Podcast – Diagnosing Dementia – Now and in the Future

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 Society, supporting early career dementia researchers across the world.

Adam Smith:

Hello, and thank you for tuning in to the Dementia Researcher podcast. I’m Adam Smith. I’m the Program Director in the office of the NIHR National Director for Dementia Research at University College London, and I’m delighted to be hosting this week’s show where we’ll be discussing dementia diagnosis in the past, in the present, and in the future.

Adam Smith:

To explore this topic, I’m joined by Dr. Josie Jenkinson, a Consultant Psychiatrist for Older People from Surrey and Borders NHS Foundation Trust, and Dr. Elizabeth Coulthard, who is a Consultant Neurologist and Researcher from North Bristol NHS Trust. Josie and Liz are both frontline senior NHS doctors supporting people living with dementia, and involved in dementia diagnosis each day. In addition to their clinical roles, they both have PhDs and are researchers in their own right, which plays a major part of their role.

Adam Smith:

Coming to the panel with an entirely different perspective, I’m also joined by Dr. Amanda Heslegrave, who is a Senior Research Fellow from the UK Dementia Research Institute at University College London. Amanda is a scientist working at the cutting-edge of her field, working in the development of new biomarkers for neurodegeneration.

Adam Smith:

I’m going to start by setting the scene. Whilst everyone may experience dementia and its symptoms differently, the pathway to diagnosis is very similar. However, even that varies across the country, and it hasn’t changed much over the last 10 years either, certainly not the tests you might go through to be diagnosed.

Adam Smith:

The push to really get a better direct diagnosis started in 2012 with the dementia challenge, and then the real push started in 2014 when the pressure to meet targets really started to be applied. This prompted a backlash in some areas, with some people asking what the point of an early diagnosis was when there were no treatments to offer, and it also drew some criticisms when GPs were incentivized, as a short-term measure, to kickstart the improvement.

Adam Smith:

That’s the history lesson done with. Almost seven years later and there are currently 427,000 people in England with a formal recorded dementia diagnosis. Overall, this represents 61.1% of everyone the NHS believes to be living with the disease in England. So that’s still lower than you might expect, but when you consider that the number of people with a diagnosis was only 266,000 in 2011, the NHS has come along a way. Facts and figures aside, of course we know that behind these statistics are real people living with the disease going through these care pathways.

Adam Smith:

That nicely leads me to my first question. Many of our listeners are early career researchers from a wide range of backgrounds and may not know how this works. So, apologies, as this will differ from country to country. Josie, I’m going to come to you first. Can I ask you to start by introducing yourself, and talk us through the typical care pathway to get a diagnosis.

Dr Josie Jenkinson:

Sure. Thanks, Adam. Thanks for having me on the podcast. It’s great to join you again. So I’m Josie Jenkinson. I’m a Consultant Psychiatrist for Older People. I work in Surrey as part of their liaison service. So we’re like the bridge between the mental health trust and the acute trust. Whereas I don’t necessarily make lots of diagnoses of dementia, I see people with dementia every day, and I see their experiences of how they move through diagnostic pathways.

Dr Josie Jenkinson:

I also have a national role. So I work with the Royal College of Psychiatrists as part of the Faculty of Old Age Psychiatry, and dementia diagnosis pathways has been something that has been very much on our minds for many years, particularly more recently with the emergence of potential new treatments in the future and the growing availability of biomarkers. So we need to be thinking about how our services get ready for these changes.

Dr Josie Jenkinson:

So in terms of the pathways that we have, I think one of the key issues, which will probably come out more as this podcast goes on, is the variability in pathways that’s out there across the U.K. I’d say the most typical pathway is probably that somebody might go to their GP because they or their family have noticed that there’s some problems with their memory, and the GP might do some initial brief testing, probably send off some blood tests to look for possible reversible causes of dementia, so some deficiencies that may cause these problems, or hormone imbalances that may cause problems with memory. Then they would send a referral on to a memory clinic.

