Podcast – Three Researchers. One Disease. Lewy Body Dementia

Voice Over:

The Dementia Researcher Podcast, talking careers, research, conference highlights, and so much more.

Dr Sam Moxon:

Hello, and welcome to the Dementia Researcher Podcast. Today, we're talking about Lewy body dementia, what it is, why it can be difficult to diagnose, and why greater understanding of this condition matters for research, care, and lived experience. This episode is being released ahead of Lewy Body Dementia Day on the 28th of January, which marks the birthday of Dr. Fritz Lewy, who first described the pathology that now carries his name. The day is recognised internationally to raise awareness of a form of dementia that is common, but still widely misunderstood. I'm Sam Moxon, and in today's episode, we're focusing on a disease that often sits in the middle of existing categories. In researching this show, I was reminded that dementia is far less tidy than we're taught. Many cases don't begin with memory loss, and some of the most common dementias are the hardest to recognise. Lewy body dementia, for example, can cause fluctuations in attention, vivid hallucinations, sleep disturbance, and things that look like Parkinson's known as Parkinsonisms.

And it's often years before it's correctly identified, which challenges the idea that dementia is a single uniform disease. But we'll hear more about that later. The focus today is to explore what defines it, why it behaves the way it does, and how different types of research are helping us understand it better. I'm joined by three researchers who all work on Lewy body dementia, but from very different perspectives, and that's really important in the fight against dementia. With me today are Dr. Ece Bayram, Dr. Joe Kane, and Dr. David Koss. Hi, guys.

Dr David Koss:

Hello.

Dr Joe Kane:

Thanks for having us.

Dr Sam Moxon:

How are we all doing? Well, I'd like to start us off by each of you introducing yourselves. So Ece, we'll start with you, please.

Dr Ece Bayram:

Hello. I'm Ece Bayram. I'm an assistant research professor from University of Colorado Anschutz, originally Turkish. Excited to be here.

Dr Sam Moxon:

Great. Thank you. And Joe?

Dr Joe Kane:

I'm Joe Kean. I'm a lead psychiatrist and a clinical lecturer, so I both treat people with Lewy body dementia and research them as well. I'm delighted to be here, big fan of the show.

Dr Sam Moxon:

Fascinating. Thank you, Joe. And Dave?

Dr David Koss:

Yeah. I'm David Koss. I'm a lecturer and a group lead at the University of Dundee, where we studied the cellular pathology of various dementias.

Dr Sam Moxon:

So a real spectrum of expertise, this should be a really interesting show. So we're going to start by thinking about the disease itself. And before we talk about specific research projects, I want to spend some time on that topic of trying to understand Lewy body dementia's disease, because it's often talked about as complex, but that can mean different things depending on who you ask. So Ece, I'm going to come to you first. And could you please start off by explaining what Lewy body dementia is and how it sits in relation to other dementias and particularly Parkinson's related disease conditions?

Dr Ece Bayram:

So Lewy body dementia is an umbrella term. It includes dementia with Lewy bodies and Parkinson's disease dementia. And overall Lewy body dementia basically means you have a dementia syndrome and you cut open someone's brain and they have Lewy body pathology in their brain. And Lewy body pathology is abnormal accumulation of alpha-synuclein protein. So for Parkinson's disease dementia, you have to have Parkinson's disease, the motor problems, an established diagnosis of Parkinson's disease, and you've had Parkinson's disease for at least a year. On top of that, you've developed the dementia. For dementia with Lewy bodies, you may never get motor symptoms, you may never get Parkinsonism, but you may also get Parkinsonism, but you develop dementia within that first year of getting that Parkinsonian symptoms or before you get the Parkinsonian symptoms or at the same time. So as you can kind of hear it, this is very clinical.

If you don't know if the person had Parkinsonian dementia, which came first, in what order, and you just have their autopsy data, you're actually not going to be able to say, "Hey, this was Parkinson's dementia or dementia Lewy bodies." You're just going to call it Lewy body dementia. And if you try to define it from a biological standpoint, Lewy dementia term comes in a bit handy. And the reason why we also use it a lot for research, is this is a tough community of people to recruit for research, to run big data analyses. So we do tend to put this umbrella term together instead, so it can help us get better information for better data analysis in the research.

