Dr. James Beck 0:00
Welcome to our final expert briefing for 2022. Our topic today is Let’s Talk About Dementia. I am your moderator, Jim Beck, the Chief Scientific Officer of the Parkinson’s Foundation, and I want to welcome everyone here. As we get going, I just want to orient everyone to the screen so you have an understanding of the different features that are being provided as part of our webinar series. At the bottom of your screen on the left, where the arrow is, there is a chat button.
The chat button is where my colleagues will be putting information for you about the webinar or links that may be of interest to you. This will be where we will share a link to the PDF of our webinar in case you want to print out the slides. We’ll have that kind of information available.
To the right of it is the Q&A, and this is where you’ll ask your questions that we hopefully will be able to get to today with Dr. Leverenz talking about dementia. We’ll ask as many questions as we can. If there are questions we can answer through our Helpline, we’ll certainly do so. For those of you who are new to Zoom, maybe in a noisy environment or maybe even have a hard time hearing, there is a live transcript. This is a computer-generated transcript. It’s not perfect, but it’s not bad either. It’s a good way to start, for certain, to follow along with our webinar.
As we start, I’d like to pause for a second before we begin to share a little bit about the Parkinson’s Foundation. The Parkinson’s Foundation is a nonprofit focused on bettering the lives of those living with Parkinson’s through improving care and advancing research. Importantly, everything we do is done in concert with our community to ensure that our actions are aligned with the needs and priorities of those living with Parkinson’s disease, which is why we have surveyed the community to understand what we should feature as part of our Expert Briefing series. In particular, we are focused on improving care for those living with Parkinson’s disease, advancing research toward a cure and empowering our global community. We do that empowerment through education events just like this one.
Again, for your convenience, I want to highlight that we’ve recorded this Expert Briefing, so it’ll be archived on our website and available in about a week’s time. As I mentioned, the slides are available for download via the chat. My colleague Danielle has just placed it in there, so for those who may want to follow along later, we certainly welcome you to do so.
I also want to get a sense of who is listening today. Let’s just talk about that with a little poll, getting to know you. If you’re following on Facebook, feel free to respond in the comments section about who you are. Are you a person with Parkinson’s, a spouse, a family member? Maybe you’re a clinician listening to this as well. This would be really great information that we can compile together to really get a sense of who our audience is as part of that.
Let’s see where we stand with our results. Not surprisingly, a lot of people are really directly touched by Parkinson’s, either living with the disease or a spouse or care partner as part of that. Welcome, everyone, to our call.
What I’d like to do now is introduce our presenter, Dr. James Leverenz. Dr. Leverenz is the director of the Cleveland site of the Lou Ruvo Center for Brain Health and is the Jane and Lee Seidman Endowed Chair for Advancing Neurologic Research and Education.
Dr. Leverenz has a long research interest in aging-associated neurological conditions, particularly the Lewy body dementias, which include both Parkinson’s disease dementia and dementia with Lewy bodies. Dr. Leverenz serves on the Scientific Advisory Council of the Lewy Body Dementia Association and is co-lead of the recently renewed NIH-funded Dementia with Lewy Bodies Consortium. With that, I would like to welcome Dr. Leverenz. You can go ahead and share your slides, and I look forward to your presentation.
Dr. James Leverenz 4:31
Thanks, Jimmy. Can you hear me well?
Dr. James Beck 4:34
Yes, we can.
Dr. James Leverenz 4:35
Okay. Let’s see if I can do this right. Can you see my slides well?
Dr. James Beck 4:47
Yes. Thank you.
Dr. James Leverenz 4:48
Okay. Well, let’s get started. Thanks for the introduction, and welcome, everyone. I was asked to talk a little bit about dementia and Parkinson’s disease in particular, and I broadened the topic slightly to include the whole spectrum of Lewy body disorders. I’ll give you a little bit of background on what that means. Just some minor disclosures, both consulting for Citibank and a company called Vaxxinity.
My purpose today really is to talk about, first of all, definitions, so we make sure that we’re talking about the same thing at the same time. There are a lot of issues around nomenclature in this area, and we want to be sure that we’re all using the same terms as best we can. I’ll talk a little bit about Lewy body-associated dementias, including definitions of things like mild cognitive impairment and what dementia really means, because I think there are a lot of misconceptions about dementia, what it means and how severe it is.
I’ll talk a little bit about at least some of my personal treatment approaches to dementia and Lewy body disorders, and a little bit about research, our consortium and some of the other activities that we have.
Let’s get started. First of all, what do we mean by dementia? Really, what we mean by dementia is that we have a change in thinking skills or behavioral changes that interfere not only with a change from previous level of functioning, but with the ability to function independently. I’ll ask a really simple question for a lot of my patients and their families: if a family member needed to leave town for a couple of days, from a thinking point of view, would that person be able to take care of themselves for that timeframe? That gives you a practical approach.
It’s not only the change in thinking skills, but also that ability to function independently, at least for some time, that’s outside of the motor symptoms. That’s kind of where dementia comes from. If you think about it, what that means is that there are a lot of people who fit the dementia criteria but are actually pretty independent. A lot of patients, maybe the spouse leaves for the day and they come back in the evening, and they fix meals, but they would feel a little uncomfortable having to leave them for several days.