Dr Josie Jenkinson:

Memory clinics are most usually run as part of community mental health teams for older people, so as part of mental health services. So, if somebody gets to a memory clinic, they’d likely be seen by either a junior doctor or a senior nurse or consultant psychiatrist, to go through an initial assessment, which usually takes around an hour, maybe a bit longer, and would involve some more detailed memory testing to what the GP did.

Dr Josie Jenkinson:

They would also, in most circumstances, the vast majority of circumstances, go for what we call neuroimaging, so some sort of scan of their brain. It would ideally be an MRI scan, but often it’s a CT scan that’s used. The person may go for more detailed brain scanning if they have a rarer dementia type, to try work out what type it is.

Dr Josie Jenkinson:

Then, once the results are in, they would likely go for a follow-up appointment and have the diagnosis explained to them, and get signposted to support services that may be available in that area. That is something that also varies a lot up and down the country. Probably 10 years ago, community mental health teams, memory clinics, would keep people on for a little while and see how things progressed, but that doesn’t happen anymore because we don’t have the resources, sadly.

Dr Josie Jenkinson:

So the most typical experience would be that somebody maybe gets their diagnosis, gets some signposting, and then will go back to their GP for follow-on care, and if there are further problems down the line, then they may get referred back to the memory clinic. So that’s probably the most typical pathway, but things are changing quite a lot.

Dr Josie Jenkinson:

So we have this big thing called integrated care, a big drive towards integrated care pathways. So that’s where often you may have professionals from lots of different backgrounds and lots of different specialties working together. So, in my area of Surrey, we have something called frailty hubs, and they have GPs, geriatricians, mental health practitioners, old age psychiatry, OT, social worker, physio, you name it, and people go for holistic review. Memory problems might be picked up there and people may get diagnosis through that system rather than the traditional memory clinic. I think that’s a pathway that’s popping up across the country.

Dr Josie Jenkinson:

People may also get a diagnosis not via psychiatry but via a neurologist or a geriatrician, potentially.

Adam Smith:

Thanks for the overview, Josie. Can I ask, what’s the typical age of the patients that would come here? I know is it in the late sixties people would start to often have symptoms but might wait some time before they go to see their GP?

Dr Josie Jenkinson:

Sometimes. I’d say more often it’s later on in life, so maybe in the seventies, early eighties, but it does vary a lot.

Adam Smith:

And then does the tests that the memory clinics do in mental health trusts and these community mental health teams, do they vary from place to place in the country or is it fairly standard? Is this a MMSE test or a-

Dr Josie Jenkinson:

So they might vary a little bit, yeah. They have had to change a bit during COVID and having to do video consultations quite a lot more. So we’ve had new versions of cognitive tests coming up. But, on the whole, probably the one that we use the most is something called the Addenbrooke’s Cognitive Examination, called the ACE-III, the third version of the Addenbrooke’s Cognitive Examination. That’s our favorite. You can add on other tests to that as well.

Dr Josie Jenkinson:

If somebody’s got quite an unusual story or they score really highly on those tests but there’s still… subjectively they really think that there’s a problem, things have changed, then we can do a lot more detailed testing via neuropsychology assessments. So, memory clinics will usually have access to neuropsychologists who can go in and do a lot more detailed testing. So that does sometimes happen, but not for the majority of people coming to clinic.

Adam Smith:

Thank you. Are people surprised when they’re referred to a psychiatrist as opposed to a neurologist? We’re going to come to Liz in a moment, but is that something that surprises people?

Dr Josie Jenkinson:

Sometimes. Not always. I think the GP’s done a bit of explaining before they come to us. I’ve had a few people be a bit surprised, but not as often as you might think. So it may be that GPs are doing a good job of explaining to people what goes on. Usually, when we send someone an appointment, we send a leaflet about the service explaining a bit more about it. So maybe that helps as well.

Adam Smith:

Yeah, that makes sense. I know through my day job I’ve come across changing care pathway models over time. I know I think in Norwich they have dementia specialist nurses who work in primary care. So, if the primary care trust feels that something is a very obvious diagnosis, they might reduce pressure on memory clinics and try to diagnose there themselves.