Dr Sam Moxon:

Yeah. And I think one of the key things there, and you talked about that, and Joe, I'm going to come to you in a second, is the difficulty in getting a diagnosis. I mean, Joe, from your perspective as a clinician, is it easy to... At what point can you tell that someone has Lewy body dementia? Is it difficult? I mean, how do you identify it? How would a patient usually present themselves? Or what symptoms would you expect to see? Or is it one of those where you eventually come there through eliminating lots of other potential conditions? I'm really interested in that side of diagnosis. How do you usually diagnose?

Dr Joe Kane:

It's a good question because it depends on quite a lot of factors. You touched earlier on on some of the most important symptoms that exist in Lewy body dementia. And obviously you have the cognitive symptoms and the functional symptoms that exist with most forms of dementia, but you also mentioned the Parkinsonism, the visual hallucinations, the fluctuations, and the sleep difficulties. And what we see is that in each respective service, we have different blind spots with respect to those four symptoms in particular. If you're not actively looking for those four symptoms, if you're not confident in how you're assessing those four symptoms, then you're not going to find them and you're not going to be able to diagnose. And therefore, it really depends on what service somebody comes into. And because in the UK especially, when somebody comes to a dementia clinic or a memory service, they will present with memory and thinking problems, the cognitive problems with which we're all familiar.

But because in the UK, it's mostly psychiatrists, they might not be as comfortable at assessing Parkinsonian symptoms as a neurologist like Ece. Somebody who is seeing somebody in a sleep clinic for their sleep difficulties may not be that well versed on identifying cognitive problems. And when it comes to neurology services, for example, there can be a slight discomfort sometimes about using words like dementia in the context of existing neurological disease like Parkinsonism. So you can only diagnose when you're adequately looking for the symptoms. And so it very much varies between different specialties and different patient journeys as well. On one hand, you'll have somebody who comes to us with a 20-year history of Parkinson's disease who's starting to have some difficulty with their attention, with their visual spatial ability. The other end of the scale might be somebody who is having visual hallucinations for the first time.

So this is a really broad group of patients presenting in a really broad group of ways, and that's why we're a multidisciplinary specialty that's trying to work together to square the circle and address our respective blind spots.

Dr Sam Moxon:

I think that's a big issue, not just with this, but across dementia diagnosis in general, isn't it, is how to diagnose a disease when often you're relying on behavioural symptoms and you can't really do a pathological analysis of somebody's brain while they're still alive. And we're going to come onto more on the difficulty of diagnosis shortly. But first, Dave, I'd like to come to you. And from the point of view as a biologist, what defines Lewy body dementia, or we can refer to it as LBD going forwards, at the level of brain pathology?

Dr David Koss:

Sure. So I mean, I think if we were to take a very basic understanding of that, that's an individual who's presented with a history of dementia, and then when it comes to their neuropathology investigation and we're finding evidence of these Lewy bodies, so this aggregated alpha-synuclein. And typically that would be in the cortex as well as in the limbic system, so areas like the amygdala. And primarily that would kind of give you and set you up for a kind of confirmational neuropathological diagnosis of Lewy body dementia. But in reality, and again, I think we're going to hear this a lot, is that the real world picture of this is very, very different. So my lab in itself works with a lot of postmortem human brain tissue, and not just my own group, but many groups across the world are really interested in comorbid pathology.

So what we're actually seeing is that it's not just these Lewy bodies that are found with many of these individuals presenting with dementia, but they also have co-pathologies. So pathologies that are associated with like Alzheimer's disease. So you have your amyloid plaques and your tau tangles. And actually when we are looking and building cohorts of different dementias, it's quite rare, at least in our opinion, to find a case that is purely just Lewy bodies. And so that kind of brings in one of the problems with that. Also, just to go back to that distinction between dementia with Lewy bodies and Parkinson's disease dementia, if I'm just looking at the brain by end stage, this primarily looks exactly the same. And so we can't really give a kind of subset diagnosis under that umbrella term.

