ISTAART RELAY Podcast – Lewy Body Dementias PIA

Narrator:

Hello, and welcome to season seven of the Dementia Researcher ISTAART Relay podcast. In this series, members of the ISTAART's professional interest areas interview each other about their PIAs and the hot topics in their fields. Each guest then becomes the next episode's host, passing the conversation along from one researcher to the next. We’re releasing one episode a day in the run up to the Alzheimer's Association International Conference, this year in London and online, showcasing the work of the ISTAART PIAs.

Thank you for listening.

Dr Patrick Lao:

Hi, and thanks for tuning in. I’m Dr Patrick Lao, and I’m an assistant professor at Columbia University, and I work on the Down Syndrome and Alzheimer's Disease Professional Interest Area. I’m the current programme chair and the incoming vice chair. So today I’m excited to be talking with Joe from the Lewy Body Dementias Professional Interest Area.

So hi, Joe. Could we start with you introducing yourself?

Dr Joe Kane:

Sure. My name is Dr Joe Kane. I’m a geriatric psychiatrist and a researcher from Queen's University, Belfast in Northern Ireland. And I am the chair of the PIA.

I will be handing over the reins to our incoming chair, Federico Rodriguez Porcel at AAAIC this summer. So, it’s been really exciting. It's been really fun, but it’s time to hand it over.

Dr Patrick Lao:

That’s great. So, before we talk about your work with the PIA, could you tell us about your own work?

Dr Joe Kane:

Sure. I’ve been working in Lewy body dementia for about 10 years. And one of the things about working in this disease area is that you really do get to experience the whole breadth of the topics that make up Lewy body dementia. And you get to bring all those strands together.

So, I started off with a very clinical angle. I worked on a programme called Diamond Lewy, which was a kind of multi step programme to look at how Lewy body dementia was diagnosed and treated within the UK National Health Service. That was my introduction to Lewy body dementia. And one of the things we did was we did a large epidemiological study of clinical diagnosis of LBD.

Even though we see pathological evidence in about 20 to 30% of brains of people with dementia, really, it’s diagnosed in what we find was around about 5%. So, we then kind of set out to try and see what we could do about that. We did, amongst other things, we developed a consensus around how to best diagnose and treat Lewy body dementia. And we did a cluster-randomized trial where we introduced these toolkits, these consensus advice pieces in the different services and saw if they helped people.

And we did find that there were some improvements in people's lives there. And then I complemented that with a bit of work with biomarkers. I used a scan, a cardiac scan, called MIPG, and we used that to differentiate Lewy body dementia from Alzheimer's disease. And that was pretty cool, that was pretty exciting.

And it’s something I’ve continued on as well, some of that type of work. And then once I returned to Belfast and returned to clinical work, I found myself doing a lot of clinical trials. And that’s what I’ve been doing a lot of locally, as well as doing a bit of biomarker work and as well as doing the work with the PIA. So, I’m a local lead for a few different trials in Lewy body dementia.

I recruit patients from my clinic, and both organise and collect the data. And it’s really great because I get to see where research sits in the life cycle of someone coming into a service, understanding their diagnosis, maybe doing a bit of patient public information work with us or advisory work with us, and then maybe coming into a trial. So, it’s great for me because it’s also clinically aligned. And although I can do, try to collaborate with scientists that really help develop my understanding in other areas, I really find that the patient and their care partners are at the middle of what I try to do.

And what we see when we go to conferences like this, like AAIC, is that we benefit from people with loads of different expertise that maybe they brought from the likes of the Alzheimer's world, but maybe they've brought from completely different places. We collaborate closely with them to try and develop new projects and new angles on this. So, it’s a really exciting field to be in. I’ve been very fortunate to work on it over the last 10 years and I’m really excited to see how things develop in the future.

Dr Patrick Lao:

Yeah, that’s great. That’s an incredible range of different types of studies, doing clinical to clinical work, to clinical trials and epidemiological studies. So, when you mentioned that there was about 30% of brains, or was it 30% of individuals diagnosed with Lewy body dementia, but only 5% of them had a pathology identified clinically?