Dementia, while it has a horrible connotation to it, I think it’s important to recognize there are people with mild dementia who can do a lot on a day-to-day basis.
Another term that we’re increasingly using is called mild cognitive impairment. That’s really different from dementia in that it shows that people have a change in their thinking skills or a behavioral change, but it’s not really interfering with their day-to-day functions. It’s at a pretty mild stage. Part of the reason for coming up with this term early on, and still, is we want to identify people at the very earliest stages, not only for practical purposes of adjusting lifestyle, etc., but also as we hopefully get into an area where we start to have disease-specific therapies, so that we could intervene at a very early stage of disease.
I think we’ll talk a little bit about even maybe ultimately trying to identify people before they develop actual symptoms, and interfere because we know the process can go on for several years ahead of time. Think about dementias where it’s interfering with some normal day-to-day activities for that individual, whereas mild cognitive impairment is where they have a change in thinking skills, but they’re really practically still functional at home.
Dr. James Leverenz 8:55
I think many people here are quite familiar with Parkinson’s disease. This is one of the original drawings about Parkinson’s. We think about the resting tremor, the increased tone, the slowness of movement, the postural instability.
It was really Friedrich Lewy who originally described some of the pathologic changes, wasn’t sure that it was linked to Parkinson’s disease, but described the Lewy body inclusions that we link to Parkinson’s disease pathology. I’ll screen here for those of you. Actually, tell me, can you see my moving arrow there, Jim?
Dr. James Beck 9:39
Yeah, so we can see your mouse.
Dr. James Leverenz 9:42
Okay, great. This is a part of the brain, the substantia nigra, or black area, basically, where we see pigmented neurons. Many of you may be quite familiar with that. This provides the dopamine into the brain that is important in movement disorders like Parkinson’s disease. On the right is somebody who’s passed with Parkinson’s disease, and they’ve lost those neurons. They’re dying, and that’s why we lose that dopamine that we supplement with the dopaminergic medications.
If we look at that area under the microscope with special stains, what you can see is this is a pigmented neuron in the brainstem, in the substantia nigra. That’s what makes that area dark. This is the nucleus that contains the DNA. What you can see is this circular object here with a halo around it, and that’s a classic Lewy body that Friedrich Lewy originally described, and that we link so strongly to Parkinson’s disease, but also another disorder called dementia with Lewy bodies that we’ll describe in a little bit more detail later. That’s the Lewy body.
I like to use the term Lewy body disease to cover all the diseases that actually can have Lewy body pathology in the brain. We’ll again talk a little bit more about that, Parkinson’s being certainly one of the most major ones.
It was more in the recent past, not very recent, but recent past, that we found that Lewy bodies seemed to contain a protein called alpha-synuclein. Alpha-synuclein, the reason we thought it was important, was because we were discovering mutations that caused certain forms of familial Parkinson’s disease. These are mutations in the gene that makes that alpha-synuclein protein that I have underlined here, and duplications of alpha-synuclein. Instead of having normal two copies, three and even four copies, people were at a high risk for developing a Parkinson’s-like disease, either dementia with Lewy bodies or Parkinson’s disease dementia.
When we went back and developed antibodies to this protein, we realized all those Lewy bodies that I showed you earlier actually contained that alpha-synuclein protein in them. Often, those of us who work in this area will call them synucleinopathies, so a synuclein pathology. It did, from a pathologist’s point of view, allow us to actually detect Lewy bodies in a very early stage and see that the changes were more extensive than we had anticipated using the older stains that have been around for many, many years.
Using those antibodies, you can now see on this picture here, this is one of those haloed Lewy bodies where we’re staining that alpha-synuclein protein. For example, now we can see that many of these Lewy bodies are actually what we call multilobulated. It’s like grapes. We can also see there are processes that contain that aggregated protein of alpha-synuclein. That helped us as pathologists to see the detection of the changes, and start to see how it might involve other areas of the brain that are important in memory and thinking skills.
It’s also important when I talk at the very end here about biomarkers for Lewy body diseases, in that we’re starting to be able to detect that aggregated alpha-synuclein that’s in the Lewy bodies in body fluids. Right now it’s in spinal fluid, but we’re also looking to see if we can detect it peripherally as well in the blood.
Dr. James Leverenz 13:31
When we add people up who have cognitive changes, dementias, in that sort of Lewy body dementia category, there are actually about 1.4 million Americans that fit this category. That includes people who start with a dementia syndrome, so they start with a cognitive issue, and we call that dementia with Lewy bodies. People who have Parkinson’s disease and then later develop dementia, we call Parkinson’s disease dementia. Then we also have noticed, and some of my early work was, that we often see Lewy bodies in people with Alzheimer’s disease. I’ll show you that data in just a second here, but almost 50% of people with Alzheimer’s disease have some Lewy body pathology in the brain.
Why is it important to make this diagnosis? Number one, a lot of people get a misdiagnosis, especially dementia with Lewy bodies. We want to be very careful with certain medications, as I’ll talk about later. We see hallucinations as a common side effect of this disease, but we want to avoid certain kinds of medications like the old antipsychotics, like haloperidol. I think a lot of families and patients are really quite distressed because they don’t know exactly what’s going on, and understanding and having knowledge about this can be very helpful.