Dr Sam Moxon:

It's really interesting, especially with brain pathology because you essentially reverse engineering from the end result. And like you say, you'd expect to see alpha-synuclein buildup in Parkinson's patients as well as LBD patients, which I guess makes it even more challenging. So on that, one of the defining challenges is diagnosis, so let's talk a bit about that. So Joe, why is LBD so difficult to identify confidently? And you touched on this already confidently and early, but I think the early point is critical as well with all dementias, the earlier you can diagnose the better. So why is it so difficult?

Dr Joe Kane:

I mean, there's two different pieces to this. It could be debated that it's as difficult as it's made out to be. The first piece is something that Dave has just touched upon, where there are other pathological processes present, they can influence the way that the Lewy body pathology is expressed. So you could have two people with the same amount of Lewy body pathology in the brain, but the person with the comorbid Alzheimer's pathology is probably less likely to have the likes of visual hallucinations than the person with the pure pathology. So we know that there are lots of other factors that influence the actual clinical expression of the pathology. I mean, the second part of it is, like I say, we're just, in many cases, just not adequately detecting the symptoms that we need to detect. And some of that's down to tricky factors. A lot of patients in their 80s and 90s will show some motor symptoms that can look like Parkinson's.

Lots of patients have delirium that can look very similar to the visual hallucinations and the fluctuations that we see in the Lewy body dementia. And when it comes to visual hallucinations as well, we have lots of patients who have visual difficulties, who have environmental factors that means that their eyes can play tricks on them. And we know that when we give people the right tools to adequately detect each of these symptoms, we know that Lewy body dementia diagnosis prevalence goes up. So we've done that in clinical services where we've introduced the right resources and the right training, and people detect it better. So like I say, there's two parts of it. There's the clinical expression of the neuropathological disorder, but also there's the fact that especially in the UK where clinical services are predominantly designed around Alzheimer's, people are trained and services are designed to look out just for Alzheimer's pathology. And that's going to continue unless we improve awareness and education and our systems to allow people to ask the right questions and access the right biomarkers.

Dr Sam Moxon:

And I think you touched on a really important point there, which we'll probably go into a bit more later, is the public perception of dementia and Alzheimer's being the same thing, which is kind of like the, not all hot tubs of jacuzzis, but all jacuzzis are hot tubs situation. All Alzheimer's patients have dementia, but not all patients with dementia have Alzheimer's. It's that sort of juxtaposition. We can come onto that later, but I'd like to turn to Ece, and I've got a question for you now, which is more around what you think the consequences are of delayed or incorrect diagnosis for people. And also the thing that's often overlooked, to the families or the people as well who are going through this with the patient.

Dr Ece Bayram:

Well, I mean, it's obvious. If you get a wrong diagnosis, your whole care planning is going to look different, your future expectations are going to look different, and how you work things around with your family relatives, they all look different. There are certain treatments that can be very harmful for people with Lewy body dementia, but they do get used in Alzheimer's. So if you get a misdiagnosis of Alzheimer's, then you may actually be damaged by your care partners, clinicians using those treatments. And we expect a faster progression for Lewy body dementia. So getting called with another type of dementia really impacts your future planning where the progression is going to be unexpectedly fast for you. So people deserve to know so they can prepare accordingly. And also for research too, we are putting these people that we misdiagnose in clinical trials, and we're probably getting false results because of that.

We see a drug doesn't work or a drug does work, and we start prescribing it clinically, but we're not seeing the effect we expect because we probably misdiagnosed the people we're putting in clinical trials. And just to add on what Joe said too, I think one part that comes very handy for all this thing is the public awareness of these diseases. Because we see with Parkinson's disease, we saw this, the prevalence increased, it's increasing in general, but also once the public knew, they started seeking care more. And once they are more aware and they're seeking care more and we get a better idea of what the exact toll of the disease is, we actually invest a bit more into those diseases. And we've seen a lot of advances in Parkinson's. So we're kind of trying to shift that focus a little bit to Lewy body dementia as well, raise awareness.

So these people won't go unnoticed, they will get proper care, but also so the research will focus more on them and actually start developing helpful tools that can help them and also their care partners.

Dr Sam Moxon:

It's really, really critical work as well. And I think another thing that underlies it, the whole thing around diagnosis is uncertainty. And another area that's overlooked, Dave, I'm going to come to you now is how that uncertainty affects the research as well, because you're working off a limited set of understandings of things. I mean, I used to work on Alzheimer's disease and you assume that it's tau apathy and amyloid buildup, but then you see things like the prion hypothesis come out and suddenly everything changes. How does that uncertainty affect you at the coal phase of doing the research in the lab?

