Podcast – Career Paths to Studying Huntington’s Disease Linked Dementia

Voice Over:

Welcome to the Dementia Researcher podcast brought to you by dementiaresearcher.nihr.ac.uk, a network for early career researchers.

Lakshini Mendis:

Huntington’s Disease is an inherited disorder that results in the death of brain cells. Disease progression leads to the characteristic hallmark symptom of Huntington’s, the uncoordinated jerky body movements, but subtle problems with mood and mental abilities are actually among the earliest symptoms of Huntington’s Disease.

Lakshini Mendis:

People living with Huntington’s can also go on to develop dementia, but this form of dementia differs from Alzheimer’s Disease and that those affected continue to recognize people and places until the very late stages of the illness.

Lakshini Mendis:

My name is Lakshini Mendez and I’m a NIHR research project coordinator based at University College London. The research I did for my master’s thesis was actually on Huntington’s Disease, so I’m looking forward to chatting to our expert panel today on the work they’re doing.

Lakshini Mendis:

On today’s panel we have Marina Papoutsi, Lauren Byrne, and Akshay Nair. Welcome all. All three of them work at the UCL Huntington’s Disease Centre in the Department of Neurodegenerative Diseases. But before we get stuck into the research they’re doing. Let’s get to know our panellists a little bit better. So, can you all tell me a little bit about yourselves and why you chose to work in this area? Marina, we’ll start with you.

Dr Marina Papoutsi:

So, my, I ended up in Huntington’s almost by accident. I wasn’t intending to work in Huntington’s, my PhD was in language and looking at language pursing. Then I started doing more clinical work, working with patients that had stroke and looking at how the brain adapts after a traumatic incident. And that kind of work led me to work with HD patients and looking how the brain adapts to the presence of neuro degeneration and how, especially with the focus in cognitive decline and at the same time, both of my grandmothers had dementia. One of them had Alzheimer’s, so its kind of brought it closer to home and trying to understand and doing do my bit, I guess to help out.

Lakshini Mendis:

Lauren, what about you? What made you choose this research topic?

Lauren Byrne:

I am actually from a HD family. My dad has Huntington’s Disease and several of my family members. So, I started thinking more and more about HD research very naturally. I did biology in my undergraduate degree and kept going for topics, picking research projects and things that would relate to neuro degeneration and then Huntington’s Disease. And I found out about [Sarah Tebretzy 00:03:00], who’s the amazing head of our director for Huntington’s Disease Centre who is this powerhouse woman leading clinical research and translational research in Huntington’s Disease was in London as well at UCL. So that’s why I decided to do a masters at the Institute of Neurology with the sole aim of trying to get into her research team. And that’s where I met Marina and thankfully got a project and worked looking at MRI scans and after her pilot brain train study, her neurofeedback study.

Lauren Byrne:

And then I met my current boss, which is how I started my work in biomarkers in Huntington’s. And here I am doing my PhD.

Lakshini Mendis:

That’s awesome. And how is your work funded at the moment? Who’s finding your work?

Lauren Byrne:

I’m funded by the MRC, the Medical Research Council. My boss, Ed Wilde, got a clinician scientist award towards the end of my master’s project whenever I met him. So, it was good timing that I asked him to go for a coffee and to talk about his research because he had just got his funding and needed a research assistant and I needed a job. So, a match made in heaven and I was keen to do a PhD and very lucky that I had a three to four-year job post for the study.

Lakshini Mendis:

Actually, I know you were funded by the [Leonard Bolson Foundation 00:04:36] and yeah, same question to you guys, I guess.

Dr Akshay Nair:

I’m a doctor, I’m a psychiatrist. So even at medical school I was kind of interested in brain, mind and kind of psychiatric symptoms. And then when I started practicing in psychiatry, I did a lot of work with severe mental illnesses, schizophrenia and then I moved into Alzheimer’s Disease around one of the areas of neuro degeneration that I’m very interested in is the neuropsychiatric symptoms. They often, some of the most disabling and distressing for patients and family members. They’re very, very hard to understand, very, very hard to treat.

Dr Akshay Nair:

And so that has kind of been my interest in what does neuro degeneration do to the brain and how does that put people at risk of developing psychiatric symptoms. So, I did some work at the Maudsley and Alzheimer’s Disease because I wanted to get a broader understanding of neuro degeneration. I applied for a Wolfson Fellowship at UCL and then I did a couple of rotations, two in the Dementia Research Centre and front temporal dementia and Alzheimer’s Disease. And I also came to work with Marina on a brain imaging study. And then I, HD we’ll talk about later. One of the defining features of HD, the psychiatric features. And so, I was very interested in the condition and so that’s what I chose to do my PhD on, the neuro psychiatry of HD basically.