Another area that we’ve looked at, this is a study I did a number of years ago, as you can see, actually almost 20 years ago. Boy, I’m getting really old, Jim. What we see in community samples of dementias, in the orange here on the right, is everybody who has Lewy body pathology who has a dementia diagnosis in a community-based sample. This was work I did when I was in Seattle. What you can see is about 50% of people have Lewy body pathology at autopsy when we bring them to autopsy. Many have coexistent vascular disease or Alzheimer’s, some pure Lewy body, but what we can see there really is that it’s a very frequent pathology that either exists alone or with other changes in the brain, in the aging brain, and causes dementia syndromes.
We’ve already seen that slide. Let’s go through the different Lewy body dementias. We’ll start with Parkinson’s disease dementia because I think this group is mostly interested in that, but we get this association.
We have diagnostic criteria for Parkinson’s dementia, and really what that means primarily is somebody has established Parkinson’s disease, classic motor symptoms, that sort of thing, and then later develops a cognitive impairment that’s sufficiently severe that it’s dementia.
As we described that earlier, I think about it very simply. A lot of patients I’ve seen with Parkinson’s dementia, they’ve been plugging along with Parkinson’s for five, 10, 15 years, and now they’re developing some pretty significant cognitive changes, and we’ll put them in the category of Parkinson’s disease dementia. We assume during life that the underlying pathology is those Lewy bodies I described earlier and that they’ve started to spread to other areas of the brain that are important in thinking skills and not just the motor symptoms that we see.
For many years, we didn’t really think that dementia was common in Parkinson’s disease. Really, a seminal study from Dag Aarsland, who’s Scandinavian, as you might imagine with that name, when he looked longitudinally at a group of Parkinson’s patients over a period of 15 years, he noticed the increasing frequency of dementia as you went further into the disease. This, of course, is a number of years, but you’re talking about 60 to 80% of individuals with Parkinson’s fitting that criteria for dementia by 15 years of disease.
This is kind of an eye-opener for many of us because I think most of us thought cognitive changes were mostly driven by the motor symptoms. But in fact, when we looked at it more carefully, it looks as if there really is an increased risk for dementia as the disease goes along.
A subsequent study he did in a similar cohort of patients was that he saw that early on in Parkinson’s disease, you can see some mild cognitive changes that fit more into that mild cognitive impairment I mentioned earlier. These are individuals that are maintaining their day-to-day activities of classical Parkinson’s disease in terms of symptoms, but now are developing some difficulties with mild cognitive impairment.
Dr. James Leverenz 18:39
I think just to quote Dag, these findings really highlighted that cognitive impairment can be a key feature from the time of diagnosis. What I hear from a lot of patients that I’ve seen is they notice that their processing speed might be slower, so they don’t go through things quite as quickly, or they might not multitask as well. Nobody truly multitasks, right? We switch from subject to subject, and that switching can take a little bit longer. It doesn’t mean that they can’t continue to do normal day-to-day activities that they normally do, but they may have a little bit more struggle with that multitasking and with the speed of processing. This is something that I’ve certainly noticed over the years as I’ve seen more and more patients with Parkinson’s.
Another study that I was involved in was really looking at a multi-centered study to look at, okay, what’s going on in Parkinson’s dementia? One question I always got, at least from the research and the clinical community, is this just Parkinson’s patients who are getting older and get coexistent Alzheimer’s disease? I think this was one of many studies that really looked at Parkinson’s patients who later developed dementia and really clarified that issue.
What you can see here on the right — sorry, move my mouse around here — is that in this population of individuals, we saw really a strong link to the presence of those Lewy bodies, particularly in areas outside of just the dopamine system, but in the memory areas of the brain and the more high-order cognitive areas. We saw some increased risk for APOE4, which has been linked to Alzheimer’s disease, but only about 30% of that 140 group with dementia actually had coexistent Alzheimer’s disease as we define it pathologically.
What that meant to me really was that it’s the Lewy body disease that’s driving that dementia process in Parkinson’s disease, and less so that it’s just coexistent Alzheimer’s disease. I would say, and this is anecdotal completely on my part, but what I also tend to see is, we can make that Alzheimer’s diagnosis pathologically when we’re looking at somebody after they’ve died, but the actual amount of Alzheimer’s changes tend to be less than what we see, say, in somebody who has pure Alzheimer’s disease. There you may see a combination of the two disorders linking together.
Again, I think this feeds into this idea that this is different than Alzheimer’s disease, and that while it’s important for us to recognize whether Alzheimer’s is coexistent with it, it’s kind of its own disease and its own process.
Many of you may have heard of the term dementia with Lewy bodies. I’ve had patients come to me and families that say, “Well, it was Parkinson’s disease, but now it’s dementia with Lewy bodies because we’ve developed this cognitive change, this memory change and other changes.” Well, strictly speaking, the way we use the nomenclature for these disorders, it never really changes from Parkinson’s disease. It really is Parkinson’s disease if it starts with that and you don’t have major cognitive changes for a year or more.
In dementia with Lewy bodies, we expect the memory issues, the thinking issues to occur prior to the development of significant Parkinson’s or simultaneously. A lot of patients I see with dementia with Lewy bodies actually present with, maybe they’re having some visual hallucinations, they’re having some thinking difficulties, maybe they’re acting their dreams out at night, REM sleep disorder, right from the beginning. I’ve even had some who have almost no Parkinson’s symptoms whatsoever, and most of the time they develop them later. Those are the dementia with Lewy body patients.