Dr David Koss:

Yeah, I mean, I guess it can be a real problem. I mean, but before we go into that, I mean, I guess I want to say that probably getting an adequate diagnosis and getting the support that you need is critical and is the foremost thing that's most important. But when we are trying to understand the mechanisms of what's going on in the brain, then knowing that you have really high level, really representative cases of the disease that you're looking at, is fundamental. And I think actually we've used a couple of terms here, but I tend to work on dementia with Lewy body cases, and I can say that I'm usually working with them alongside a cohort of Alzheimer's cases.

At least in our hands, we typically find the variability between those that have got a clinical and neuropathological diagnosis of dementia with Lewy bodies to be the most variable. They don't seem to behave quite as one group would expect. And whether or not that's down to the diagnosis, a clinical diagnosis, or we're missing something, we don't really know yet. And so I think the kind of... and again, I guess we'll probably touch on this later, that the development of biomarkers and various things that we can do to assess and be more definitive in life, may lead on to kind of an improved understanding. But I mean, certainly when we're looking just in terms of the level of pathology also, we can see a huge amount. So we have individual cases where there's many, many hundreds of Lewy bodies in one particular brain region, but actually we'll have others that are just as severely impaired that actually only have one or two in the brain area we're looking at.

So understanding what the significance of that is, I mean, one interpretation would be that the Lewy bodies themselves are not toxic, but why one individual forms so many Lewy bodies and another forms much less, is also a really important question that I think we need to understand. And I would hope in future research we'll begin to kind of further stratify even these large terms of dementia with Lewy bodies with a better understanding of the influences of comorbid pathology, but also perhaps relative distributions of Lewy bodies throughout the brain. And research is kind of moving in that direction and there's strong evidence to suggest that not all Lewy body dementias will present exactly the same.

Dr Sam Moxon:

Yeah. And I think that constant sort of small steps in the right direction is, but as with all dementias, is the way we make the progress. And it can sometimes be a little bit overwhelming. I'm sure you felt the same at times, but then you see big breakthroughs and it's like you remember why it is that you're doing what you're doing and you realise how important it is. So it's clear that we've got a condition that doesn't follow a neat path and it presents differently between people and can sit between diagnostic categories, which is why the research matters so much. And I think it's now a good time to dive into the research that everyone's doing. So Ece, I'm going to come to you first, and could you please describe the main questions your research is trying to answer in relation to Lewy body dementia for the audience?

Dr Ece Bayram:

So my research focuses on underrepresented groups in Lewy body dementia research. And in general, I work on neurodegenerative Parkinsonian diseases with cognitive issues. So I basically assess sex, gender, ethnicity, race differences for risk factors, clinical profile, progression, daily impacts, and pathology in these diseases. And we all touched on that a little bit, how LBD looks very different from person to person. And we see some major differences between these larger sex groups, gender groups, and also ethnicity and race groups. And our data that exists right now is a bit predominantly made up by older white men, which is great. We're very thankful to them for all the data they provided. So we got to learn a lot about this disease, but we have to look beyond that and understand the disease for all, so we can get results that will be applicable and helpful for all.

Dr Sam Moxon:

That's really important as well. And I wonder, is that partly indicative of different care structures in different parts of the world that allow some areas where you get higher levels of diagnosis doesn't mean there's necessarily more people, but it's just getting picked up more.

Dr Ece Bayram:

Absolutely. And even the care partner, their culture, their sex, their gender, their background, it impacts Lewy body dementia diagnosis and care a lot, because we rely a lot on care partner reports for our diagnosis. And then we do shape our treatments with what is possible, based on that care partner's abilities as well. So we rely a lot on these individual differences, not just for the patient, but also the care team around them. And that is kind of why we typically talk about it's not an individual disease, it really affects the whole community that the person belongs to, because the whole community comes together and takes part in the care of that person.

Dr Sam Moxon:

Definitely. And I have one final question. I know you have a prior engagement to shoot to, but based on your research so far, what do you think is the main thing that researchers and clinicians should be more aware of?

