders (PD, Lewy body dementia, multiple system atrophy) at some point in their lives.  The remaining 20% could be due to post traumatic stress disorders, anxiety disorders, or antidepressants.  The determination of which synuclein-related disorder is present is dependent on the pattern of neurodegeneration, as each disease has a different pattern to spread.

Prodromal PD is the stage between pre-clinical and clinical, where the disease is in the brain, but an individual does not have a diagnosis based on motor symptoms.  In PD, the prodromal period is unusually long.  Evidence has shown that there are some symptoms that may occur 10-20 years before the diagnosis.  These include olfactory loss, constipation, orthostatic hypotension, and RBD.  Most of these symptoms are common in people who don’t have PD, so having these symptoms does not mean the person will have PD later in life.  It is the combination of symptoms that can come to a prodromal diagnosis. The only diagnostic marker that is strong enough to happen on its own to make a diagnosis of prodromal PD is RBD.  Interestingly, most prodromal symptoms are non-motor – such as autonomic function, blood pressure, cognitive issues, and RBD – whereas  motor symptoms are required for a PD diagnosis. 

There is a lot of research into RBD, and the next stage is how to treat it.  It is difficult because there is no preventative agent for PD, and finding people for a study who have prodromal PD who don’t exhibit motor symptoms requires screening large groups of people.  There are many medications in the pipeline that are focused on genetics in PD and alpha-synuclein.  Once there are medications to treat disease five years in advance, the clock can be turned back to 10 years, 15 years, and earlier.  The earlier the disease is identified and treated, the slower the progression, and lesser the severity.

For information on PD and sleep, please see this Stanford Parkinson’s Community Outreach webpage: 

PD and Sleep

For a recording of this webinar, please see this WPC YouTube webpage

See my notes below of the January 19th webinar. 

Regards, 

Joëlle Kuehn

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“Prodromal Parkinson’s Disease and RBD: What is the Link?” – Webinar Notes

Speaker:  Ron Postuma, MD, MSc, movement disorder neurologist, McGill University

Webinar Host:  World Parkinson Coalition (WPC)

Webinar Date:  January 19, 2022 

Summary by:  Joëlle Kuehn, Stanford Parkinson’s Community Outreach 

RBD sleep behavior:

• Acting out dreams, but normally you can’t because you are paralzed in that stage of sleep
• Normal state is that people don’t act out their dreams or move in their sleep
• When you have REM sleep behavior disorder, the paralysis stops working  
• It usually stops working because of PD or related conditions
• Not the only thing people do in the middle of the night.  More common: sleepwalk and sleep talk:
  • Common in children and adolescents
  • One-third of population has experienced some form of this
  • Example – scream in sleep
  • RBD is not this
• Bed partners are usually the ones who notice.  Sounds like they’re on the phone.

Does RBD always lead to PD?:

• Do some people get it early in life as a sign they may have PD later?
• About 80% of people who have the diagnosis of RBD have synuclein related disorders (PD, Lewy body dementia, multiple system atrophy)
• 20% could be post traumatic stress disorders, anxiety disorders, antidepressants:
  • If your dreams are horrible or aroused enough, you can still act out your dreams
  • They may have a family history of this

Do you need to go to a sleep lab to diagnose, or is a patient’s description enough?:

• Depends on the situation   
• If someone has PD, and their story fits what I’ve hear all the time and fits the standard description, it usually is RBD
• If you have PD, you have a 50/50 chance of getting RBD
• If you are someone who has no other health conditions, there are other explanations that could be present
• Even if the other explanations only accounts for 20%, given that only 1% of population has the condition, it’s important to explore all possible disorders
• If someone has PD and the symptoms match, you usually don’t do a sleep study or further testing, if it fits
• If it is isolated and does not fit the standard, that is cause for further testing and look further

What are the different stages of PD?:

• At-risk state: factors like having PD genes that make you at risk for PD, but not exhibiting any symptoms
• Pre-clinical: disease is in your brain, but so far no symptoms, no signs, no need for intervention, but will have in the future for sure, and it will to have an impact.  Would only see on scans
• Prodromal: between pre-clinical and clinical, can be a very long time
• Clinical – doctor tells you you have PD based on motor symptoms like tremors or rigidity
  

What is prodromal PD?:  

• Some sign or symptom that shows the disease
• The disease is there enough that it is causing something
• Not at threshold yet where doctor makes a diagnosis
• In PD, the prodromal phase is very long.  On average, over 10-20 years on average 
• Many symptoms you can get in prodromal phase
• Most common is olfactory loss
• Olfactory loss is also what presents itself earliest, around 20 years before diagnosis.  Happens gradually
• Constipation, orthostatic hypotension, having to urinate more often, erectile dysfunction
• These are also common in people who don’t have PD, so having these issues does not mean you will have PD later in life:
  • It’s a combination of all of these symptoms that give you the prodrome
  • Add up all things that are diagnostically strong markers, and you can come to a prodromal diagnosis
  • Once put everything together, can get pretty high confidence that someone has it
• Only diagnostic marker that is strong enough on its own to make a diagnosis of prodromal PD is REM sleep behavior disorder:
  • Everything else is non-specific
  • 80% of time, it’s PD
• Interesting that many of the prodromal symptoms are non-motor   
• Disease is starting in olfactory areas, and areas that control autonomic nervous system, like skin, colon, salivary glands… not necessarily the brain