Dr Josie Jenkinson:

Yeah. There are so many emergent pathways, it’s quite difficult to keep track of. A lot of places are doing things very differently. People are beginning to be a bit more inventive.

Dr Josie Jenkinson:

Sadly, community mental health teams have been… for older people in particular, have been under-funded and under-resourced for many, many years now. So I think a lot of this is trying to fill the gaps in services. Actually, CMHTOPs… sorry, using the abbreviation there. So that’s community mental health teams for older people. They used to be able to do this work a lot more completely, but they were better resourced to do that, and that resource has gone but the need is still there. So people are finding different ways to fill that need.

Adam Smith:

So that makes complete sense. Of course, we should say that this varies massively across the world. In other parts of the world people might be seen only by a family doctor who does the whole process, or by neurologists, psychiatrists or geriatricians and medics. It’s so variable. If anybody’s got comments to make about the care pathway in your country, please do drop those in the comments below.

Adam Smith:

So, just to recap then, typically, somebody goes to their GP, they do some tests to discount anything that might be another cause, and then they refer on to a memory clinic, receive a battery of tests over what? Is this one or two visits?

Dr Josie Jenkinson:

It could just be over one visit, but sometimes over two. The person might also see an occupational therapist as well as part of their assessment, to do other bits and pieces around how they’re managing in their daily life, as well as the more paper-based cognitive testing that we do.

Adam Smith:

I suppose, importantly, because as we’re going to come on and talk about biomarkers later on, the tests we’re talking about are cognition tests, maybe a CT or an MRI scan, and I guess a conversation, a consultation to talk about subjective memory.

Dr Josie Jenkinson:

Absolutely, yeah. The story is the most important thing. So, speaking to the person in detail about their experiences, and also their friends or family is really important. So we always try to get someone to come with the person to clinic to give the account of what’s going on. That’s incredibly helpful because, sadly, often the person coming with the memory problem isn’t able to give as detailed a story about what’s been going on. So getting that collateral history is really important. The scan and the cognitive testing are useful and important, but the story of what’s going on and how things have progressed is really key.

Adam Smith:

Liz, that brings me really nicely actually to come to you now. Thank you for being very patient and waiting. Can I ask you to introduce yourself and tell us the difference? So you’ve been very patiently listening there to a psychiatrist. You’re a neurologist. How does this differ in Bristol and the patients you see?

Dr Elizabeth Coulthard:

Right. So I’m a Dementia Neurologist and run a dementia clinic. When I set it up in 2011, it was in parallel to the community mental health run service that was just as Josie described. Really we set it up as a diagnostic service.

Dr Elizabeth Coulthard:

So we were referred people who were particularly young or had a strong family history of dementia, or where there was a suspicion that the underlying diagnosis wasn’t dementia but might be a dementia mimic, particularly where that might be something that’s treatable, patients were referred to us. And also if they have a movement disorder or other unusual neurological features, if they have epilepsy, we quite often receive a referral to try and make a diagnosis when it’s not been obvious with the first set of tests that have been done.

Dr Elizabeth Coulthard:

So, lots of our referrals come from community mental health teams. We also take referrals from GPs and, as you say, the story gives a lot away, and I think GPs and other psychiatrists and community mental health nurses are very good actually at sifting out patients who perhaps don’t have a typical story and need to be seen by a neurologist. That’s the core of the service that we run.

Dr Elizabeth Coulthard:

We focus a lot on the history, but also on physical examination to try and determine what the problem might be. We do a range of blood tests to look for the sort of things that can sometimes mimic dementia. We might repeat some of the neuroimaging or do slightly different neuroimaging, perhaps some functional brain scans.

Dr Elizabeth Coulthard:

I’m not going to touch too much on biomarkers at this point because I know we’re coming onto that later, but those are some things we use to refine our diagnosis and are really coming to the forefront now. We mainly use CSF biomarkers in our clinic, but we also occasionally use molecular PET scans, so amyloid PET scans.