Dr Joe Kane:

So, when we do autopsy studies of people with dementia, we find Lewy body pathology in about 30% of those brains. Now, in a good percentage of those brains, there’s also a good amount of Alzheimer's pathology there. And we know that Alzheimer's pathology interacts with Lewy body pathology and in different ways that we’re only just really starting to understand. But it’s such a big jump from that huge proportion of people who have that pathology to the clinic whereby, 5% in a Lewy body dementia research clinic.

You know, in other services, you know, there are some services that might not see people with Lewy body dementia for months at a time. And our argument has always been that a big part of that is, yes, starting to co-morbid pathology and how it influences the expression of that pathology, but also the fact that there are symptoms there that not everybody is accustomed to looking for. And, you know, these are symptoms like REM sleep behaviour disorder, in which someone acts out their dreams. And we keep telling people that if they're not comfortable asking about these symptoms, you won't detect it.

And if you don’t detect the symptoms, you're not going to make the diagnosis. So, we feel that even though the pathology is a big part of it, we feel that the detection is also a really significant part of it. So, we need to approach it from both angles, really.

Dr Patrick Lao:

And you mentioned that the guidelines that you published, they helped, the clinical guidelines that you published really helped sort of fix that gap.

Dr Joe Kane:

Yeah, I mean, it’s great when there’s a huge body of evidence on which you can draw in a clinic and when you can rely on really good randomised controlled trial data and, you know, phase 4 studies. But the reality is for a lot of the less common dementias and for lots of different conditions in general, you're relying on different study designs. You’re relying on a little bit of expert opinion. You’re relying on some anecdotal data as well.

So that was where that came about, how that came about. Rather than just do a systematic review and dredge the really, really good quality, robust data there, we were able to go out into our Lewy body dementia community. We were able to gain consensus through this process that we call a Delphi, where everyone or a good proportion of people needs to agree with a certain statement before it gets accepted into the guidelines. And whilst it’s not perfect by any means, and even just today, I shared those guidelines with colleagues that were approaching me and asking me for advice.

So yes, you can throw somebody a really good journal article which tells you about this or tells you about that, but to be able to say to somebody, here are consensus guidelines on how you should diagnose and treat this condition, it’s just so invaluable for busy clinical staff. So that’s been really rewarding, and we’re actually in the process of updating those.

Dr Patrick Lao:

Oh, that’s great. Yeah, and I think that’s where biomarkers can really come in handy if the clinical diagnosis is tricky. So, you mentioned using cardiac scans to differentiate between Lewy body disease and Alzheimer's disease. Could you tell me more about that?

Dr Joe Kane:

Sure, one of the things that has always struck us about Lewy body dementia is that we see in the patient's symptoms evidence of pathology, not just in the brain, but throughout the body. A large proportion of people with Parkinson's disease and a large proportion of people with Lewy body dementia will not necessarily describe cognitive problems as their first problem. And what you see is a lot of constipation. You see a lot of autonomic dysfunction.

And there is some good autopsy data to suggest that in a fair proportion of people with Parkinson's disease and other Lewy body diseases, that there is some degree of spread from lower down in the peripheral nervous system up in eventually to the central nervous system. So, the idea behind the cardiac scans is that we leverage that fundamental difference between Lewy body dementia and Alzheimer's disease and try to identify pathology in the peripheral nervous system. And theoretically as well, doing that at a very early stage. And the cool thing about this scan is that, you know, in Japan, for example, nearly everybody suspected of having Lewy body dementia gets this as one of their first scans.

So, there’s really good data out there. And what we did back in my PhD work was we compared this cardiac scan, which demonstrates adrenergic dysfunction. Due to Lewy body pathology. And we compared that with the other famous biomarker we have, which is the dopamine DAT scan.

So, which does look at the dopamine uptake in the striatum. And we find that even though it was very good biomarker in the UK population, wasn't quite as effective as the DAT scan. But there’s been a lot that has changed in the Lewy body dementia sphere since then. And that we’re now looking at disease earlier and earlier and earlier.