Lakshini Mendis:

So, welcome all and kick-off with maybe talking a little bit about what symptoms associated with H link dementia. Just because, well I haven’t heard too much about it in that context and maybe you can just shed some light on that.

Dr Akshay Nair:

So, I see a lot of patients in clinic. I think so HD is really kind of characterized by three pillars of symptoms. So, there are the motor features. In the introduction, you mentioned the hyperkinetic symptoms, so career and involuntary movements, people also get slowing, unsteady gait in coordination. So, it’s quite actually a diverse movement disorder. The second pillar of the HD symptomatology are the cognitive features. So, this would I guess be what you may call the HD dementia. And these largely fall into the executive function bracket. So, people with HD have difficulty… They get a lot of cognitive rigidity. They have difficulty processing things or keeping up and changing their minds and can get overwhelmed quite quickly. Sometimes they can be a bit impulsive in their decision making. It’s those kinds of executive functions that are typically go wrong, especially early in the disease when the degeneration is relatively limited.

Dr Akshay Nair:

And then the third kind of pillar that I’ve been treating for the last couple of years in my clinic is the other neuropsychiatric features. So, HD is associated with a lot of psychiatric disorder. So, I see a lot of depression, anxiety, irritability, sometimes aggression. I rarely treat, well not, let’s say not uncommonly treats psychosis. So quite a wide range of psychiatric features.

Dr Akshay Nair:

And so, the three together really kind of make up the clinicals symptomatology of HD. And I think some of the things that are quite challenging about it are the interactions between those three things. So, when people have cognitive impairment, that means that they’re quite rigid in their thinking, it’s then quite difficult if you’re trying to treat them for something like irritability or depression. So, it’s a very devastating dementia really. And certainly I know I say this as a psychiatrist obviously, but I certainly think HD has this huge prevalence of neuropsychiatric features and a lot of burden in terms of distress and disability comes from those features above and beyond some of the other dementia’s where neuropsychiatry is certainly less prevalent early on.

Lakshini Mendis:

Thanks. And then we talk a little bit more about the research you guys are doing. So, Marina, if I start off with you, maybe you can fill us in on some of the work that you’re doing.

Dr Marina Papoutsi:

So, my work is kind of has two broad aspects. One of them is looking at cognitive impairment in HD and also some of the risk factors that affect impairment. More importantly, I look at cognitive simulations throughout the lifespan. So, education and professional hobbies, intellectually stimulating hobbies like chess playing or reading, things like that. How does that have an effect on the progression of Huntington’s Disease? This is a kind of work in progress. We’ve seen a lot of research in Alzheimer’s, talking about exercise and cognitive stimulation and also in healthy aging. And how that has an effect and slowing down the cognitive decline. But this hasn’t been really studied at all in HD.

Dr Marina Papoutsi:

So, this is some of my more recent work. And also, in parallel to that, I also work on developing non-invasive interventions to try to intervene and try to delay again cognitive decline. So, at the present time, respectful of what kind of lifestyle people have adopted in the past. Like what can we do to try to slow it down? And the critical thing is about them being non-invasive is that it could be work in conjunction with other disease modifying drugs that are much more invasive and therefore you need something to balance it that it can be readily used together.

Lakshini Mendis:

Thanks. And Lauren, actually how does your work fit into this area? Does it fit in? Is it complementary?

Lauren Byrne:

My work probably fits more into the current efforts to develop disease modifying therapies in HD. So currently we’re really excited about gene science in our Huntington lowering drugs, which at the moment are delivered through intra thecal injection. So, through lumber puncture. My work with Ed was running a study called HD CSF which was in an observational study where we’re collecting or have collected spinal fluid which is call CSF, or cerebral spinal fluid, and blood from HD patients with matched phenotypic data and MRI data.

Lauren Byrne:

And this is going to be the first longitudinal collection of CSF in Huntington’s Disease, which we just completed collection a couple of weeks ago. So, we’re starting to analyse the data and it’s going to be super important for the current trials, particularly for developing the tools that we are using to measure efficacy and end points.

