Podcast – Neuropsychiatric Symptoms in Dementia

Voice Over – Welcome to the NIHR Dementia Researcher Podcast, brought to you by dementiaresearcher.nihr.ac.uk, in association with Alzheimer’s Research UK and Alzheimer’s Association, supporting early career dementia researchers across the world.

Megan: Hello, and welcome to another podcast brought to you by the dementia researcher website. I’m Megan O’Hare and today I’m joined by three panellists who all work in and around the world of psychiatry and dementia. In the UK, there are 850,000 people living with dementia, which probably know, but did you know that approximately 90% of people with dementia are affected by neuropsychiatric symptoms at some stage. This term generally refers to things like agitation, hallucinations, delusions and depression that occur as a result of neurodegenerative disease. Today we will be talking specifically about apathy and depression and also treatments for the various symptoms listed and the impact of the severe side effects these drugs can cause and how we can use that information to develop safer drugs.

I’d like to welcome our panellists today:

Isabel Foote, a PhD student at the Wolfson Institute for Preventative Medicine at Queen Mary University, who you may remember from a podcast we did at the end of last year as having an irrational fear of slugs [laughing]

Byron Creese, a senior research fellow at the University of Exeter who’s area of interest is neuropsychiatric symptoms in dementia

And Miguel Vasconcelos da Silva, a PhD student and dementia theme manager and research nurse who splits his time between King’s College London and the University of Exeter.

Welcome to you all. Shall we start with a quick round table to expand a bit on your areas of research, a bit of background to you and your work, so shall we start with Isabel?

Isabel: Sure, so hi everyone. As a bit of background, I got interested in dementia because when I finished college I helped my Grandad in looking after my Grandmother who had Alzheimer’s Disease. And then after that I trained as a nurse in Birmingham so I looked after quite a lot of patients in the hospitals that had dementia and also whilst I was doing my training I got really interested in research and my tutors kind of encouraged me to pursue that so I did a MSc in Neuroscience at King’s College London and there I did a completely different kind of research project which was lab-based looking at inflammation and depression and that kind of taught me a bit more about the biological basis of psychiatric diseases which I found really interesting and then basically I got really lucky because now my PhD project that I’m doing at the Wolfson Institute of Preventative Medicine at Queen Mary is focussed on the link between depression and dementia so it’s kind of two passions. And, my project basically looks at, I’m looking in large data sets to see whether there’s any shared genetic and environmental pathways or mediators that are associated with both depression and dementia to try and understand a bit about the biology that might be underlying the link between the two disorders and then also we’re setting up a case controlled study where we’re trying to find biomarkers that might be able to differentiate people who have depression only from people who have depression with cognitive impairment to try and understand whether there’s a difference in these two patient groups.

Megan: Ok, and Miguel, I think you are also a nurse, so you and Isabel can talk about that [laughing]

Miguel: Interesting, yes, so good afternoon everyone, so I qualified as a nurse in 2009 and in Portugal and since then I’ve worked in care homes where I’ve had direct contact with people living with dementia and there carers or family members as well, so that’s where I developed my interest in dementia. And by experiencing the, how people have been afflicted some of the symptoms as well so direct contact with patients, after that I worked in hospitals for about three years and I had, in the Stroke unit where we had clinical trials ongoing and other research projects and that’s how I developed as well my interest in research and then came the opportunity to do Stroke research and then from there to move on to dementia research and after a couple of years working in the dementia research the opportunity came for me to do my PhD project, which I am looking into apathy in people with dementia in care homes so that’s how it’s, my history and nursing background so quite interesting as well like yours.

Isabel: Yeah.

Megan: Great, and Byron.

Byron: So my background is in psychology, I worked, after my degree I worked in the oil industry for a few years and then started my PhD at King’s College with Clive Ballard and that’s where I landed in the area of neuropsychiatric symptoms. I finished my PhD five/six years ago and then since then have kept my focus on that area but I apply lots of different methods to finding out about neuropsychiatric symptoms in dementia so that could be genomics, just started some transcriptomic work to do with drugs but also clinical research in neuropsychology as well. So quite broad.