Dr Elizabeth Coulthard:

So that’s the core of the service. And then, because 50% of my job is research, running clinical trials, one thing that became obvious many years ago really was that the clinical trials now required people to be at an early stage of disease, so either pre-symptomatic or with mild cognitive impairment. But the patients with mild cognitive impairment or mild memory symptoms, the whole way that the NHS is set up is actually to keep these patients in primary care and to reassure them and say, “You don’t have dementia.”

Dr Elizabeth Coulthard:

So we have this mismatch between the patients we need to do research on, so we think we’ll probably only find treatments that are effective if we try them in the early stages, and the patients that are referred up to clinic who would almost always be in the later stages.

Dr Elizabeth Coulthard:

So we actually moved to set up a new sort of service that’s linked to our cognitive disorders clinic, our standard dementia clinic, and we call that now brain health clinic. So we actually advertise to see people who’ve got mild problems, if they want to be seen. So, as you raised at the start, there is obviously an ethical debate about giving a diagnosis for an untreatable condition early in the course of the illness, but unless we do stratify patients and diagnose them early, understand their condition, we won’t be able to get them into research, and if we don’t get patients into research, we won’t be able to get treatments.

Dr Elizabeth Coulthard:

So if patients want to know a diagnosis, we see them in our brain health clinic where we try and do biomarker-led, early, accurate diagnosis, particularly of Alzheimer’s but also Lewy body disease, which is a different type of dementia, as I think most people will know.

Dr Elizabeth Coulthard:

We come up with the best evidence for prevention where we can. For example, if someone’s got very high blood pressure, then we know that in mid-life high blood pressure is a risk factor and that we see… These patients are often a bit younger so we might advise them about simple risk factor reduction, physical activity, hearing loss. There’s varying levels of evidence for this, but we try and come up with a personalized prevention program, and also enter people into clinical trials where we can. So we’re running this brain health service alongside our standard cognitive disorders service, which is very much diagnostic.

Dr Elizabeth Coulthard:

We’re now just actually setting up another focused Lewy body service to really hone in on the problems that people with Lewy body dementia have, and offer them a bespoke, skilled service. So, we are trying to set up those services where perhaps they are not covered by the standard community mental health team, where they are useful. Obviously we learn a lot all the time about what is useful, and partly that’s by who comes. So we can see people want to come to the brain health clinic and cognitive disorders clinic, they want to have a diagnosis, so we offer those services.

Dr Elizabeth Coulthard:

While we’ve been offering this service, Bristol has changed quite a lot. So, Bristol became one of the first areas to offer GP led diagnosis. So, going from a community mental health team to a primary care led diagnosis meant that the GP then had resources to supply everybody with a dementia navigator. So everybody who was diagnosed with dementia has a named person, a dementia navigator, to help them through the course of the illness. But the effect of that was, because there was a shift from mental health psychiatry led diagnosis to primary care led diagnosis, actually more patients ended up being sent to us in neurology because there was more diagnostic uncertainty.

Dr Elizabeth Coulthard:

So we didn’t know what would happen when we had this primary care led service. We didn’t know if everything would stay in primary care, but actually what happened was, we got more… So now we’re a much bigger service. We’ve got three consultants, two… actually only one at the moment because one’s on maternity leave… specialist nurses. We’ve got a neuropsychology team that helps support us so we can do that detailed neuropsychology.

Adam Smith:

You’ve brilliantly answered every follow-up question I already had planned, but-

Dr Elizabeth Coulthard:

Sorry.

Adam Smith:

No, no, no. But it did raise several other issues that I hadn’t thought about. So, of course, I was going to go on to ask you about the difference between neurology and psychiatry, but I think actually between you what you’ve done is paint this picture whereas you might think of this as two different care pathways but they’re really not. They are obviously very well-connected.