In my Parkinson’s dementia patients, generally speaking, again, we’re seeing these motor symptoms of Parkinson’s, maybe some mild multitasking difficulties, but really the main thing that’s going on is that we’re seeing that Parkinson’s early, and it’s not until years later that we see any kind of significant cognitive changes.
Dr. James Leverenz 23:08
Now one argument that I don’t think we have an answer to yet is, are Parkinson’s disease and dementia with Lewy bodies just variants of the same disease? They have some very common clinical symptoms, right? They generally speaking both have motor Parkinson’s symptoms. We can see visual hallucinations in both, and they have some pretty unique aspects to them. We see fluctuations. We see motor fluctuations in Parkinson’s, but in both, we can see fluctuations in the level of alertness and thinking skills.
A patient I saw very recently, during one visit on one day, I had a hard time waking him up. He kept falling asleep during the visit. The next day, literally less than 24 hours later, wide awake, answering all my questions. You see these fluctuations in cognitive ability, similar to some of the motor symptom fluctuations we see.
Another common symptom we see in both is the REM sleep disorder where people act out their dreams. Usually it’s not the patient, unless they fall out of bed, but the bed partner that notices, or somebody in a room next door that hears them yelling and notices the bedspread’s all over the place.
Is it timing in terms of how we make that diagnosis? Criteria-wise, yes. We have that one-year rule. If it’s Parkinson’s dementia, that means the Parkinson’s disease started first and the cognitive and behavioral changes occurred later. Whereas in dementia with Lewy bodies, we see that happen within the first year of the Parkinson’s motor symptoms or previous to it. Are they variants of the same disease? That’s a really tough question.
My answer generally is that there’s a biological reason why somebody starts with, say, Parkinson’s motor symptoms and has insignificant cognitive changes for a year or a couple of years or 10 years or 15 years, and then somebody presents to me with a dementia with Lewy body syndrome but without any motor parkinsonism. There’s a reason behind that. The reason I think it’s important is because I think it really tells us something about the biology, and it also tells us something about, when we’re starting to get disease-specific therapies, that we want to be sure we’re identifying these differences and that people may respond differently.
I think in Alzheimer’s disease, we’re starting to see that in my center here, where we’ve got the multiple sclerosis center below us, and they have types of multiple sclerosis that don’t respond to therapies and others that respond quite robustly. Similar also to cancer, where breast cancer is not just breast cancer. I think these are telling us something about the biology, and it may be important when we start to develop better disease-specific therapies.
The last group I was going to just touch base a little bit on under the Lewy body dementias are patients with Alzheimer’s who also have Lewy body changes in their brain.
Just for historical context, this is obviously an older picture. The upper arrow here is Alois Alzheimer, who described Alzheimer’s disease in the original changes in the brain. Here is one of his student associates, and this is Friedrich Lewy, who described the Lewy bodies of Parkinson’s disease and dementia with Lewy bodies. Already, they were kind of linked together.
What we found over the years, in fact, is that when we look in patients who have Alzheimer’s disease, whether it be sporadic or even familial forms, we frequently see coexistent Lewy body changes in the brain as well. It’s often common, and when it’s more widespread than just a part of the brain called the amygdala, we often see those patients have some of the same symptoms as dementia with Lewy body patients and often develop frequent Parkinson’s-type symptoms as well. It’s another form of Lewy body dementia, so to speak.
These patients in particular, because they have Alzheimer’s changes, are going to be very important to recognize because we do have some of the new therapies, as some of you have heard about, attacking some of the pathology of Alzheimer’s. We think in this circumstance — this is my hypothesis, my theory — that it’s actually the Alzheimer’s that’s driving that Lewy body change to occur. Maybe treating the Alzheimer’s in this circumstance will be very important.
Dr. James Leverenz 27:51
Let’s talk a little bit about symptoms that we see in the Lewy body dementias. One thing I notice, particularly in those patients who don’t have coexistent Alzheimer’s disease or significant coexistent Alzheimer’s, is their cognitive picture’s a little bit different. Rather than starting, for those of you who’ve seen people with Alzheimer’s disease, you’ll notice that they struggle putting new memories in and holding on to them. You may have a conversation with them, or you may ask a question, and five or 10 minutes later, they ask the same question again or they don’t remember an event from the previous day. Encoding that new information can be problematic.
In terms of memory, what I tend to notice particularly in Parkinson’s is patients struggle with pulling up information from memory, but if you give them a hint, they can pull that up. What that means is they’re storing that information. It’s more of a retrieval issue than it is a primary encoding of that memory information. What we tend to see more of is executive dysfunction, and I’ll put under that things like multitasking, staying on track during conversations, things like that, that can be really prominent in the Lewy body dementias. I look for that when I see somebody coming in, even for evaluations, say, with dementia with Lewy bodies. I’m looking for that early executive dysfunction, that multitasking difficulty, and actually relatively retained memory for hinted memory, as I mentioned earlier.
All of these diseases can cause some apathy, some decreased interest in activities. I think the Lewy body diseases tend to have more depression associated with them and more visual-spatial difficulties. I think that feeds into some of the visual hallucinations and visual perceptual issues. Some of the parts of the brain that help you interpret visual information can feed into that psychosis, which is really about the visual hallucinations.