Megan: So, at the beginning I listed a, fairly horrific list of neuropsychiatric symptoms: agitation, hallucinations, delusions and depression and the fact that 90% of people with dementia will be affected by these symptoms at some stage, Isabel you are focussing mainly on depression, what have previous studies shown about the relationship between depression and dementia?

Isabel: Yeah, so there’s kind of two key main trains of thought in which depression and dementia could be linked basically there’s been a number of meta-analyses that have been performed that show that there’s an increased risk of dementia in people who have depression by about, it varies between about 2-fold and 6-fold increase in risk. There’s been in 2017, Gill Livingstone and colleagues did a big Lancet commission report that basically looked at modifiable lifestyle risk factors for dementia and they calculated PAF scores which are population attributable fractions, they managed to calculate a percentage of the risk factors and how if you took that risk factor out of the picture by preventing that from happening, you’d decrease the incidence of depression, of dementia by a certain amount and basically depression came out as one of nine key risk factors to target, and they found that even if you accounted for the kind of confounding of the other risk factors, 4% of incidence could be decreased by managing depression so that’s…

Megan: So it suggests it’s modifiable…

Isabel: And so, some of the other areas not just with depression but with other modifiable lifestyle risk factors basically, incidence in western countries has actually started plateauing and they think it might be because there’s better treatment of other kind of risk factors like depression but also cardiovascular risk factors that might, that kind of highlight the potential of targeting these risk factors and preventing some cases of dementia.

Megan: This might be quite a naïve question, but you sort of, I understand how you can reduce for cardiovascular disease what, how can you reduce your risk of depression and therefore dementia

Isabel: I think it’s more about effective management of depression and in some cases some people don’t necessarily get treatment for it or they just think their depressed and so they don’t necessarily go to the doctors or something for it and that, whereas in terms of cardiovascular risk then there’s been a lot more, kind of, health promotion in what to do in reducing it yourself, whereas that’s still kind of being developed in the depression field. But, with having antidepressant treatment and things like that it could be that, it could prevent some cases of depression which might then lead on to preventing dementia, however the other train of thought is that rather than, because when they’ve done life course analysis of when depression is a risk factor for dementia it seems more that later in life it’s a risk factor, and because there’s evidence coming out that there’s a prodromal period of about 30 years in dementia, so that’s about 30 years before people get traditionally diagnosed with dementia there’s actually biological changes happening as part of the disease process, there’s this problem with this reverse causation because actually people might be getting depressed as part of their dementia trajectory…

Megan: So that’s a prodromal symptom essentially

Isabel: So maybe it could be that the prodromal symptom and actually it is part of dementia rather than being an independent risk factor so that’s kind of the key area of trying to understand a bit more about the link and how you might go about treating it and preventing dementia from happening.

Megan: What, when you say later in life, what time period, what age is that?

Isabel: So it’s more kind of from about late 50s/60s onwards

Megan: Is there any gender difference, this is quite a common thing at the moment, or like a…

Isabel: I don’t know about gender difference, I know that depending on how many times you have had depressive episodes and the severity of the depression really further increases your risk of dementia. But, in terms of the gender differences I’m not sure so much.

Megan: Miguel, let’s move on to you and another symptom, apathy. I believe it’s considered one of the most common neuropsychiatric symptoms, could you tell us maybe how apathy is different from depression?

Miguel: So, you’re right to say that apathy is one of the most common symptoms in dementia so a recent paper from Professor Ballard has reported a prevalence about 36% of apathy in people with dementia which could range between 17-82% so you can see kind of varied but also how it could be big prevalence as well. So, one of the main differences I would say, so people with depression they’ll be tearful, they’ll be wishing to die, they might experience some of the symptoms that people with apathy will have which is the loss of interest, not engaging, but people with apathy won’t be tearful, they will not be wishing to die, they just lost the interest in the world around them, they will engage in activities, they might not be interested in doing new things as well, so those are the main characteristics of apathy.