Lauren Byrne:

For example, being able to measure CSF in Huntington was crucial for the phase one of that trial. There was a lot of news on it last year where we were able to show that the drug could lower the Huntington protein in the CNS. Without the ability to measure Huntington in the CSF, we wouldn’t have been able to show that target engagement. So, developing tools like this and bio fluid, biomarkers will hopefully help that. And that’s where mine fits in with the rest.

Lakshini Mendis:

And Akshay what about yours?

Dr Akshay Nair:

Yes, so as I said earlier, my interest is the neuropsychiatric symptoms that people get in dementia. And until we have a cure, obviously we need to continue to develop ways that we can care for people. And understanding why people develop certain neuropsychiatric symptoms is a lot of the focus of what I do. In particular, I’m actually interested in the concept of motivation and what drives us to do the things that we do or seek out the things that we want to do. So, people with lots of dementia’s develop what’s known as apathy, the kind of Denovo loss of motivation. And it’s kind of less well-publicized as compared to things like irritability or aggression. But apathy in dementia is actually quite a devastating symptom. So obviously, the loss of drive to do very basic things like wash yourself or eat or look after yourself can have a huge effect on your health.

Dr Akshay Nair:

And in HD, as compared to things like depression and irritability, we don’t have any treatments for apathy at all in clinic. And there’s also a very intimate link between HD and apathy. So, as HD progresses, there’s a lot more apathy, there’s a lot of apathy in the condition. So, my PhD is about the neural and computational basis of motivation and apathy.

Dr Akshay Nair:

So, I do a bit of work at the Max Planck Centre developing computational models of normal human motivation and then thinking about the neural basis of those models and then coming up with hypothesis as to why people with HD develop apathy. So, in particular, I’m interested in basal ganglia circuitry and how disruption to basal ganglia circuits puts people at risk of losing motivation.

Lakshini Mendis:

Yeah, that’s great. It all sounds like really interesting work. It’s looking at different aspects, I guess, of Huntington’s Disease as well, which is so important. And if I just put this question to the whole panel. We sort of touched on this, but some of your answers about how do you think the research you’re doing in Huntington’s Disease is relevant then to understand other types of dementia. So, I know actually you touched on this more broadly with the work that you’re doing, Marina and Lauren maybe-

Dr Marina Papoutsi:

I think the advantage of HD is because there’s a genetic test, you can actually observe the progression of the disease many, many years before people start manifesting symptoms. And because HD is actually the most common dementia, genetic dementia, you have much larger cohorts compared to let’s say familial AD. So, it gives you this amazing opportunity to actually monitor disease progression many, many years, to understand the mechanisms that are there in the brain already to try to protect the brain from declining rapidly.

Dr Marina Papoutsi:

So, for example, looking like I said before, the lifestyle factors, things like that that can affect cognitive decline in HD. And I think going back to other diseases that could be related, let’s say Parkinson’s Disease where they don’t really have very good biomarkers at the moment. It’s a much more complicated disease especially because the cause of the diseases is unknown. But you can sort of start to see to what extent do these factors actually have an effect on this disease. So, you can try to make some parallels between the disease and see whether what works in one disease and to what extent it works in another disease, if that makes sense.

Lakshini Mendis:

Yeah. It does.

Lauren Byrne:

Yeah, just building on that, having that pool of people that we know for sure are going to get the disease can help us build models for how we approach neuro generation. So, for example, neurofilament light is a protein that can be measured in CSF and blood which is kind of hot topic now in neuro degeneration. And we can do a lot of very exciting and interesting research in Huntington’s Disease. And that’s some of the work that I work on. But we can hopefully look to what point can we start to look at when does this protein increase compared to healthy controls and gene carriers. We expect it to be quite early on. At the minute it seems to be one of the earliest things that changes in Huntington’s Disease gene carriers, which is quite exciting.

Lauren Byrne:

So yeah, that’s probably very similar to what Marina was saying.

Dr Akshay Nair:

The only other point that I’d like to make is that, studying psychiatric symptoms from a neuropsychiatric perspective can be quite useful because obviously in psychiatry, in general adult psychiatry, we don’t know quite a lot about what is normal motivation or what is depression and what is anxiety for example. And so, looking at neurological conditions where these things develop quite commonly may give us some clues as to the circuitry that’s involved in normal function and also in the general psychiatric population as well.

Lauren Byrne:

Just one more thing to add. So, in terms of treatment for other degenerative diseases. Huntington’s is almost paving the way for this new generation of types of drugs that will be lowering toxic proteins and things like tau or beta amyloid. They’re already starting phase one trials, very similar to what we’re already doing at Huntington’s Disease. So, they’re learning a lot from what we’re doing already. So, it’s nice to be helping in that.

