This transcript has been edited for clarity.
Indu Subramanian, MD: Hi, and welcome to Medscape. We’re so excited today to be talking to Professor Ronald Postuma. He’s a professor of neurology at McGill University. I am Dr Indu Subramanian. I am a professor of neurology at UCLA, and I run the Center of Excellence at the West Los Angeles VA for Parkinson’s Disease.
Welcome, Ron. We’re very excited to cover some areas, especially around prodromal Parkinson’s disease; touching on REM sleep behavior disorder, which has really been something that you’ve been a world leader in; and finally touching on some very new classification systems and some of the new ways that we’re thinking about a biological definition of Parkinson’s disease. Thanks for agreeing to talk to me today.
Perhaps you could just define a little bit about prodromal Parkinson’s disease.
Prodromal Parkinson’s
Ronald B. Postuma, MD: When we think of Parkinson’s disease, we classically think of tremor. In fact, tremor is probably the least important symptom. It’s mostly slowness, stiffness, and difficulty walking — that’s Parkinson’s disease. By the time you show up in a doctor’s office with Parkinson’s, on average, you’ve had the disease in your brain for somewhere between 10 and 20 years, or even more than that.
There’s a whole period where the Parkinson’s pathology is progressing and you have no symptoms or signs. After that, you start to develop some early symptoms and signs. For a period, probably on average, 10-15 years, you have subtle symptoms and signs of Parkinson’s disease, but you’re still not ready to be diagnosed with Parkinson’s disease by a doctor. That’s what prodromal Parkinson’s is.
Subramanian: What kind of signs and symptoms are we talking about?
Postuma: They follow an order. Probably the most reliable early thing that you can get is loss of the sense of smell. Maybe 20-25 years before, there’s often very gradual loss of sense of smell and people are completely unaware of it, at least half the time. Family members will sometimes know it, but people will say, “Oh, I never smelled well.”
Another one that happens, but is very nonspecific because many people have this, is constipation. If you look at people who are constipated in their 30s, they have an increased risk of developing Parkinson’s. Is it a prodromal factor? Is it a risk factor? Who knows? There are a few other things, like people who have depression or anxiety have an increased risk for Parkinson’s disease.
The one that I mostly work on is called REM sleep behavior disorder. That’s really unique because it’s so powerful. Normally, when you or I dream, we’re supposed to be paralyzed and we’re not able to move when we dream. If you dream you’re running and the legs don’t work, or you’re dreaming that you’re trying to yell and your voice isn’t coming out, that’s your body going, you’re trying to run and something’s wrong. Your legs aren’t working. That’s the normal thing.
People with this condition lose the ability to be paralyzed, and so whatever they dream, they do. If I’m dreaming about speaking in a lecture like this, my wife will hear it. If I’m running in in my dream, I’ll be making running movements in bed. That’s REM sleep behavior disorder.
It turns out that probably on the order of 80% of people who get this condition in their 40s, 50s, and 60s in fact have Parkinson’s at an early stage. They’ll either get Parkinson’s proper, as we classically define it, or they’ll get dementia with Lewy bodies, which, of course, overlaps with Parkinson’s almost completely in many cases, or sometimes multiple system atrophy.
Everything else is rare, at 1% or 2%. Really, most people with this disorder get Parkinson’s. That’s what we’ve been studying for a long time.
Subramanian: You said 80% go on to develop Parkinson’s. What do the other 20% with REM behavior disorder end up getting?
Postuma: Of course, that’s 80%, assuming you survive long enough. When we follow over, say, 15 years, you can see a curve that just keeps going down. It never actually levels off. At 20 years or 25 years, is it at 100%? Some people think so. I don’t think there’s such a thing as 100% in life, but it’s a large majority.
You can get rare other conditions. If you have a stroke in exactly the same territory that’s affected by the Parkinson’s or multiple sclerosis plaque in exactly the same territory that is responsible for keeping you paralyzed when you dream, sure, you can act out your dreams, too. We are now recognizing these very rare antibody-mediated syndromes: the CASPR2s, the LGI1s, and IgLON5, which is probably the most important. These are uncommon conditions, but maybe about 1% of REM sleep behavior disorder patients have that as a cause.
After that, there’s a little bit of posttraumatic stress disorder, a little bit of antidepressant-induced disease. I think some of those really won’t get Parkinson’s over time. Then, of course, there’s a vast category of things that are not really REM sleep behavior disorder, but something else that sounds like it, like sleepwalking, sleep talking, or snoring yourself awake when you have apnea, which of course doesn’t apply at all. It’s 80% of people in a lab with a diagnosis of REM sleep behavior disorder get something like Parkinson’s.