Megan: Yeah, I think, it’s a word you use quit e a lot, you sort of understand it but I’ve never really thought of it in a clinical situation and it’s actually a diagnosis, is it?

Miguel: So, yes, that’s one of the other things as well, so currently there’s not a clear diagnosis of apathy as well. So there’s no clear as well, way of diagnosing, and clear way of treating, so there’s still a lot of debate but currently, Alzheimer’s International Association is trying to do some work and develop some research around it to help us understand better and to have a clearer diagnostic system for apathy as well. I don’t know what your thoughts are as well, the overlap about depression and apathy.

Isabel: That’s a big problem in the depression field is the fact that actually, there is probably a collection of syndromes rather than depression being the same cause for everyone and if you look at like the DSM-5 criteria there’s, it’s so opposing of, as long as you’ve got a certain number of symptoms it could be someone’s got, you know, raised hunger, some people have decreased hunger, some people sleep more, some people sleep less, some people have apathy, so, you get this problem where they could actually be a number of different causes and probably disentangling that would be useful in the area of dementia because it might be that there’s certain symptoms that are more of a problem in dementia which I think apathy it seems like it’s a big one.

Miguel: Yeah, distinguish between that, it’s quite important so we can have more direct approach in treating those symptoms.

Megan: Yeah, I was actually going to ask, are there treatments for apathy?

Miguel: So currently there are no available treatments and there are recommendations and mostly are anti-depressants, are mostly widely used. But no recent papers published that prove to be effective in treating apathy.

Megan: Ok, maybe Byron, let’s bring you in at this point, before we get down to the biological pathways bit which is my favourite bit [laughing] – you wrote in the section ‘are there any specific points you would like to make’ that we should hammer home just how awful the symptoms are, that patients have worse clinical outcomes if they’ve experienced neuropsychiatric symptoms, so could you maybe just let rip and tell us about that?

Byron: Yeah, I think I forgot I wrote that!

[laughing]

Byron: I think what I meant I guess was it’s, it’s important to describe the prevalence of the symptoms and the fact that there aren’t any available treatments in the context of what Miguel was talking about so depression, apathy and the context of dementia after the diagnosis, but it probably also applies to pro-dromal dementia as well, that Isabel was talking about.  But in the context of Alzheimer’s I think it’s important to really understand what the individual goes through with these symptoms, and it’s just really, really unpleasant. So, I mean, I’ll talk, I’ve got kind of psychosis on my mind a little bit more at the moment if I can just step to that…

Megan: Sure, sure…

Byron: For example, if you have a situation where you have someone with dementia who has delusional thoughts and so what that can often mean is that someone feels like they’re food or drink has been poisoned, that a spouse or loved one is cheating on them, I can’t think, I was trying to think of the proper word [laughing]…infidel, spousal infidelity. So, or that their house is not their home, right, and these are like, you can imagine as well as the cognitive decline, and the cognitive impairment actually then what an individual has to deal with on top of that cognition impairment is these really unpleasant symptoms.

Megan: In a way, they affect your personality, so how you interact with the world and then how the world interacts with you, you know the cognitive decline is almost more accepted than behavioural traits like that

Byron: Yeah

Isabel: Yeah, certainly when I was working on the elderly wards, there is actually quite a lot of relatives that would come in, a patient would come in and it would be because a relative couldn’t cope with the kind of more behavioural and personality sides of the disease rather than the fact that they kept forgetting things, so I think it is something that’s kind of not spoken about as much as the memory impairment? That actually…

Byron: Yeah

Isabel: It impacts people’s lives

Miguel: Yeah

Megan: We said 90% of patients will experience these symptoms at some stage, it’s not associated with a later stage then, it could be really early on?