Occasionally, with the hallucinations, people lack insight and think they’re real. But I have quite a number of patients who tell me they see little children, they see a dog in their room, and they know they’re not real and kind of laugh at it. The insight that we tend to see that’s very poor in Alzheimer’s tends to be less so in the Lewy body dementias. Most patients recognize that they’re struggling with some difficulties.
Formed visual hallucinations are something that we typically see. Usually, it’s of animate things. A person may look out the window and say, “I see little children playing out there,” and the spouse is saying, “No, there’s really nobody out there right now.” One thing that I’ve often done from a clinical point of view is make sure you ask the question. I have a number of patients that I ask, “Do you see things that other people don’t see?” and they’ll say, “Yeah, I’m always seeing this dog in the corner.” The spouse will look at them and say, “You’ve never mentioned it.” They say, “Well, it doesn’t really bother me. I knew it wasn’t real.” Which is kind of interesting in and of itself, but that's something that we see.
I always put this in because it's one of the funnier hallucinations, but this patient with Parkinson's disease actually said, "I see squirrels driving tractors in my backyard because I know they're not real, but they're having trouble reaching the wheel with their tiny arms." It was the most elaborate hallucination I've ever seen. He laughed at it. It wasn't causing him any distress. Sometimes the hallucinations can be distressful to patients, but that sort of formed visual hallucination is something we tend to see specifically in the Lewy body dementias.
Dr. James Leverenz 00:31:46
The REM sleep disorder that many caregivers or care partners are familiar with is something we see where people act out their dreams. Typically during dream sleep, you may talk in your sleep a little bit. You may move around a little bit, but you're basically paralyzed from a skeletal muscle point of view. You're breathing normally, your heart rate goes, but most people are sort of semi-paralyzed during this dream sleep. In fact, what we find is in people who have Lewy body disease, that paralysis of dream sleep tends to disappear. It's pretty specific. In people who have this kind of sleep disorder, it can happen many years before any other symptoms occur, either of Parkinson's or dementia with Lewy bodies. In fact, up to 10, 15 years.
It's strongly associated ultimately with the findings of Lewy body pathology, of whatever kind that we're talking about here. Again, typically it's that you're acting out the dreams, and occasionally it has to be treated because people are so active that they fall out of bed, things of that nature, and have actually hurt themselves.
It tends to respond to clonazepam, which is an anxiolytic. I like to not use clonazepam if I can just because it's not very good for your thinking skills. It's a benzodiazepine, kind of like Valium. I don't think people think as well on it than off of it. We do give it at bedtime so they can sleep some of that off. I usually start with a little melatonin, which for some patients really does the trick, before I move to something like clonazepam.
If it's like the hallucinations, if it's not bothering somebody, I don't treat it. It's important to consider it from that perspective. Other sleep disturbances can also occur: sleep apnea, restless leg, some of these other things. It's often frequently more than one disorder. Probably from my perspective of identifying people at the very earliest stages, when we see this REM sleep disorder and it's confirmed with a sleep study, these are people we know are at high risk for developing a Lewy body disorder. Hopefully this will be a clue or a cue for preventative therapies as we develop them down the line.
Dr. James Leverenz 00:34:10
Laboratory tests, I'll go into some of these specifically in a bit, but we do some standard blood tests just to make sure there's nothing else that's causing a problem. We can measure spinal fluid tests for Alzheimer's disease, so we can detect and there's an image for Alzheimer's disease now that we can use to see if there's coexisting Alzheimer's, which again may be important as we look at Alzheimer's-specific therapies. But things I tend to focus on a little bit more are things like dopamine transporter scans. I personally don't use FDG PET or the myocardial cardiac imaging, but I'll show you a little bit of what that's about. I know some places use those quite a bit.
Many of you may be familiar with the dopamine scan, the DaTscan. It's really detecting whether the neuronal input to the part of the brain that's important in motor function in Parkinson's disease, whether it's getting a reduction in that input. This is what a normal one looks like. You see that bright signal in the part of the brain called the striatum. Somebody with Alzheimer's disease, again, without Parkinson's symptoms, we don't see much change here. And here's somebody actually with probable dementia with Lewy bodies, but we would expect to see something similar in Parkinson's.
I would say in Parkinson's, straight Parkinson's disease early on, often one area tends to be affected more, which is why many of you may have noticed that certain individuals with Parkinson's will have onset for one side more than another side.
FDG PET is really detecting areas of activation or decreased activation in the brain. It's looking at glucose utilization. What you can see in Parkinson's disease and dementia with Lewy bodies is the area in the posterior of the brain, the visual areas of the brain, can be affected more strongly. Again, I tend to think of that as being an area where we might see more, maybe the visual processing that causes not only visual-spatial dysfunction in terms of cognitive skills, it may lead to some of the hallucinations and things that we see so commonly.
There is a test called the MIBG, which detects input into the heart. I know in Europe they use this sometimes, but you see this reduction in the Lewy body disorders, where you can see here in an Alzheimer's and a normal control you see that innervation. Not something we use commonly in the U.S., but something to be aware of, another test that can be done.