What we are starting to think of is these cardiac scans and these DAT scans, dopamine scans, as being complementary rather than head-to-head biomarkers. And we also think that, you know, certain phenotypes may demonstrate that the biomarker may be more effective in certain phenotypes. So, it’s still very much there. It's still part of our diagnostic criteria.

It's something that we’re learning a bit more about, but it’s always been a cool angle. I find that not only researchers and clinicians, but patients really buy into that because they, as soon as they hear that constipation is a symptom or urinary incontinence or heat or cold intolerance is a symptom, they will inevitably say, "Oh yeah, I had that. "I’ve had that for a few years." And it’s crazy once you start going and systematically asking people about their bowels or systematically asking them about their sense of smell. There’s a huge proportion of older people that are affected by that.

While they're not necessarily the best means of discriminating Lewy body dementia from Alzheimer's disease, it does show us that there’s different pathological processes, and we need to somehow leverage those.

Dr Patrick Lao:

Yeah, I’ve heard about some alpha synuclein biomarkers, maybe some PET tracers at an early development, as well as the seed amplification assay. And that seems to only work in CSF right now, but not necessarily plasma. How would those change the field?

Dr Joe Kane:

Well, the seed amplification assays have really sparked so much interest in the field. They have been really useful in CSF, and the USDLB Consortium and some of our colleagues in the likes of Newcastle upon Tyne and Amsterdam, they've really lent into the CSF analysis. But what’s also interesting is that you can use the seed amplification assays on other tissues. My understanding is that in blood it’s quite difficult because it’s quite easy to get false positives because of the clumping together.

But what a lot of my colleagues in the States have been using, and something that we’re really looking forward to talking about on our PIA Day, is the use of skin biopsy. So, with a very small punch biopsy in the skin, we can put them into these seed amplification assays. For those that don’t understand, it’s basically a mechanism of growing the alpha-signed eukaryotic fibrils until they're detectable. And even in very, very small quantities in the skin, they can be grown and detected, and they can indicate that there’s evidence of this pathology.

And you're right, although there is promising data around markers that we can use in neuroimaging, those aren't scalable yet, they have their issues. The idea of a skin biomarker or a CSF biomarker is just so much more seemingly within reach to clinical practise, and it’s something we’re finding out more and more data about. And until we get that really good PET tracer that’s really stable and really scalable, I think we’re going to continue looking into this evidence of pathology through places like the skin, but also CSF and elsewhere.

Dr Patrick Lao:

And you mentioned with clinical trials, what are the targets for those?

Dr Joe Kane:

And there’s different targets for them. They're not necessarily the places where you expect to look for. So, one of the trials that we’re looking at led by University College London is called the TOPHAT trial. So, it is using ondansetron, which is widely used as an anti sickness, anti emetic drug in cancer and oncology practise in particular.

Although we have long thought of the Lewy body dementia as a disruption of dopaminergic systems, and then later on, cholinergic systems, and the likes of the use of ondansetron, it’s actually serotonergic. So, it’s looking at the upstream effects of the dopamine degradation that causes hallucinations that we see in Parkinson's disease and Lewy body dementia. So, in some of the other studies, they're looking at different targets as well. And it’s a really exciting time in Lewy body dementia research because these targets are emerging and because they are quite diverse.

And that’s before we even get to that idea that we hope is coming later on down the line of somehow modifying that Alzheimer's pathology in people with Lewy body pathology. So, range of targets, all it takes is one of them to work for it to transform the field, but there’s certainly plenty in the pipeline and plenty of because for optimism as a consequence.

Dr Patrick Lao:

Yeah, that’s great to hear, especially because you mentioned the different clinical subtypes and so there might be different strategies for different groups.

Dr Joe Kane:

It's no secret in Parkinson's in particular; there’s different clinical phenotypes represent very different symptom groups, prognoses, and different responses to medication. We’re fairly confident it’s going to be the same in Lewy body dementia, but we need the big sample sizes and the big studies to do that.

Dr Patrick Lao:

Great, so thinking more broadly, are there any emerging topics at the field that you want to highlight?