Isabel: Yeah, it seems like it could be early on

Miguel: Yeah

Byron: I think apathy and mood symptoms in particular can emerge earlier on, the kind of psychotic symptoms, hallucinations and delusions seem to appear later in the disease and a lot of these symptoms fluctuate as well so I think the 90% figure would be like accumulative prevalence right across 10 years of disease or something

All: Yeah

Megan: Ok

Isabel: And also I think sometimes it’s hard because people who might have depression or apathy early on this disease process it might just be put down oh that person’s aging and it’s kind of normal depressive feelings of that point in life kind of thing so sometimes it doesn’t get taken into account that then when people then look back on it retrospectively they realise oh actually maybe this was a change, or something changing in that person and that was actually part of the disease process, so

Megan: So maybe let’s get on to a bit of basic biology, Isabel you said you actually worked in a lab for a while, Byron before we started recording said that he no longer works in an actual lab with pipettes…

Byron: Because I’m not very good at it

[laughing]

Byron: Luckily my boss is patient and nice…

Megan: And listening right now! So, what are the specific pathways, because you talked about genetic, shared genetic pathways that maybe might underlie the link between depression and dementia

Isabel: Yeah, so, a lot of the evidence that underlies kind of the biological plausibility of there being a link between depression and dementia actually at the moment is more from lab work and not from the genetic side. From looking also at, in cohorts of, just in biomarker studies for example. There’s actually a lot of different biological pathways that have been shown to be impaired in both depression and dementia like there’s been evidence that people, you have hippocampal volume loss, there’s chronic inflammation, all sorts of things. The kind of two that I’m more focussed in my work are HPA-axis dysfunction and chronic inflammation. So basically, the HPA-axis is the Hypothalamic-pituitary-Adrenal-axis and it is the way that is the way the brain controls the response to stress so you get a stressor and then you have the hypothalamus and the pituitary gland that release hormones that tell the adrenal glands to release cortisol and basically there’s two types of receptors, you’ve got the glucocorticoid receptor and the mineralocorticoid receptors of which there are a lot of them in the brain, especially in the hippocampus.

Megan: Which is an area affected in dementia?

Isabel: Exactly, it’s an area of the brain that’s very important in kind of learning and memory and also some emotional regulation. Essentially, the cortisol binds to these receptors but if you have a kind of increased exposure to chronic stressors or there’s a problem with the system the cortisol doesn’t, the adrenal glands essentially don’t get told to stop producing cortisol so you get this problem of getting glucocorticoid resistance in receptors which then means that you have these elevated levels of cortisol which can then lead to all kinds of problems like neuronal damage or inflammation and this is a kind of one of the big areas that people are looking at in how stress and depression might lead to then having cognitive impairment because cortisol, elevated cortisols also been linked to increased amyloid beta-production which is one of the really important pathological proteins in Alzheimer’s Disease, so it’s kind of this chain of events and it, then it, on the other hand you’ve also got a lot of studies that have shown that there is chronic inflammation in depression and dementia in the periphery so there’s been a lot of biomarker studies that have found increased levels of inflammatory cytokines in people’s blood and also CSF. And so it seems the inflammation and stress dysregulation could be one of the really key factors that are kind of accumulating problems in these brain areas that are then leading to the co-morbidity of depression and dementia.

Megan: And this would happen, you know, so many years before, and then over time that’s how the symptoms come out later?

Isabel: Yeah, and also it could be that that’s why maybe you’ve got a kind of cognitive reserve that is kind of a threshold so each individual will have certain genetic risk factors that are protective and again, they are going to increase their risk of getting dementia and it, if then they are exposed to these kind of chronic stressors then maybe that will push them kind of over this kind of edge of what they can like withstand within that area of the brain and then they get to the point when the neurodegeneration happens if that makes sense, but it is quite messy area because obviously a lot of the work being done is kind of cross-sectional or and done enough time points to really measure over a long period of time so you can’t really get a great grasp on exactly the processes going on, so.

Megan: Ok, Miguel, I think you are also looking at the genomics and genetics of apathy, is that right?

Miguel: Yes, that’s right, yeah. So, the idea behind is, there’s not been many studies done around apathy so majority of results and findings of various studies have been inconclusive around apathy so we know very little still about apathy. Most studies around genetics have candidate genes studies and there again left us with very little information about. The idea about going into genetics again is because previous studies in other areas of psychiatric symptoms they’ve helped understanding better symptoms and creating clearer phenotypes so then we can start treating and looking further into it so therefore we decided to do a genetic association analysis in the future stages of my project.