Dr. James Leverenz 00:37:01
The test that I'm most excited about right now, partly because of the kind of work I do, is that alpha-synuclein that we saw in the Lewy bodies. We can actually see that aggregated protein in the spinal fluid using a technique called RT-QuIC. You can see the RT-QuIC here. It's one of these circumstances where a finding in another disease really led to a test that could be quite remarkably accurate for the Lewy body disorders. This detects aggregated proteins right now in the spinal fluid, and it can detect those Lewy body aggregates of the alpha-synuclein protein.
It works very well in Parkinson's disease, where part of the grant that was mentioned earlier by Jim is to study this in dementia with Lewy body patients and in Alzheimer patients with what we think is Lewy bodies. We're kind of starting to use this, but as I talked about spinal fluid tests for Alzheimer's at the same time, we may be able to also do a test for Lewy body changes as well. I think this will really help in terms of improving our accuracy of diagnosis.
Really briefly, some current treatment approaches. I would say there aren't many actually approved therapies for Parkinson's dementia per se. For dementia with Lewy bodies, in some areas the cholinesterase inhibitors, things like Aricept and Exelon, or donepezil and rivastigmine, have been approved in some countries for cognition. As I'll mention in a second, there does seem to be some additional benefits.
For antipsychotics, I try to avoid using them. If I have to use them, I tend to use a very low dose of things like quetiapine to try to avoid causing any worsening of Parkinson's symptoms or sedation. We talked about melatonin and clonazepam for sleep disturbance. I'll sometimes use an antidepressant for the depression if sufficiently severe.
Just some old data showing an effect of the donepezil, in this case rivastigmine or Exelon, in patients who are on the pill versus not with Lewy body dementia, and showing a significant improvement. I would say versus Alzheimer's disease, where these were originally developed, I think the Lewy body patients respond more robustly.
Some other benefits of using that is we tend to see people's alertness improve, so we tend to see less falls. This is a study showing a reduction in fall frequency. And actually, one thing that I've consistently seen, not always, but for people who are having those hallucinations that are on the more mild side, they go away. I've had patients come in and they say, "Yeah, he's thinking a little better." And I say, "What about hallucinations?" "You know, it's funny. They went away." Or if they come to me already because somebody thought they had Alzheimer's disease on one of these, they actually improved as well. It's one of these beneficial side effects we see with this class of medication.
Dr. James Leverenz 00:40:21
Where do we go from here? From a research perspective, we don't have a therapy at this point that treats Lewy body pathology itself, although some of the therapies and some of the approaches that are being used for Alzheimer's disease, like the monoclonal antibodies, are going to be used to try to see if they can attack those aggregates of alpha-synuclein in some way.
One of the areas that we're very involved in from a research perspective is how do we get better at making a diagnosis of what's going on? Can we both diagnose it and get a sense of severity of the change in the brain, as well as develop a blood test so we can screen larger groups of people at a much lower cost? The NIH is definitely behind this, and a number of studies were funded back in 2017, including ours, which was to collect fluid for people who have dementia with Lewy bodies or Parkinson's dementia. That includes blood, spinal fluid, we do imaging, we do a lot of testing, memory testing, testing their motor function, and kind of link all that material together so that we have a resource that we can use.
The newest grant that was just renewed is actually using that marker, that alpha-synuclein marker I talked about with the RT-QuIC technology, to see if we can in fact not only detect the Lewy bodies in things like spinal fluid and blood, but also detect levels of that and kind of get a sense of severity of disease. This will be really important if we can do that, and it's a hypothesis right now that we can do that, because if you have a therapy that's specifically addressing the Lewy bodies, we want to be able to detect number one, do you have them? And number two, are these therapeutics impacting those Lewy bodies? That's one of the areas we've had great support from the NIH in this area.
This really comes out of the National Alzheimer's Project in terms of funding studies, and it was really focused in the Lewy body area around developing better resources for detecting the disease.
I'm going to skip ahead because I want to give you time for questions. The Dementia with Lewy Body Consortium originally had 10 centers. We now have nine centers around the country, and I can show you a picture of where they are right now. They're kind of clustered a little bit on the East Coast and on the West Coast, and I apologize to those of you who may be in the Midwest. But this is a consortium where everybody's agreed to collect this material over time and to put that data and the biofluids into a common resource. Investigators from everywhere can utilize these to really accelerate the studies of Lewy body dementia.
With that, I'm going to stop because I think this is about my time I was supposed to stop, and open up for any questions that might have popped up.
Dr. James Beck 00:43:36
Dr. Leverenz, that was fantastic. Really appreciate the presentation. Really clear information, and I think it's really generated a ton of questions. If we can, let's just dive right into it.
You've touched on these a little bit, but I think it's worth just kind of reiterating. This is a question from one of our viewers, a reverend, who really asks: how different are the dementias? When we talk about Alzheimer's dementia, Lewy body dementia and Parkinson's disease dementia, you touched on it a little bit, but in a nutshell, how are they fundamentally different? If you can, in a nutshell. Within the time allotted.
Dr. James Leverenz 00:44:24
Well, you saw that little circle I said of the different pathologies that we see, and what we're increasingly recognizing is most dementia is multi-etiological, we call it, in which there are multiple pathologies going on, certainly Lewy body pathology being one of the main ones. I would say in Parkinson's disease, particularly individuals a little bit on the younger side, it's primarily driven by that Lewy body pathology. It really does look different than what we see in Alzheimer's, for example.