Dr Ece Bayram:

I think the most important thing is misdiagnosis rates are higher when you look at females or non-white populations. And that kind of tells us that we're missing a lot of people beyond the typical research crowd we get. We're missing information about a lot of those people. And if you're seeing more females show up with that Alzheimer's phenotype, even when they don't have Alzheimer's pathology, if you see more comorbidities for Hispanic Black communities, there's a reason why, and we have to explain why to provide better care for them.

Dr Sam Moxon:

Great. Thanks, Ece. Thanks for joining us, I know you have to shoot now, so we'll be down two, but the show goes on. Thanks, Ece. So Joe, I'm going to turn to you now, and this is becoming more and more fascinating as the episode goes on, partly from a personal perspective. We lost my grandfather a couple of years ago. He had dementia and he basically presented and accelerated during the lockdown. And we never got a good diagnosis, but one of the carers... so one of the clinicians who came into the care home suspected that it may be Lewy body dementia, based on disrupted sleep and sometimes behaviours that were quite a rational response, to claiming they could see things that weren't there. And at the time, I didn't know enough to understand why they were suggesting Lewy body dementia, but hearing you talk about it, it's starting to make more and more sense.

And I think that's why it's really important to have that clinical perspective, because much of your research focuses on diagnosis and clinical features. And so could you tell us a little bit more about that, about what it is that you're working on? And I think it's really critical that people understand why it's important to have clinicians involved in research, especially in something like this.

Dr Joe Kane:

Yeah, thank you. Thank you for sharing that, Sam. One of the reasons why it's really important to have clinicians involved in research, and researchers are involved in clinical work, is because it's the stories that drive all of this. And yeah, with the science, we come up with these hypotheses and we come up with their own methods and perspectives based on what's out there in the data, but what really challenges you and what really inspires you and really makes you ask questions that you don't see being asked elsewhere, are the people in the clinic and there's no better opportunity to get asked a load of questions you don't know the answer to, in a clinic, especially a Lewy body dementia clinic. So it's real privilege to be able to do both of those things. And you're right, early accurate diagnosis is critical, because one of the first things we do, no matter what the disorder is, no matter what the subtype is, we all go to Google.

We all go to try and find out and equip ourselves as much as we can, about what faces us. We want to understand the symptoms that's affecting us or our loved ones, and for us to lend a perspective and a meaning to that. And I think that's really underrated when it comes to dementia diagnosis. Because that person's on a journey and their care partner and the rest of their family and friends are on the journey with them. And to be able to draw together their experiences and their symptoms and say, "This is why you're experiencing this symptom, and this is what it means for you," is incredibly powerful.

Dr Sam Moxon:

Definitely.

Dr Joe Kane:

And it's a difference between a hammer blow diagnosis in a clinic and somebody walking out of the clinic informed and reassured and ready to tackle, however difficult, ready to tackle what faces them over the next months and years. So that really drives me forward and inspires me. And my research work initially really focused on the way that we do that in the NHS and in the UK. And what we tried to do as part of this programme called the Diamond Louis programme was to try and get a sense of what people's experience was in the NHS, how they were treated, how long they waited, and then we set about trying to improve that experience. And I suppose it started off with a process of working out just how common Lewy body dementia is in the UK. Now we found that it was just around 5% of all dementia cases, which is much, much lower than we were expecting when you look at the pathological data.

But the really interesting thing and the thing that has influenced much of what I've been telling you tonight about detection has been the fact that when we look between different areas, there were huge differences in the prevalence of Lewy body dementia as a proportion of all dementias. And the only way that really makes sense is if it's a difference in detection.

And so we then set about trying to see what we could do about that. We spoke to patients, we spoke to clinicians, we spoke to care partners, we did some very detailed deep dives into people's journeys and their past notes, and find out what people have been telling us all along is that people with Lewy body dementia wait longer for a diagnosis than somebody with Alzheimer's disease. We found out that around 50% of people who had Lewy body dementia were initially diagnosed with some other form of dementia, and that then somebody, just like the clinician did in your relative's case, revisited the case, looked at it from a different perspective, and asked the question, "Is this Lewy body dementia?" So then we set about trying to rectify that and we introduced, we drew together a lot of the resources that were available at the time, including the diagnostic criteria, and we kind of created resources, toolkits that are available online, and we tested how well they did when they were being used in clinical services.