Megan: I think maybe we bring Byron in again at this point to talk about treatments as we’ve talked a bit about the pathways and, I know you have some thoughts on the treatments.

Byron: Yeah, so we’re, so if we’re talking about treating depression and apathy in the context of dementia then there’s, historically anti-depressants were used that are the same drugs that are used to treat major depression in younger adults but there’s really limited evidence that those work in the context of depression in dementia so perhaps an indication there’s other things going on biologically. I at the moment am working a lot in the area of anti-psychotics so these are drugs that would typically be used to, to, to treat symptoms more along the lines of agitation, aggression and psychosis, they’re modestly effective really at best and, but they also have quite a severe profile of side effects so they can cause stroke, thromboembolic events, pneumonia and other infections, falls, fractures, and there’s an all cause increase risk of mortality so it’s important to find out why, what kind of drugs work and what don’t work and whether drugs, why drugs are unsafe, we don’t really know why they are, so I’ve been doing some work trying to find that out but not using humans [laughing] given the obvious ethical barriers, we don’t want to do that. So, instead what we’ve done is generate lots of transcriptome-wide expression data from anti-psychotic drugs in cell lines, wasn’t me because I’m not going there! So I’m collaborating with some colleagues in Exeter on that, so but we’ve generated lots and lots of transcriptomic data and using the expression profiles of anti-psychotics what we’re trying to do is compare that to expression profiles of disease to see if there’s any areas where it looks like the transcriptome of drug and disease is positively correlated, so the, which, which might indicate that the drug is exacerbating the disease state, at least on a transcriptomic level and that can give us clues to then move forward and maybe isolate some mechanisms in different biological models.

Megan: Ok, so this is disease state without having taken any of the anti-psychotic drugs?

Byron: Yeah

Megan: So you’re just looking for elevated transcriptome levels that at the same areas as what the drugs would also do, so therefore you wouldn’t want to put the drug in the disease state where you would…

Byron: It’s basically the reverse of what’s done in drug repurposing quite commonly, where what you look for is a negative correlation so the drug is pushing the transcriptome upwards and the disease I pushing the transcriptome downwards, you would take that as evidence that the drug is reversing the transcriptomic state of the disease which would be a good thing…

Megan: Back to normal or hopefully

Byron: Whereas just kind of looking at the opposite of that and positive correlations or, yeah, positive correlations yeah, so and it’s not a conclusive, it’s more of a triage so we can kind of identify and prioritise areas for further investigation but the key thing is trying to do that without working in, working with new human data so we only, we only really, realised the dangers of anti-psychotics once they’d been used in humans in many clinical trials and in many thousands of patients so.

Megan: And they would have been clinical trials in patients who didn’t have dementia initially because they are anti-psychotics that are used for other…

Byron: No, they would have been clinical trials of people with dementia and agitation psychosis and so on…

Megan: Right

Byron: But they detecting the side effects is, requires very, very, very large clinical trials, compared to detecting the clinical therapeutic effects so often in a clinical trial of several hundred people you might not notice subtle side effect differences with the drug, you would only notice if it was massive, if there was a massively increase in side effects.

Isabel: And also sometimes side effects take a while to kick in…

Byron: Right

Isabel: So you need a longer timeframe which you don’t always have

Megan: By which point the clinical trial has finished

Isabel: Yeah, so sometimes it’s not until patients are in a clinic then people start realising that oh actually this side effect is happening

Megan: Yeah, it’s not a new symptom, it’s a side effect

Byron: Real world monitoring after a drug’s been licensed but, yes, I think in the, there’s a space to kind of do some work to find out why some of these drugs are harmful and if we can demonstrate that in principle that can be done in vitro that would be helpful

Megan: Ok, so are there any final points you’d like to make before we end today’s podcast – any key challenges of research in this field, I mean, Byron’s mentioned not using humans [laughing]

Isabel: I do think one of the other sides of it is in the studies that do focus on humans a lot of the focus is on European ancestry, especially in terms of genetics but also in terms of all the other types, epidemiological data and everything it’s looking very much at what are risk factors for white Europeans and it might be vastly different in other ethnic groups so I think that’s going to be something that maybe comes out a bit more because for example there’s some evidence that shows that APOE4 is not actually a risk factor, a genetic risk factor in Afro-Caribbean populations so and that’s one of the really big ones that people are focussing on so that’s going to be quite an interesting take on the field and how they manage that kind of problem.