I think those biological differences, those changes are different, and are really going to influence how we treat these diseases as we develop more disease-specific therapies. I may have a synuclein, a Lewy body therapy. I have an amyloid therapy for Alzheimer's. I may have one for frontal dementia, another kind of dementia. I think those are going to be specific. I think it's important that the better we can diagnose, the more accurate we can be in treatment.
Dr. James Beck 00:45:26
I think you bring up a really good point, especially with that pie chart and some of the other information you presented, that people can have multiple types, at a biological basis, of dementia. Does a person with Parkinson's, clearly if they're living with Parkinson's, they're not protected against Alzheimer's. They can develop Alzheimer's on top of that. Are they at increased risk? This is a question that comes in as well about that.
Dr. James Leverenz 00:45:57
As far as we can tell, no. It doesn't seem like there's an increased risk. I think as you saw in some of the data I showed in the one study we did, it was about 30% of the Parkinson's dementia had Alzheimer changes as well at autopsy, which is sort of the end of the disease. What that means is 70% of Parkinson's dementia patients had relatively pure Parkinson's or Lewy body changes, with maybe stroke changes or other changes. So, definite difference there.
Dr. James Beck 00:46:33
Yeah. Thinking again about some of the symptoms that are associated with Parkinson's disease and, again, related to dementia, recognizing there's a slightly different biological reason why we see these different cognitive changes, is Alzheimer's type of dementia really different than Parkinson's disease dementia? Is it the sense that having Parkinson's disease and dementia, is that worse than just having Alzheimer's disease dementia? Maybe that's a difficult thing to say, but are there added complications? I think if you're living with Parkinson's disease already, adding dementia on top of that can add some challenges for a person and their family.
Dr. James Leverenz 00:47:31
No doubt. I'll get to that last statement. There's no doubt. It's kind of a double-edged sword. I don't remember if I mentioned that earlier. For plus or minus most Parkinson's dementia patients who don't have coexistent Alzheimer's disease, which is the majority, have insight. They know what's going on. They can tell that they're struggling with certain things, and that can be of some benefit, especially early on, for the people around them that are trying to help.
The downside is, when you recognize you're struggling with your thinking skills, there's a certain, right, there's a having some ignorance can sometimes be beneficial. I rarely see depression in Alzheimer's disease because most patients with Alzheimer's don't recognize they're having a problem, and so for them everything's going just fine. It's everybody else that's struggling. Whereas in my Parkinson's dementia patients and dementia with Lewy body patients, they usually have some insight. Depression can be part of it, a normal reactive depression. And of course, you're also interacting with medications. So the hallucinations and the Parkinson's motor treatments can interact.
It's good to see an expert, I think, in that circumstance, somebody who has a lot of experience with Parkinson's as well as perhaps some of the cognitive and non-cognitive issues, because it can be complex. I do think Parkinson's patients, as I mentioned earlier, tend to respond better to things like the drugs originally developed for Alzheimer's, like the Aricept-type medications. Often we can do things like help with the hallucinations and the sleep disorders. So there are ways that we can approach that, at least from a symptomatic point of view.
Dr. James Beck 00:49:20
As a person with Parkinson's who may be listening to this, and they saw the scary numbers from Dag Aarsland's study that are really beginning to, I think people recognize, what do they need to be on the lookout for about this? Is it just simply that recognition that they're off, they're not able to do the things they used to do mentally? Is that a sign?
Then how do they start having a conversation with their family and maybe their caregivers, their clinicians, about what to do next about this? What should be the genesis of starting that conversation?
Dr. James Leverenz 00:50:03
Well, it's a hard one. As I said, to some degree, people around you may notice things and may mention things as well that they're noticing. But again, a lot of patients will tell me they notice that they're struggling. I think simplifying your schedule and trying to be focused on one thing at a time can be really helpful in terms of those early minor multitasking difficulties, things of that nature.
When you start to think it's interfering with your day-to-day functioning, or people around you are noticing, that's probably a good time to see your physician, get a checkup, make sure nothing else is going on. Obviously, a really common thing we see, literally this morning, is somebody with underlying probably mild, probably Alzheimer's in this circumstance, but developed a urinary tract infection and became very disturbed in that circumstance. Sometimes a rather acute change, where it happens over a couple days, not over a couple of months to years, will suggest something else is going on. It's good to get a good general checkup. I think most movement docs these days are pretty sophisticated in this area, and I think that's where it's useful to see a specialist.
Dr. James Beck 00:51:25
Yeah, absolutely. Then, as you go and see the specialists, is it simply a clinical approach? You showed some very interesting imaging approaches, but I don't know if those are widely used as part of a normal diagnostic encounter. Or is it simply people may take a specialized written test, if you will, assessment? Or is it just your clinical interaction with a person who's concerned about their cognitive status? How do you go through this evaluation process?
Dr. James Leverenz 00:52:04
Well, one thing that we noticed is the old tests that we, I think we always do some sort of memory testing at the bedside. I recommend that strongly. In the old days, we used to use something called the Mini-Mental State that was really designed for Alzheimer's and not so much for Parkinson's cognitive changes. We saw a lot of patients where we weren't detecting changes.
Most of us end up using something called the Montreal Cognitive Assessment, or MoCA, because it's a little broader and it picks up some of those subtle cognitive changes we can see in Parkinson's. Typically we'll do one of those. If we see a change there that we think is concerning, then we may discuss other kinds of tests that we might use.