Adam Smith:

If the majority of the patients you see in neurology end up coming as a tertiary referral from memory clinics anyway when they’ve ascertained that this is something out of the ordinary or there’s something else going on, or, of course, as you said, their GP might refer to you particularly if the person’s very young, I guess. That’s looking… I’m assuming that people concerned about things like Huntington’s and motor neurone disease and these other neurodegenerative diseases as well.

Adam Smith:

So you’ve brilliantly demonstrated, I think, that the care pathways, whilst vary across the region, neurology and psychiatry work well together. Well, I’m going to say they work well together but maybe lots of neurologists-

Dr Josie Jenkinson:

They certainly can, Adam. From my point of view, in an ideal world, we would have access to the different specialties and just tailor your approach to whatever the person needs, and we would work a lot more closely together rather than having this kind of hub and spoke model with the GP having to make lots of different referrals, it doesn’t make sense to me.

Dr Josie Jenkinson:

Having more integrated care where you have access to multiple specialties who work quite closely together I think can work really well. In our integrated care system in Surrey, that does happen actually. So you’ve got geriatricians, neurologists and psychiatrists all working within the same service, or connected to the same service. I think that’s probably a better way, if possible.

Adam Smith:

And it sounds like that’s the case in Bristol as well. The idea of brain health clinics I love. In fact, I’m sure I read an article just recently how they’re setting some of these up in Scotland right now as well. Sorry, Liz, go on, you were going to say something.

Dr Elizabeth Coulthard:

I was just going to say that we’ve formed a network because there are a few of us setting up brain health clinics and, yes, Edinburgh is very prominent. There’s Oxford. Then also Manchester and South London and The Maudsley. So there are a few centers around that are starting to run this sort of thing, and we’re sharing our ideas to try and make sure that we’re aligned. I’m not sure how aligned we’ll end up being, but it seems sensible to have some core measures that we all take.

Adam Smith:

This is really nice, and this is gradually leading me in the direction I want to go with this conversation as we move slowly towards bringing Amanda in here. I think you touched on an important point about mild cognitive impairment, which we talked about earlier, and bringing forward this issue that we know that MCI is dealt with differently in the country if the tests you perform don’t answer the questions with any certainty and it gives you an indication there’s something maybe there but it’s too early to say.

Adam Smith:

The approaches I’ve come across are either send people home and say, “Come back if it gets worse,” or other places will give out a diagnosis of mild cognitive impairment and discuss changes you can make to lifestyle to maybe improve that or to prolong those conditions.

Adam Smith:

MCI as a diagnosis is a controversial one in its right, isn’t it?

Dr Elizabeth Coulthard:

Yeah. To me, it’s not really a proper diagnosis, it’s a kind of a description of a stage. [inaudible 00:23:46] to us and say, “I’ve got some mild memory symptoms,” we turn round to them and say, “You’ve got mild cognitive impairment.” What they need to know is what that means for them in the future. So we need to know how to prognosticate people with mild symptoms, and I think everybody at that stage should be offered research.

Adam Smith:

So after you discharge at the moment from secondary… Well, do you discharge? Do you keep them on your books for a while or do you keep patients… Do you refer them back to primary care?

Dr Elizabeth Coulthard:

Are you talking to me? So, yes-

Adam Smith:

Sorry, yeah, Liz.

Dr Elizabeth Coulthard:

Yeah. I try not to discharge anybody but I have to because I want [crosstalk 00:24:29]

Adam Smith:

You want to keep them for your trials, that’s why!

Dr Elizabeth Coulthard:

No, no. I want to see what happens, and you get to know someone really well as you do the diagnostic process and you want to… So we routinely do offer yearly follow-ups but obviously that comes at a… There’s a limit to the number of people you can follow-up. So sometimes we do have to discharge, and sometimes also it’s not useful for someone to come up. Some people really like it, they can get some feedback about how they’re doing, and others don’t. So we’re quite flexible, as much as we can be, with our follow-up, but I think that’s quite unusual. I think, on the whole, people are discharged.

Dr Josie Jenkinson:

Who funds your service, Liz?