Subramanian: Your work has historically been following sleep studies in populations and then seeing who converts to having Parkinson’s disease over time. Can you tell us a little bit about that work?
Postuma: We started this about 20 years ago. I was doing a fellowship in Toronto, and we were aware of this group in Montreal that had a bunch of REM sleep behavior disorder patients with Jacques Montplaisir. I called him up and said, we need to follow these patients because it looks like many of them — maybe 10%, 20%, or 30% — are going to get Parkinson’s. What a great opportunity to watch. We didn’t know the answer was 80% at that point.
What we did originally was try to look at everything else, these other things that I talked about. We tested their sense of smell. We checked their motor state. We did some cognitive assessments. We just kept following them year after year after year. As time has gone on, we’ve realized that it’s almost all of these people, in fact, who have converted to having Parkinson’s.
What we’ve been able to do is map out the changes over time. This whole thing I told you about olfaction first and then constipation, that comes partially from these studies where you can see that, right when I see the patients, their olfactory sense is already gone. It does seem to progress slowly, and if you draw the curves back, it looks like it starts about 25 years before.
Clearly, we start to see subtle motor abnormalities developing 5 years before and cognitive abnormalities also about 5 years before, or 7 years before maybe, maximum. Directly witnessing a person gradually get Parkinson’s in front of our eyes over 10-15 years, we’re getting a picture of how this disease starts.
RSD Tests and Treatments
Subramanian: Very interesting. When you have a patient like this in your office, acting out their dreams or fighting in their dreams, what would be the studies that you would order? What do you tell them?
Postuma: The most important thing is that not everyone who says they act out their dreams at night has REM sleep behavior disorder. Like I said, including sleepwalking and sleep apnea, there are many mimics. If you know how to take a history, I’d say you’re right 80%-90% of the time. It’s really very classic. Usually, the spouse will tell you about it.
They need a bed partner who will tell you that they’re acting out their dreams — exactly that. They don’t walk. They stay in their bed most of the time unless they throw themselves out of bed. They don’t get out of the room like a sleepwalker might do because they can’t, because their eyes are closed. There’s a very characteristic history.
That’s generally not enough to make the diagnosis. You need to confirm it, and that’s generally with polysomnography. That means they sleep overnight. You don’t need to see them dream. You just need to see that they’re not paralyzed when they dream.
They go into the REM sleep. There are electrodes on the chin or on the arms, and you can see that the loss of tone that they’re supposed to have is gone. They continue to have tone. You’ll often see them acting out dreams or making little twitches at night as well. That’s the diagnosis. When you’re there, now you’re talking to a prodromal Parkinson’s patient.
Subramanian: Wow. You’re effectively already telling them that they have prodromal Parkinson’s.
Postuma: In the old days, before this hit the internet and everyone started knowing about it, it would be a more difficult conversation to raise the issue, saying “By the way, this is associated with other neurologic disorders, things like Parkinson’s. I think I should keep an eye on you.” That would be news to them.
I must say, that’s almost never news to them now. When I see them, they’ve gone on the internet, they’ve looked all over, and they come in terrified that they have Parkinson’s. It’s a bit of a different conversation.
Terrified maybe isn’t the right emotion to be experiencing, but certainly concerned. They probably do have Parkinson’s or dementia with Lewy bodies — same thing, again — or multiple system atrophy, much worse. It really is important to keep following these people because things are going to happen. You want to be there for them when it happens.
Subramanian: Are there interventions or changes in their lifestyle or any other sorts of things that you tell them to start doing at that point?
Postuma: Unfortunately, not particularly. That’s one of the most difficult things. I do tell people to get a large amount of exercise. Exercise is certainly good for your health in general, for sure. There are some suggestions that exercise could protect the neurons from degeneration. I don’t know if that’s true or not, but the suggestions are certainly very interesting. That is very obvious advice.
People should lead a healthy lifestyle. I don’t give them particular interventions on diet except for eating healthy. I don’t think we have the evidence base to really say, as a physician, I am telling you need to eat this or eat that or do this or do that. I think we need a very high level of evidence before we start using the authority of a physician to tell people to make changes in their life that might have impact otherwise.
The most important thing is I say, I’m seeing you once a year no matter what. You’re in a research protocol now. If you want to quit, it doesn’t matter. Come back and see me. When you start saying, I’m too tired to come in, I can help you. I can give you levodopa. I can treat your constipation. I can give you a selective serotonin reuptake inhibitor (SSRI) for your depression or a cholinesterase inhibitor for your cognitive impairment. There are actually many things you can do for Parkinson’s, so it’s very important to follow these people.