How much do you buy into the idea that there are different types of disease starting in different places?:

• How do we understand how RBD relates to a different types of disease
• Different types of disease: PD, dementia with Lewy body, multiple system atrophy
• Different types of diseases each have a different pattern to spread 
• There is a different pattern of neurodegeneration
• I don’t know what the right answer is on that

Where in brain is the critical pathology in RBD?:

• Probably in two areas
• Most common are in the Pons, near the midbrain, around the locus coeruleus:
  • Involved in transmission of noradrenergic
  • Area is the flip-flop switch that switches you in and out of paralysis during sleep
  • There is a circuit with the nucleus medulla
  • It’s a brain stem degeneration, lower than the motor areas, and earlier in the disease process

Areas impacted during prodromal PD:

• Autonomic function
• Blood pressure issues when you stand up
• Gait dysfunction
• Cognitive issues
• REM sleep behavior disorder
• Note: when see these in combination, it is most likely prodromal PD
• Treating RBD doesn’t make a difference in the other factors

Why do some people get PD, and others get dementia with Lewy bodies?:

• RBD is a sign that the synuclein is present
• They both have the same protein – alpha synuclein
• Lots of possibilities:
  • 25% of people over 80 have early changes of Alzheimer’s in our brain   
  • Dementia with Lewy Bodies is when you have PD and Alzheimer’s at the same time
• We don’t have a complete idea of why that is the case                

    Next stage in research – how to treat:

• When drugs are being developed to treat PD, it makes sense to develop them for before the person even gets clinical PD or dementia
• Difficulty is actually doing this
• Difficult because we don’t have a preventative agent for PD:
  • A reason for this that by the time you have PD and it’s diagnosis, the disease is established and we may have already missed the chance to make real differences in some of the symptoms
  • Another is that we don’t have drugs that are good enough
  • Lots of medications in the pipeline that are exciting and focused on genetics of PD, and synuclein                
• Next step is taking medications we know should be used early, and convince pharma companies and government agencies with funding to invest and try the medications     
• Research is expensive, and takes time, and would be a long trial (can be up to 15 years)
• Future of PD research is going to people who are stratified to be at a high risk of developing a synucleinopathy within the next 5 years and treat:
  • If that works, can roll the clock back to within the next 10 years, within the next 15 years
  • This can help slow down disease progression, the earlier you treat, the slower the progression

NAPS study with NIH:

• North American Prodromal Synucleinopathy 
• Formal large study, run big trials, follow patients

Also part of smaller studies:

• Bunch of people who do research in area who get together 
• Bounce ideas and try to combine forces
• PD is not uncommon, 1% of the population has the diagnosis.  Not everyone who has these symptoms goes to the doctor and receives a diagnosis.  People may think symptoms are normal
• Not every sleep center or hospital has enough patients with PD to conduct a study
• Smaller studies/projects combine patients and projects 
• Having researchers combine forces and data and projects allows for more research
• Sharing data collected from patients allows the ability to answer questions that normally can only be answered by research studies with thousands of people
• Idea is to have a network ready so that when a therapy comes along, it is easier to roll it out
• Enough patients in the world now to run 2-4 pharmaceutical trials at a time
• First one to do it has the easiest job finding people because they have a directory and second trial would get leftovers

Arguments are very persuasive and positive… where is the resistance?:

• False assumption/belief: companies may not get FDA reimbursement/license for disease modifying therapies.  If you have convincing science, FDA will read the literature and you have a good chance
• Reluctance because no one wants to be the first
• We don’t want to be the one who makes all the mistakes when we do it the first time.  No one wants to be first, because they will make mistakes and those are expensive
• We have to show companies that it’s not as risky, and that it’s worth it

How can you screen the general population for a trial for prodromal studies where there aren’t necessarily any symptoms?:

• Can’t bring the whole general population into a sleep clinic
• There are personal devices like Apple watches and FitBits that monitor activity.  Some monitor EEG activity, brain activity in the sleep
• Are there clever ways to diagnose prodromal conditions in the community?  Should we be screening the general population before a therapy is available so we have a list of participants once a therapy is available?  Don’t do until there is a disease modifying therapy 
• It is easy to screen for RBD if you are aware of it:
  • Speaker put out an ad asking for people who move a lit and kick in their sleep to call a number, someone screened those people who called, and 70% of the people they could screen via phone had RBD
  • If you are aware of it, you can screen no problem 
• Difficult part is then once people are in the clinic and being able to diagnose masses of people at one time:
  • These people need some sort of monitoring to determine if they are asleep, what stage, etc. 
  • If this is thousands of people who respond, there isn’t always the capacity to do that
• If we want to identify RBD in the community, we are required to have other devices which directly record brain waves and muscle tone, as opposed to just movement