I would say the dopamine scan, for example, I'm using more frequently when I'm not sure what's going on, or if there's a component of this that's Lewy body disease, or I'm not sure if I want to try a dopamine medication for the motor symptoms because maybe they're having hallucinations, and I want to make sure there's a deficiency there that we're going to be treating and trying to help.
Some of the other tests, as I said, I don't typically do the FDG PET. I don't usually use the MIBG for the heart innervation. But those are tests that are used, and people may hear about them.
In our center here, which is very focused, people tend to come to us because they want a specific diagnosis. We do tend to do a bit more aggressive, not therapy, but diagnostic testing. We do a lot of DaTscans and especially spinal fluid testing because we see a certain pattern in Parkinson's and dementia with Lewy bodies. Again, we hope in the not-too-distant future, and I really believe within the next year, we'll probably be using a lot more of the alpha-synuclein test in the spinal fluid to detect people where we're not sure if this is a Lewy body disorder or not.
Dr. James Beck 00:54:12
Yeah, I think that would be really, a lot of fingers crossed on that ability because that was a question one of our listeners had: can you actually detect Lewy bodies in a living person? Right now, that's not capable, but having the ability to understand whether their condition is related to alpha-synuclein, to Lewy bodies, will be really helpful.
As we think about, as you've mentioned, some of the symptoms associated with this depression you see a lot with your Parkinson's and Lewy body patients, how do family members support their loved ones in this? How do they grapple with the depression, with the apathy on this? Is it something like really encouraging people to exercise more? Or do you suggest some type of medication, therapy?
Dr. James Leverenz 00:55:04
Well, I never argue against exercise and physical activity. There's no doubt, almost across the board, physical activity is very beneficial for people as much as they can. Obviously, within the context of somebody who has severe motor Parkinson's symptoms and they're falling, we have to be very careful there. But good physical activity, and that doesn't mean going from zero to marathon running. It means nice walks and getting out there.
Actually, we think from a cognitive point of view, there was a study many years ago showing that people who participated in studies did better than people who did not. I think part of that's the social interaction, that there's a few challenges, a few new things, but in a supportive environment, can be very helpful for people.
I do think there's a biological basis behind the depression. Obviously, there's the insight aspect, so it's a normal response to knowing things are changing. But I also think there's a biological aspect. So I do tend to use some of the antidepressants for the depression. It's really a discussion between myself and the patient about whether they want to do that. For apathy, actually those medications, the Alzheimer medications, the Aricept, the Exelon, can be very helpful for apathy. It's something, again, I see many patients with Lewy body disease respond well to.
Dr. James Beck 00:56:30
Thank you. That's something really to consider. I thought it was really interesting when you bring up the idea that people participating in studies seem to do better. What about these brain teasers, different crossword puzzles, Sudoku, other types of things, the brain training? Is there evidence that suggests that may be helpful? Or what's your experience, even anecdotally, with how that might engage the mind?
Dr. James Leverenz 00:57:00
I could be wrong, but I actually think the social interaction is better than the brain game, to be honest with you. I just see people consistently do better when they're able to get out and about. Now, maybe that's a, I'm trying to think of the right term to use, but it may be people who get out and interact more are the ones who are doing better from that perspective and feeling more social. But it does seem like some social activities are helpful.
Nothing wrong with doing brain games. I would say I'm a big Sudoku user, but I use it at night to help me fall asleep. So, like, you know, halfway through a tough one or something. I'm not sure it's helping my brain any, but it does help me go to sleep a little bit earlier.
Dr. James Beck 00:57:51
Yeah, I certainly understand that. I've become a big fan of Spelling Bee, the New York Times. That's helpful as well to keep me engaged. Recognizing the time, I want to thank you for your time with us today, Dr. Leverenz. I just wanted to close out with a couple additional slides to remind our audience that we've finished our last in the Expert Briefing series for this year, and we'll start again in 2023.
For those individuals who were looking for supports as part of their living with Parkinson's, the Foundation has a number of resources available with our Aware in Care kit, our library, online resources including topics today about dementia. And then again, our PD Health at Home series, which is really quite wonderful. We have our podcasts for those who like to listen to it. Podcast, for those who may not be familiar with it, just basically like a radio station on your phone. You listen to a specific session, and you can follow it over time.
If you're a professional listening in, we have professional education opportunities and again, for those who are interested in genetics and Parkinson's disease, our PD GENEration study. Right now it's open for people who have a diagnosis of Parkinson's disease, but I know there are some questions that have come in through the chat about those who may be interested who may be at risk. We don't have the resources yet for that, but hopefully we may in the future as part of our work.
Last but not least, we had lots of questions come in. We were not able to answer them all, but certainly encourage you to go to our website where you may find some answers to your questions, but also our Helpline: 1-800-4PD-INFO and Helpline@Parkinson.org.
Before you go, as I mentioned at the top of the call, we really value the feedback and listen to our community. As this webinar comes to a close, it's not just a black screen that's going to happen, but a browser window will open up. Here's an opportunity to tell us a little bit about you and give us some feedback about this webinar. We pass that feedback on to our presenter as well, Dr. Leverenz. Please, before you go, give us your feedback so we can use it to improve our series and make it better for you. With that, I bid you all adieu and look forward to seeing you all again in the new year.