Subramanian: Are you treating their REM behavior disorder when you’ve identified it?
Postuma: There are a few treatments that you can use. You don’t have to. If they just notice it, and they came in and have no risk for injury, then you can leave it alone. The only consequence of REM sleep behavior disorder, as near as I can tell, except for maybe it wakes you up once in a while and they can’t fall back asleep, is injury. Falling out of bed, and most important, hitting your bed partner is actually probably the biggest risk for injury. They may also throw something across the room, shattering things.
If the bed environment is safe, you don’t need any medications. We sometimes use melatonin. We sometimes use clonazepam. Clonazepam certainly helps. Melatonin might help. We don’t really know. They have side effects, so we use them with some caution, I must say.
Subramanian: Is exercise also impactful for the REM behavior disorder?
Postuma: It’s good for your general health, but it doesn’t affect the actual sleep.
Subramanian: You mentioned also the people who might present with REM behavior disorder who are on medicines that may influence it. Are there medications that you screen for and take people off of?
Postuma: It’s basically the antidepressants. Antidepressants are motor activators, so they help you move more in general, but particularly in sleep. Quite commonly, an antidepressant will trigger REM sleep behavior disorder that was always there but just not in its full expression. Sometimes withdrawing the antidepressant can reduce the REM sleep behavior disorder, assuming the patient doesn’t need it.
One note of caution: REM antidepressants — SSRIs, for example — also reduce REM sleep. There can be a period of a few days where there’s a rebound and they have more REM sleep. Actually, that’s a little bit more dangerous during that time. We withdraw them if they’re not needed. Of course, if a person needs an SSRI for their bad depression and their REM sleep behavior is not a big deal, then they can continue it.
Parkinson’s SynNeurGe Staging
Subramanian: Pivoting now to the new frameworks that we’re talking about, there’s been a large amount of new information coming out about gene testing, imaging, but also most recently synuclein measurements and seeding assays. You also, I noticed, are an author on a paper that just came out in The Lancet about the biological classification of Parkinson’s.
Postuma: This is sort of a conceptual shift. You start thinking, so now they have Parkinson’s. They have a bunch of symptoms before Parkinson’s. First, it’s motor symptoms that are early. Then it’s olfactory symptoms that are early. You keep pushing it earlier and earlier. Maybe we need a paradigm shift completely.
If we had cancer on the bone of our arm, we would not say you only have cancer if your arm hurts if you have a pathologic fracture. You have cancer if you have cancer. Similarly, with diabetes, we don’t wait until severe urinary incontinence because you have so much sugar in your urine before we diagnose diabetes. We go and look for diabetes.
A disease is not classified by its symptoms necessarily all the time. Neurology has always followed the process of we wait for a person to get symptoms, then we define a disease. About 2018, there was a complete shift in Alzheimer’s from being an amnestic syndrome of cognitive impairment that’s due to Alzheimer’s pathology, to Alzheimer’s pathology and then let’s go look for the amnestic cognitive impairment and then stage it. You can make a diagnosis of Alzheimer’s disease in a person who does not have dementia, for example.
A similar process has been happening in Parkinson’s disease. The big thing that’s changed this is the presence of new diagnostic tests. The most important diagnostic tests are the synuclein assays. Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, for that matter, are what we call synucleinopathies.
An abnormal protein called alpha-synuclein is deposited in your brain. We think that’s what probably causes the damage. Regardless, it certainly marks a certain type of damage that is Parkinson’s disease.
Now we can take a bit of your cerebrospinal fluid (CSF), we can take a bit of your skin, we can probably even take a bit of your blood and document that there is this abnormal synuclein present. That changes the game, doesn’t it? We’re not going to wait for clinical symptoms. We can say, you have synuclein in your brain. This is not normal synuclein. Maybe we need to start thinking that you may have a very early phase of Parkinson’s disease.
That has many challenges. How many people have synuclein who are walking around who will never get Parkinson’s disease? Well, maybe we need another level. Maybe we need to show that the synuclein is having some consequences and some neurodegeneration associated with it.
One of the staging systems that we are involved in, we did exactly this. This is the SynNeurGe staging system. That’s the one I’ll talk about most because I’m most familiar with it. The idea is that we can biologically define Parkinson’s on the basis of diagnosis of a synuclein deposition (“syn”), whether that be in the CSF, the skin, or these other varieties of ways.
Then we document that it has consequences. “Syn,” “neur,” neurodegeneration associated with it. That might be a DaTscan. That might be some of the other scans that we have. With those two things, you can actually make a biological definition of Parkinson’s disease.