Dr Joe Kane:

Sure, I mean, the real thing that’s on everyone's lips from my perspective is the trials and because so many of us are working in clinics, we’re working closely with participants, working closely with advocacy groups and charities and it just totally transforms the conversation when you can talk about interventional trials and not just observational ones. Obviously, we've still got a lot to learn from observational trials, but it really transforms the dynamic in the clinic when you talk about, there are new treatments on that, that might be on the horizon, do you want to be a part of that? The thing is with the trials becoming more and more of an issue is that they really made us reflect on the trial environment and their trial design.

One of the things that PEA has done really well has been to examine trial design. So, we've always relied very heavily on things like outcome measures for things like Parkinson's, for things like Alzheimer's disease. We use the likes of the CDR, for example, which are designed for Alzheimer's disease and don’t always necessarily reflect the experience of the patient. And we were also conscious that some trials might be failing because their outcome measures aren't specific to Lewy body dementia.

So, it’s really made us think very hard about trial design. It's made us think about how we leverage biomarkers in trial design, how we look towards the start of kind of stratified medicine process of maybe using some of the Alzheimer's biomarkers to work out when someone's got mixed pathology. And the other thing that we really identified as a very significant need has been a DLB or Lewy body dementia specific rating scale. And that’s what we've been working on over the past few years.

I’ll be presenting at AAAIC some of our work with that. It's been really exciting because it’s allowed us to engage the Lewy body dementia community. All of us working together on this one question with many kind of sub questions to it. And we've made really good progress, but we do have some way to go.

So that’s been something which has really captured people's imagination in the field. And I think it’s brought us together as a community. And we’re hopeful that if we develop the right tool that it will actually catalyse trials and encourage some of these novel targets to be investigated. And for the regulatory authorities, people like the FDA, for example, to buy in to these treatments if they do appear to be effective.

So obviously I’m biassed because it’s something I’ve been working very heavily in, but I do think that’s generated a lot of interest.

Dr Patrick Lao:

Yeah, totally agree. When you can start talking about interventions to patients and participants, it really changes the entire conversation. So that’s been really helpful to set the scene for what I want to talk about next, which is the work of your PIA. So, you mentioned a little bit of how you’ve been reevaluating the design of clinical trials.

But are there some other examples of how the work of your PIA supports research?

Dr Joe Kane:

Sure. Sure. In the PIA, we in the PIA have had a quite diverse approach to our work groups. And we've got four different work groups and one of them is really heavily invested in trial design.

We also have work groups on biomarkers, on developing research consortia, and also on prodromal Lewy body disease, which is, I suppose, analogous somewhat to mild cognitive impairment. And Alzheimer's disease. And one thing that these things, one thing that these working groups have all done is they've functioned as a lightning rod for the international Lewy body community. And it has provided such a great vehicle and such great exposure.

And it’s allowed us to move beyond the three or four or five traditional giants in Lewy body dementia research, to diversify, to democratise our community, and to bring more and more people into the community. And we have had people that have started off doing some of these projects, like a publication for the trial methods group, for example. And in the case of my colleague, Dr. Rodriguez Purcell, he started off doing a systematic review on trial methods and now he's about to lead the PIA.

And then in other working groups, we've got really experienced colleagues working on biomarkers and really forwarding the conversation there. And again, what they've done really well is just energised the broader community. So, where you previously looked at some of these great reviews, you had maybe four or five people from the same groups, same centres, contributing to them. And you look at some of our PA papers, and there’s loads of authors from all over the world.

And the people that have worked on these projects have stayed in Lewy body dementia, stayed in the PIA, and they developed projects of their own. So, the exposure and the ability to grow our network has been something quite different from anything we've been able to do in the Lewy body dementia community.

Dr Patrick Lao:

Yeah, I’ve always appreciated the ability to participate in working groups generated by the PIAs. And exactly what you're saying, bringing groups together from all over the world, giving early career researchers a chance to sort of contribute and work with some of the giants in the field. You mentioned a prodromal working group, and I’m interested about that. How long is the disease force in the prodromal stage?

Dr Joe Kane:

Great question, and the answer is we don’t know. One of the things that we've been really lacking has been longitudinal Lewy body dementia data. And again, there’s been a few well-resourced centres that have really got their act together and put really cool longitudinal projects in place. But the fact of the matter is that we don’t fully understand conversion from prodromal disease to full blown Lewy body dementia.