Lakshini Mendis:

Yeah. Leading the way in your field almost as well. That’s awesome. And so, I guess because all three of you come from different backgrounds and you’ve taken various career paths to get to this place where you are, still looking at different aspects off the same disease. I was just wondering if you can highlight to some of our early career researchers the advantages of coming from varied parts.

Dr Marina Papoutsi:

I probably have the least relevant background to where I am now. But I think it kind of goes to say about the importance of bringing people in research that don’t necessarily have a clearly medical background or a bio science background. My first degree was in literature and then I did a degree in cognitive science and new informatics and then one thing led to the other. And I think there’s a lot more people now that are entering research careers in clinical topics such as dementia that have a diverse background and you just bring a different way of seeing things and a different way of doing things that I think can only be a strength versus a weakness.

Dr Marina Papoutsi:

So, in a sense it’s kind of nice in the lab, in Sarah’s lab we are a very diverse crowd, so there are quite a few clinicians and quite a few basic scientists. There’s a lab and there’s neuro images, so we try to approach things from all aspects as you highlighted. So, we do different stuff. We look at the cognitive, we look at the neuro imaging, we look at the lab. And we do clinical trials. So, we try to approach things from all perspectives possible to try to narrow down things and how to bring research forward.

Lakshini Mendis:

And are there any challenges because you come from different backgrounds and almost speak sort of maybe slightly different jargon languages and that kind of thing?

Dr Marina Papoutsi:

Difficult to understand the wet lab. If you don’t come from a wet lab background, it’s very difficult to understand. So, we constantly have this divide [crosstalk 00:00:19:49].

Lauren Byrne:

See I’m a [crosstalk 00:19:50] crossroads of everything. At lab meetings, I try and ask questions that I know the answers to, but I know that other people… In both of your talks, your talks can be really very cognitive and if you haven’t done psychology, I know there’s the lab people are sitting and being like, “What is cognitive reserve?” So yeah, I think there is some difficulty. I think the biggest issue for us at the minute is that we’re in different geographical spaces. So, I think our go side is very tight because we’re on the open office and work a lot together and have a lot of social kick Fridays and coffee mornings and are very social as well as work hard together. So that helps. But I think if we could all be in the same place, there would be a lot more across the hall Huntington’s Disease Centre, a lot more cohesiveness.

Dr Akshay Nair:

I don’t really have anything from a clinical perspective, I suppose. One advantage is you’re very acutely aware of clinical problems so you can see when people are perhaps drifting into areas that are quite as far from the clinical need but the flip side is obviously, for young career researchers, you have to compete with really great scientists like Marina and Lauren and that’s fine, but it’s just part of the challenge of being a clinical academic.

Lauren Byrne:

I think Akshay undersells himself a bit. [crosstalk 00:21:30].

Dr Akshay Nair:

Absolutely not.

Lauren Byrne:

Actually, he’s an extremely bright scientist himself and a very good psychiatrist.

Dr Marina Papoutsi:

So, one more thing is actually really important, the fact that the clinic and the lab are actually very closely linked and that allows us A, to reach out to the patients and their families and establish a really… We have generally really good relationship with all of the patients and then take part in our research again and again and again, and they feel motivated but we have this really, like patient comfort and making sure the patients know what they’re getting involved is really, really important and in gaining their trust and having these stress relations is really, really important.

Dr Marina Papoutsi:

I think the fact that the clinic team is integrated the lab makes this work even easier because they know the clinicians very well personally because they go to the clinics and then through that, we can get to know them in the research side as well.

Lauren Byrne:

It’s very much a key component of the MDT, the multidisciplinary team and I think definitely on the HD side of things, it gives them a lot of hope to be taking part even if it’s not to help themselves, to help their children and future generations.

Dr Akshay Nair:

Can I add one advantage is just picks up from… I know we’re talking about disadvantages, but… From a psychiatry perspective, I think as a being a psychiatrist working in HD, it comes back to what Lauren was saying about the nature of the community and as compared to other disorders, other conferences you go to, with HD you really are exposed to everything from cell biology to cutting edge disease modifying treatments, to care, end of life issues, the management of neurological conditions. You really get exposed to the whole gamut of clinical medicine to some extent.