Miguel: Yeah, I agree with you, but I think it’s good that we’re start somewhere, we have some initial steps so for example in apathy there’s not much data available, there’s not been genetic studies or large cohort studies, most studies done in the past didn’t have apathy as a primary outcome but they looked into apathy so just the same thing with some of the genetics studies we start somewhere maybe small scale and that will then leverage data or information that will lead us to big studies and probably understanding better the picture of the symptoms that we have but I agree with you that we have to be more, more multicultural, more international as well as we say.

Byron: So I think one key thing kind of as we’re building all these kind of new studies is actually getting a handle on what apathy and depression are, I think Isabel mentioned it earlier, the DSM-5 criteria is really, really complicated and in dementia we’re at the moment using ratings scales rather than yes/no diagnoses and that in a way might be more helpful because then you’re really just looking down at the symptoms that are present rather than a clinical diagnosis. I’ll probably get a slap on the hand from the nosology police for that sort of comment

[laughing]

Byron: But yeah, we’ll see, but I think it’s, what I’m trying to say in all seriousness, I think we haven’t really settled on as Miguel, for apathy but also haven’t really settled on what these, these symptoms really look like or what, settled on a criteria and that goes for psychosis, it goes for depression, it goes for apathy, it goes for agitation and there’s people, it’s an active area that’s being worked on but it’s important that, to settle on some of those definitions before…

Megan: Doing the large…

Byron: Yeah, the large, basically you don’t want to do an analysis on a phenotype that turns out to be a load of rubbish!

Megan: Yeah, if they change the goalposts, so you haven’t included the right people

Isabel: And I do think the depression, especially because there’s so many possible symptoms and causes in terms of applying it to dementia research obviously not, so many people have depression in their lifetime, 1 in 4 people, and not everyone is going to go on to develop dementia so you don’t want to make people have undue stress about oh I might be really at risk of getting dementia when actually they’re not at all so I think that’s going to be a really a key area to try and work out whether people who have depression in dementia show any kind of biological difference or symptom difference in comparison to people who have depression but no cognitive impairment because then you can kind of focus on the right patient population rather than having these preventative strategies that are just focussed on everyone with depression because that could cause undue stress and ethical concerns there so. But I feel like Miguel your work is kind of looking a bit at that, where you’re focusing really on apathy in people with dementia and I think that’s a really good way forward to go because then you’re looking at a sub-population and it might be more homogenous so you might be able to find more genetic markers that are useful than say I don’t know apathy in the entire population so.

Miguel: Yes, so I think that’s like you said, it’s a nice way to move forward and to be, have a direct approach to it as well. And trying to define clearly what is apathy in this instance, try to have a better understanding, a clear phenotype for it, so then we can treat it more adequately for the population that we’d need to treat so we still have a long way to go and we will work towards it and hopefully we’ll come back with some interesting results from the work that I’ll be doing.

Megan: So, we’ll interview you all in a year!

[laughing]

Megan: OK, thank you very much for today, I hope you’ve enjoyed it, if any of our listeners have anything to add on this topic, please do post your comments in the forum or drop us a line on twitter using #ECRDementia. We have profiles on all of today’s panellists on our website and there you will also find a transcript of the podcast. Finally please remember to subscribe and leave a review on this podcast through our website, iTunes, Spotify, podbean or soundcloud and tell your friends and family and colleagues, thank you!

Voice Over – Brought to you by dementiaresearcher.nihr.ac.uk, in association with Alzheimer’s Research UK and Alzheimer’s Association, supporting early career dementia researchers across the world.

END