So I encourage everyone to have a look at the DIAMOND-Lewy toolkits online. And the first part of that was an assessment toolkit in which we basically produced a flow chart telling people how to recognise the signs and symptoms, and to put it together. And we tried to support not only your psychiatrists and your neurologists, but perhaps people like GPs, nurses, allied health professionals, to support them in making a diagnosis and raising that question. We found that when we introduced this toolkit into services, that Lewy body dementia was diagnosed more frequently.

Dr Sam Moxon:

Oh, wow.

Dr Joe Kane:

Which was quite powerful when we were able to see it. The other thing that we were able to do is we drew together all the information on treatment and we introduced that into a number of services, and we found that when people were given the right resources about treatment in a presentable, usable way, we found that there were clinical benefits, particularly on the wellbeing of the care partner.

So it's really transformed the way I work as a clinician because it's made me realise that there is a pathway from this masses and masses of research that's out there. And when presented in the right way and framed in the right way, you can make a difference to the diagnosis and therefore on the patient's wellbeing. So that's been the main focus of my initial work. More recently, I've been involved in trials. So we've been testing new medications, or rather medications that are old and existing, but for the first time being used in the Lewy body dementia. And we've been working really closely with patients and care partners to try and get them into the trials process. We're running a few trials in Belfast at the minute, and it's really interesting because it is a bit of a leap of faith on the part of people with Lewy body dementia and their care partners.

It's tricky to come into a trial and it's a big commitment on their part, but to be able to accompany a patient on that journey is really curing and really gratifying and a really good way of not only seeing how you can help that patient, but maybe those that are coming after them. But just to echo what Ece says, the care partners play such a big role in supporting somebody coming into a trial. And for that reason, we're not as good as we could be when it comes to recruiting some populations, making it as easy as possible for people to come into studies, and making sure we're supporting them in all the ways we can. So that's very much what we're looking at in the future. Better ways to rate someone's level of difficulties and practical ways to transport them, coming into trials. So that's been much of the focus of my work recently.

Dr Sam Moxon:

That's fascinating. I'm always fascinated by the repurposing of currently approved drugs, because not only you potentially give the patient something that's going to help, but also the regulatory process is so much quicker. You can get it to people quicker than taking an entirely new drug through clinical trials, shaving years and millions off that process. So it's really powerful.

Dr Joe Kane:

And to be able to say to patients, "We know this drug, we know the side effects, we know how well it agrees or disagrees with people, we know what to look out for." It's a lot more reassuring than, "This is a brand new medication that's a little bit of a mystery for us." We have some data that's come from smaller studies, but in contrast to some of the other medications that we're looking at, we've been using them for years, we've been using them safely, we've been using them in different environments, and that makes it a lot more acceptable and tolerable for those involved.

Dr Sam Moxon:

Yeah. Makes the regulators happy as well. Dave, I'm going to come to you now. So your work looks more closely at what's happening on a, certainly molecular level, it's closer to the work that I did around dementia, and it's really finding those underlying mechanisms. And I wonder if you could dive into that and explain what you're studying and why it matters for Lewy body dementia. I'm sure the audience will find it absolutely fascinating.

Dr David Koss:

Sure, thank you very much. So I think before I actually deep dive in, I mean, I think it's important to represent the vast majority or wide array of topics that people are looking at at the moment. Because really, when we're still trying to get to understand and grasp why is there a neural dysfunction, why is there cell death, what's going on, we're still ultimately at a loss as to exactly why that is. And so I guess like many other neurodegenerative diseases, we've started by looking at the hallmark pathology, so Lewy bodies and alpha-synuclein. For a long time, alpha-synuclein has been known and focused in on as a kind of synaptic protein that's important at the presynaptic terminal and helps release neurotransmitter vesicles. And so one idea, of course, is that if these alpha-synuclein molecules are being trapped up into these Lewy bodies, you've got a loss of that synaptic presynaptic function, but you've also got this buildup of a toxic Lewy body within the cell. And maybe that's a catalyst for killing the cell.