Dr Akshay Nair:

So even just for trainees out there who are thinking about doing HD, it is a relatively rare disorder, but I think the exposure that you get to science is second to none from my experience anyway. I think conferences that I’ve been to on specific disorders or that are more top level to do with psychiatry tend to have one higher level focus and rarely dip into the levels that you’d get at a HD conference.

Dr Akshay Nair:

So certainly, as a training experience and as an educational experience, I think working at HD has been fantastic for me certainly.

Lakshini Mendis:

Well that was going to be my next question. What advice do you have for people thinking about getting into this area, but Marina and Lauren, do you have anything else to add to Akshay’s?

Lauren Byrne:

Ask that researcher out for coffee if you want to get involved in the research and hope for the best. The trick is finding what you want to do and then just annoy people until they take you on.

Dr Marina Papoutsi:

I think, particularly now, it’s a really exciting period in HD research with all the clinical trials happening at the moment. We’re doing a lot of exciting projects looking at people that have the gene 20 years from onset. The young adult study. We have the clinical trials running and we do a lot of other stuff in parallel, more observational things to try and understand again, the disease progression and things like that.

Dr Marina Papoutsi:

So, it’s all kind of come together and I think in the next few years, we’re going to have a very big breakthrough, especially with the first clinical trial, the [inaudible 00:25:05] coming up in the next year hopefully. So, there’s a lot of really exciting things in a really, really exciting time for HD research and for the patients obviously. And I think if somebody is interested in neurodegenerative research, this is a really good time to get involved and gain a lot of exciting experience about from biomarkers to running a clinical trial, to looking at neuro degeneration 20 years from onset.

Dr Marina Papoutsi:

And these things hopefully will create a new generation that will then move on to other diseases like Alzheimer’s or PD. We saw recently with the NFL for example, with Alzheimer’s Disease that it seems to be a real good market for that. So, there’s a lot of experience that one can gain in HD, that can be transferred to other diseases later on as well.

Lauren Byrne:

Because I think that’s going to be the key for all of these diseases is treating before the degeneration really happens. So, we’re going to need always to monitor, pick up these degeneration, whatever it may be, more maybe once you get over a certain age, like an annual check-up for… In terms of NFL for example, we see it in 10 years from now in the clinic. Take blood NFL, when you come in on your yearly visits, oh it’s slightly raised above your predicted level for your age and CAG repeat length. Maybe go have a lumbar puncture or go have an MRI scan and once you build up, have all these different tools to monitor different pathologies and then hopefully the drugs have already come by then. That’s going to be the key because it’s hard to cure something that’s already damaged half the brain. So, a lot of these diseases, once symptoms occur, there’s already been a significant amount of damage, Huntington’s we know there’s changes 20 years before in brain scans before the diagnosis, of motor symptoms.

Lakshini Mendis:

Great. So, thanks all. I think that’s probably… It’s already time to start wrapping up, but it’s been a really interesting discussion around… I’ve learned more about Huntington’s Disease in general and then how the work you’re doing is applicable across to other neurodegenerative diseases. And then yeah, just some tips I think for our early career researchers as well, which is always so important.

Lakshini Mendis:

So, I’d like to thank our panellists today, Marina, Lauren and Akshay. Thank you for joining us. Listeners don’t forget that you can share your views on this topic by posting your comments in the dementia research forum. You can also say engage with us on Twitter using the hashtag EZR dementia. Are you all on Twitter, by the way?

Lauren Byrne:

I am on Twitter, yes.

Dr Akshay Nair:

Yes.

Lakshini Mendis:

Are you happy for our listeners to start engaging with you [crosstalk 00:28:13] and what are your Twitter handles if you could just share it?

Lauren Byrne:

Yeah, LaurenBurns7337.

Dr Akshay Nair:

Let me look mine up.

Dr Marina Papoutsi:

My initials, so MP_Neuro.

Lakshini Mendis:

Awesome. And Akshay’s just looking up his.

Dr Akshay Nair:

Okay I’ve got it. So obviously I use Twitter a lot as you can tell. It’s _A_Nair

Lakshini Mendis:

Perfect. Okay. Well, we have those details up on our post as well. So, feel free to follow and engage with today’s panellists. And finally, don’t forget to subscribe to the Dementia Research podcast. Leave us a review on SoundCloud or iTunes, preferably five stars of course. But yeah, I’ll leave that up to you and tell all your friends and colleagues about us. Thank you very much.

Dr Akshay Nair:

Thank you.

Voice Over:

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