We don’t fully understand the role that the biomarkers have to play in that. We don’t fully understand what things like Alzheimer's pathology has to play in that. And then the other big, huge thing is that we believe that the prodromal phase of Lewy body dementia isn’t just a cognitive one. And although we think of MCI in the context of AD to be very much driven by the cognitive symptoms, we also believe that there are significant groups of people out there ticking along without much in the way of cognitive symptoms.

And the first evidence of their disease is psychiatric disease. So, the first time somebody has to ask the question is this Lewy body dementia could be their first depressive symptom, could be that they get psychosis or new hallucinations. And then there’s also another group whereby we think that people get delirium. We know that people with Lewy body dementia, for example, get delirium more frequently in the lead up to diagnosis than people with Alzheimer's disease.

So, we also don’t know how that delirium onset prodromal disease then interacts with the full-blown dementia diagnosis. And it’s a little easier and we've got a little bit more data. And in the PIA, we've produced a couple of really nice systematic reviews on the conversion from mild cognitive impairment to dementia and the neuropsychological characteristics of those patients. But huge, huge gaps remain around the psychiatric and delirium prodromes.

And that’s something which is something we've got to really work on as a community and get the data and that’s not that easy.

Dr Patrick Lao:

Yeah, and I think that really highlights the need for early intervention if those are some of the earliest signs. Those are really impactful on patients' lives.

Dr Joe Kane:

Yeah, I mean, different clinicians have different blind spots. And I’m a psychiatrist and if I see somebody with psychiatric symptoms, focus on the psychiatric symptoms and I’m maybe not always looking as closely as I could do about the likes of cognitive symptoms, even with disease progression. So, we need to work out how this changes the behaviour of clinicians in different services with their different blind spots. And we've achieved so much in the realm of dream enactment behaviour, REM sleep behaviour disorder, kind of sleep physicians are now really, really good at identifying people at a high risk of the Lewy body dementia.

And we could probably do better when it comes to psychiatrists, old age psychiatrists, neurologists, and geriatricians, maybe asking a bit more systematically about some of these psychiatric symptoms and scrutinising for delirium a bit more closely. But we need the data, we need the studies and we can’t really move forward until we've done those.

Dr Patrick Lao:

Yeah, and I think that’s why these focus areas are so important, bringing together different scientists with different backgrounds to cover those blind spots. So, what brought you to the PIA and how did you get first involved?

Dr Joe Kane:

I had to rack my brain about this because I’ve been involved in the PIA for many years now. And I first got involved with one of the PIA working groups just after the pandemic. And I had paused my research work. I had moved from Newcastle, which is one of those traditional giants in the field, and moved back to Belfast, didn't have the same and doesn’t have the same pedigree for Lewy body dementia research.

And I really wanted to continue the work that I'd done in my PhD. And this call went out saying, do you want to work on a paper about international consortia? I co-led that with Fabrizio D’Antonio, and we worked really closely with Dag Arsland and Jim Nevins, who are some of the absolute giants in the field. And it was so much fun putting that together.

It was hard work, but as part of that project, we basically had to reach out to all Lewy body consortia that were occurring throughout the world. And it really gave me an idea of what the network looked like and really put me in contact with people I would never have had contact with either. Shortly after that, I was asked to be communications chair. And at the time I was tweeting a lot and that worked really well with tweeting about some of my favourite subjects.

And it was a really nice way and a really exciting time to get people that were interested in Lewy body dementia interacting. And we ended up going out for drinks at AAIC and social media and getting out there has become a big, big part of who we are as a PA. Definitely not because of me, but because of my successors. And then it was shortly after that that I became vice chair and then chair.

So, it’s been absolutely transformative for me as someone who, although I’ve been fortunate enough to work with some of the real luminaries in the field, I am a little bit isolated, it could be argued. And the PIA just changes that, the PIA just put me in the middle of these networks. And it gave me the opportunity to work on some really exciting grants, to collaborate with people I would never have collaborated with before. And sounds trite, but they're all my friends now.