After that point, you can say, well, does this person have clinical symptoms? That constipation that they have, is that just constipation or is that actually Parkinson’s? Has it been Parkinson’s all along?
It’s a real shift in the way that we do this. The system that I was involved in is SynNeurGe — “syn,” “neur,” and “ge,” genetics, which (not to get too into the details) is another way of making a diagnosis of Parkinson’s in people who don’t have synuclein. The details are not important, but it’s a conceptual shift that’s important.
Just like we don’t wait till a person has too much urine before we diagnose diabetes, maybe we need to think about Parkinson’s like that. When we start thinking about Parkinson’s like that, maybe we can start preventing Parkinson’s. We don’t have the drugs yet, but maybe we don’t because we’ve been waiting for too long.
Subramanian: There has been some controversy in this field. We don’t know how much normal synuclein is still there because two patients can be very different with different reasons for their elevated synuclein. Whether it actually says for sure that you have Parkinson’s, I think, is still controversial in our field. It sounds like you’re quite defined in your thoughts about this.
Postuma: There are two aspects to it that you have to distinguish. One is, do we think excessive synuclein is damaging to the cells? That’s a biological question. I personally think it is. If you are born with a gene that will give you more than the absolute normal synuclein that we all have, all this gene does is increase your normal synuclein; you are guaranteed to get Parkinson’s. That’s as good evidence as I can think of that synuclein is important in the pathophysiology of Parkinson’s disease.
We don’t even need that. It is an astonishingly good diagnostic test. For example, if we take a person who has parkinsonism and we do these synuclein assays, something like 95% will be positive on that assay. The ones who don’t will usually have an alternate explanation, like they have a gene that is associated with Parkinson’s without synuclein.
If we take those who have the olfactory loss, which is that superdiagnostic test, we’re looking at 98% of people. When you have a diagnostic test that’s that good, it starts to change the way you need to think about how you diagnose the disease. If you’re walking around, you have an abnormal synuclein and you have neurodegeneration that we can document, maybe you have Parkinson’s. Why do we have to wait until you have a tremor before we say you have Parkinson’s?
I really think these diagnostic tests have changed things. For now, they have not changed my clinic. I do nothing differently in my clinic. I see people who come in with a tremor, with rigidity, and I don’t do any synuclein tests because it doesn’t change anything, really. We don’t need them clinically right now. I can give you levodopa, I can treat your symptoms, and you can be better.
When we have a neuroprotective therapy that, say, targets synuclein, we have a synuclein-reducing agent, we have a synuclein aggregation inhibitor, or we have a GBA inhibitor, if we have any one of these other neuroprotective agents, now the stakes are different. Now we really need to know, do you have the pathology in your brain — not just do you have tremor, but do you have a pathology that means that I’m going to give you this drug, which is going to cost $20,000 a year and requires an intravenous infusion once a month for the rest of your life?
I better make sure you actually have the underlying pathology, that we’re not wasting everybody’s time and everybody’s money. I think that’s really where things are going to change. These diagnostic tests are going to start changing clinical practice when we have disease-modifying neuroprotective therapies.
Subramanian: One last question. For the REM sleep behavior disorder patients that you’re following forward, is there at all a sense that these sort of tests would be useful in that population?
Postuma: You almost don’t need them to make a diagnosis because it’s that high. Let’s take their REM sleep behavior disorder, and let’s add olfactory loss. You put those two things together, and you’re in the 95% territory already. Throw in a little bit of motor abnormalities, throw in some constipation, and we’re looking 98%-99% certainty.
I actually don’t need those tests in my practice, even now. Will they be useful? Well, it’s going to be useful maybe in the future. Again, it’s the same conversation as in Parkinson’s. Why do we have this artificial boundary between a REM sleep behavior disorder patient and a full Parkinson’s patient? That’s a completely artificial boundary.
These people have synuclein in their brain. They have neurodegeneration that causes their REM sleep behavior disorder. Whether they have a tremor now or whether they’re demented now doesn’t change the fact that I’d really like to do something about this, the earlier the better. When neuroprotective therapy becomes available, yes, I think I’m going to get that skin biopsy. I’m going to make sure it’s really synucleinopathy before I commit them to a lifetime of therapy.
Subramanian: This has been a great discussion. We look forward to hopefully neuroprotective therapies that we can apply to these patients, given all these new ways to detect people earlier and earlier.
Postuma: Absolutely. Thanks very much.
Subramanian: Thank you.
Indu Subramanian speaks with REM sleep behavior disorder expert Ron Postuma about when RSD is prodromal Parkinsons’s disease and new strategies to classify PD.