But it's also alpha-synuclein is a compound word, so sy being synapse, but nuclein being nucleus. So it's also known that alpha-synuclein is expressed in nucleus. And I think it's probably fair to say that over the last 10, maybe 15 years, there's been some growing evidence to suggest that alpha-synuclein in the nucleus, of course, it's there for a reason, it does something important, and there's growing evidence that it may have something to do with repairing DNA. So it might actually be important for detaining our genes. And so again, along this line, if alpha-synuclein is becoming modified in some way and being trapped in these Lewy bodies, perhaps actually these neurons that are particularly vulnerable for DNA damage are losing their ability to maintain their genes. And this then has downstream consequences such as cellular dysfunction because they're no longer able to regulate a vast majority of the cellular processes.

So that's really the angle that my lab looks at. We are interested in one, characterising the levels of DNA damage, but also the types of DNA damage, and also the cell types in which this is occurring. So not just the neurons, but also in the astrocytes, the microglia and so on. And so we've started to profile this and try to understand that in, say, compared to something like Alzheimer's disease, how does the damage differ between dementia with Lewy bodies and Alzheimer's disease.

And actually, if you look at the literature, the resolution in which people are able to understand the types of DNA damage that are occurring is still quite limited. So we're now trying to apply new protocols to be able to be specific about, oh, it's actually this type of DNA damage, this lesion that's elevated rather than a general measure. And by that, I think that will give us a better understanding of perhaps the rules that alpha-synuclein are playing in repairing damaged DNA, but also about the kind of toxic cellular environment that's kind of being built up by this disease. And these all kind of feed into ideas that we could have identified drug targets that we can potentially treat.

To go back a little bit, I guess we've also been looking in various models to see whether this DNA damage is present and at what stage of the disease development. And like a few other groups, we're now seeing that actually this DNA damage signature, this elevation seems to occur very early prior to a lot of cellular dysfunction and prior to symptomatic onset. So again, this is kind of telling us that not only can we detect specific DNA damage repair pathways which we can target, but there may be a relevant therapeutic window in which we can intervene with this and potentially make a difference. I guess this further kind of follows on from, I guess, what you guys were discussing about repurposing drugs. I mean, DNA damage and repair has been something that's been the main focus for cancer research for many, many years.

Dr Sam Moxon:

Yeah. I was thinking that, yeah.

Dr David Koss:

And so I'm not saying that we would be able to immediately take a drug and repurpose it. There will be libraries and libraries of drugs that would be relevant, that we can access and speed up and accelerate the treatment. So again, it's a driving force for our research, not because we think it's the one and only cause of Lewy body dementia, because I can quite certainly say it's not, but is it something that's realistically possible to take, and has a clear translational value, then yes. And I think we kind of... Like Sam, you were saying about your grandfather that had dementia, we have a responsibility to these people who are undergoing these illnesses, to be able to deliver something that improves their quality of life.

Dr Sam Moxon:

Absolutely. And my mind is sort of racing now about... The genetic system me has got a million and one questions and I'm thinking about AI to try and speed up the search for repurposing of drugs, and we could sit here for a few more hours, but I think the most important thing to come from listening to both of you actually is that it's clear that the disease simply can't be understood from a single perspective. And so I've got a question for you both, and I'll come back to you first, Dave, which is, how important is it that the clinical, biological and population level research continue to connect with each other as we continue on this journey?

Dr David Koss:

I mean, I don't think we're going to be able to understand such a kind of diverse disease without this. And even just in terms of a pathology at pathology level. I'm actually thinking about a data set right now on a graph where the dementia with Lewy body cases are segregated to two populations, and I have no idea why. The signal is up and some of the signal is down. And I think without better understanding the history, the background, the genetics, the presentation, and maybe a more fine-tuned diagnosis, I think we've got no chance.

Dr Joe Kane:

Absolutely. I mean, it's one of the things I actually love about working in Lewy body dementia is the fact that there has always been a recognition that we need to be multidisciplinary. And if you stumble across a group of people who are researching Lewy body dementia at a conference, I don't know what the collective name for a group of researchers is, but if you come across a group of us, it'll be a fairly diverse bunch, at least in terms of specialty. I know Dave, I know Ece, and the history of Lewy body dementia. You can see the contributions from different people coming from different perspectives, scientifically, methodologically, ideologically. And it's one of the cool things, is that it kind of forces us to work in as diverse and engaging a way as possible. Because if we don't join the dots there, we're never going to get anywhere.