We go to AAIC, we look for each other, and we have fun together. And yeah, it’s been such a privilege and such a boon for my career and for my life. So, I’m very, very grateful.

Dr Patrick Lao:

Yeah, speaking of AAIC, you mentioned you have one presentation. Does the PIA have any other activities going on?

Dr Joe Kane:

Yeah, we’re really excited that this is maybe our biggest AAIC for many, many years in the PIA. We have lots of activities going on. We were in PIA Day after a brief hiatus last year. We’re back to PIA Day and we’re really happy with the programme we've got lined up.

We've got a kind of a panel discussion that’s going to look at not only the data around the seed amplification assays, but also how they might start to influence our decisions in the clinic and how you might start figuring out clinical dilemmas using those biomarkers. We also, as part of that PIA Day, are really looking forward to awarding our first PA publication of the year award, which is an amazing paper. I’m not going to let the cat out of the bag, but we’re really excited that it’s such a quality paper for our first award. Then straight up after that, we always really engage enthusiastically in the postdoc and student prizes.

Probably one of my highlights of AAIC every year is visiting the Lewy body posters and seeing the early career researchers and the great work that they're doing and sharing it far and wide. So, there’s that. And then I think we've got three featured research sessions. I’m in one of them.

And one small part of a really exciting session that’s going to talk about the integration of some of the new biological frameworks that have been developed in Lewy body disease and in Parkinson's disease and how it might relate to not only trials but also practise and our cohorts as well. Then the last thing I’m really excited about attending is a clinical toolbox session, which I think is on the last day. As a clinician, you're looking every bit as much for some really good clinical presentations as much as breaking research. And our PM members, Bhavna Patel and Kate Wyman are going to be sharing a really broad multidisciplinary look at how to manage some of the more troublesome symptoms in Lewy Body dementia.

So, I’m really looking forward to that. And I’m really looking forward to seeing everybody and being face-to-face. And I’m really looking forward to seeing what my colleague Federico has in store for the next few years of the PM.

Dr Patrick Lao:

Yeah, congrats. That sounds like a really productive programme at AAAIC. And I’ll have to stop by and check some of those out.

Dr Joe Kane:

Please do, please do. You'd be very welcome.

Dr Patrick Lao:

All right, well, thank you so much for your time. I think it’s time to end today's podcast. Before we go, I do have a final question. So, what advice do you have for someone who's just learning about ISTAART and how has it helped you being involved?

Dr Joe Kane:

I think one of the things that ISTAART has helped with is to provide, we talk about providing a platform, but it’s actually a bit of a pedestal. It kind of raises you up. It's really levelling and it really puts you at the same level of some amazingly talented and experienced people. So, my advice is to take that opportunity with both hands.

And what always surprised me earlier in my career is that when I went up, I’m usually quite nervous in doing so and kind of gingerly approaching really experienced, really important researcher in the field. How keen they were to speak with just about anybody on our topic. How keen they were to provide people with opportunities. And how keen they were to, especially with ISTAART, involve people as much as possible.

So, my advice would be, it’s such a great opportunity. Use it, try and set your shyness to the side and ask that question because I guarantee it’s not a stupid question.

Dr Patrick Lao:

Yeah, completely agree. So, thank you, Joe, for taking time to join us today.

Dr Joe Kane:

Thank you, Patrick. Really nice to speak with you.

Dr Patrick Lao:

So, thank you for listening. You can find profiles of myself and my brilliant guest and information on how to become involved in ISTAART on our website. There’s a link below in the show notes. So, I’ve been Dr Patrick Lao, and you’ve been listening to the Relay podcast from Dementia Researcher and Alzheimer's Association.

Hit subscribe on YouTube or in your favourite podcast app to ensure you don’t miss an episode. Thank you. Goodbye.

Narrator:

You have been listening to the Relay podcast delivered as a collaboration between Dementia Researcher and ISTAART. This podcast is made at University College London with generous funding from the NIHR, Race Against Dementia, Alzheimer's Association, Alzheimer's Research UK, and the Alzheimer's Society. Please like and subscribe and share your thoughts in the comments.