And so it's one of the things that really attracts me to this, that comes with its challenges, obviously, but it's always been very, very clear that if you are discussing Lewy body dementia, but excluding the neuropathological aspect of it or the clinical aspect of it or the epidemiological aspect of it, you're missing a huge, huge part of the picture.

Dr Sam Moxon:

Yeah, I think you made a really important point there about the diversity, which is dementia research isn't just biologists and clinicians. You can have speech therapists, you can have computer scientists, you can have mathematicians, you can have so many different perspectives. And I think that's really important, especially when something is as complex as this. And we made do a second podcast because I feel like we could talk about this for hours, and I think it's very clear it's also a disease that doesn't get enough public discussion, and that as such has a lot of misunderstanding around it. But I think we're probably coming close to the time to wrap up the discussion. And so as we come to the end, I've got a final question for you both, which is that if someone listening to this takes just one thing away about Lewy body dementia, what would you want that to be?

Dr Joe Kane:

Sure. I mean, the one thing that I would say to anyone, maybe a clinician or researcher is something that I've said, right? If you're not looking for these symptoms, you're not looking for Lewy body dementia, and you are therefore missing it. So if you're a researcher that's designing some sort of AD observational study or a biomarker study or qualitative study, and you're not looking out for the symptoms that are characteristic and diagnostic of Lewy body dementia, if you recruit a decent number of people, there will be a lot of people with Lewy body dementia that are in there, and that's obviously going to compromise your research in a way. So you have to look for it. Everyone, be they developing a new trial for AD or examining the care partner experience, they need to be including at least some questions about Lewy body dementia, be it screening or just understanding symptoms in whatever your screening criteria or your inclusion or exclusion criteria are. So it's there, it's not going away, you need to look for it.

Dr Sam Moxon:

Yeah, absolutely. And yourself, Dave?

Dr David Koss:

Yeah. I guess if you're considering building postmortem cohorts of dementia with Lewy bodies or any form of Lewy body dementia, I think you should consider, if at all possible, to look, one, in terms of a pure case, so cases that have no Alzheimer's related pathology, and those that have mixed. And I'd be fascinated to see the differential signals that they get out of each of their assays, simply because I think it seems like it's such a modifiable pathology or group of conditions. And I think equally in Alzheimer's disease studies, I think we shouldn't underestimate the possibility that there'll be individuals in there that also have comorbid Lewy body pathology and therefore some elements of Lewy body dementia. And we need to get better at treating dementia cases in a kind of very detailed way, rather than pooling them all together.

Dr Sam Moxon:

Absolutely. I couldn't agree more. Well, as I said, it's probably time to wrap up. So I'm going to start by thanking Dr. Ece Bayram, Dr. Joe Kane, and Dr. David Koss for joining me today. This episode has been released ahead of Lewy Body Dementia Day on the 28th of January, so mark your calendars, which aims to raise awareness of a condition that we've clearly seen affects many people, but is too often misunderstood. And all this week, dementia research will be turning a spotlight on LBD. So do visit the website for more information, for blogs, content, dementiaresearcher.nihr.ac.uk. You can also join the conversation in the Dementia Researcher Community app where we continue to share events, blogs, and podcasts throughout the year. And finally, and I think most importantly, we want to thank the Lewy Body Society for helping bring our guests together. They're a small UK-based charity, and for a charity of their size, they really do amazing work.

So please check out the website at lewybody.org. And if you're thinking of fundraising, I can't think of a better charity right now. And finally, I'm Sam Moxon. You've been listening to the Dementia Researcher Podcast. Goodbye, and we'll see you all soon. Bye everyone.

Dr Joe Kane:

Thank you, Sam. Thank you, everybody.

Voice Over:

The Dementia Researcher Podcast was brought to you by University College London, with generous funding from the UK National Institute for Health Research, Alzheimer's Research UK, Alzheimer's Society, Alzheimer's Association, and Race Against Dementia. Please subscribe, leave us a review, and register on our website, for full access to all our great resources. Dementiaresearcher.nihr.ac.uk.