Dr Elizabeth Coulthard:

We’re part of neurology. So we’ve got the sort of payment by results system. I guess it’s the CCG, but it’s not commissioned in the same way as a standard memory clinic where the parameters are set quite differently, which is why we don’t have quite the same set of rules, I think. This may end up changing.

Dr Josie Jenkinson:

It’s interesting.

Dr Elizabeth Coulthard:

Yeah.

Adam Smith:

I didn’t touch on this because I think this is probably a podcast in its own right, but talking about money, of course diagnostic tests, I mean the money’s got to come into play here, right? It sounds to me like Josie’s service is cheaper than Liz’s service because you’re going to order lots more diagnostic tests and see people for longer, which costs more money. Bringing this together to find a cost-effective service as well must be something that NHS bosses look at.

Dr Josie Jenkinson:

Yeah. Evaluation of these pathways is really important, and I don’t think it’s done enough to look at costs and outcomes, historically, as new pathways have arisen. Generally, services arise because they seem like a sensible thing to do and to fill a need, but they don’t always get evaluated.

Adam Smith:

So if you’re out there and you’re listening and you’re a health service researcher, you should definitely maybe consider turning your attention to the dementia care pathways.

Adam Smith:

Amanda, I ask you to introduce yourself and tell us about your work.

Dr Amanda Heslegrave:

Okay. So I’m Amanda Heslegrave, Senior Research Fellow at the UK DRI fluid biomarker laboratory. I did my PhD actually at the Institute of Neurology looking at… I was interested in oxidative stress and its effect on mitochondria in the brain, and some years later landed back at the Institute of Neurology, where they gained quite a bit of funding to set up a neurodegenerative disease biomarker laboratory. It was kind of to draw together expertise and try and get something going so we could… well, so we could do some good research really.

Dr Amanda Heslegrave:

So we started in 2012 doing that and at that time, as has already been mentioned actually, we were really limited to looking at research studies where they were taking CSF from people going into memory clinics or people going into other disease clinics, or whatever, because we knew, or we know, that actually, the fluid that surrounds the brain is obviously going to give us the most information about the diseases of the brain, and in lots of cases, and it’s common to all of the neurodegenerative diseases, I believe, you’ll see aggregated proteins.

Dr Amanda Heslegrave:

So, we were able to look at these proteins in CSF, and because of the place and the situation we are at UCL and the Institute of Neurology, with the National Hospital for Neurology and Neurosurgery next door, we were able to work with lots of neurologists who were also researchers, and so were able to get access to people who wanted to take part in research studies.

Dr Amanda Heslegrave:

So, in this way, we spent the first few years looking to see if we could find novel biomarkers in CSF and improving methods to actually measure things like beta-amyloid and tau proteins, and also neurofilaments in the CSF. So that’s where we were then.

Dr Amanda Heslegrave:

One of the things I was particularly, and I still am actually, interested in, is looking at how we differentiate disease. That’s a really big problem that leads on to the thinking about clinical trials for a drug and stratifying people onto the right trial. If you don’t know what they’ve got really, you can’t put them on a trial because you don’t know what you’re trying to cure. So that’s still an interest of mine.

Dr Amanda Heslegrave:

But, in the meantime, a few years in, so about 2015, we got hold of some new technology and this technology, basically it’s a super sensitive assay platform. That makes it sound very simple actually, and it is really. Basically, we were able, using this new technology, to actually move and look at the proteins that we knew were active in the brain, causing these diseases in blood. Actually, it feels like it’s taken a long time to me, but it’s probably really quickly that we’ve moved from being able to look at things in CSF, to look at those proteins in the blood and say, “Yes. These are giving us a picture of what’s going on in the brain, and all we need is some blood from someone with a disease,” or whatever. So-

Adam Smith:

Do you mind if I ask you some-

Dr Amanda Heslegrave:

Yeah. No.

Adam Smith:

… what might be stupid questions, just to help me? You can get more information still from CSF than you can blood even now?

Dr Amanda Heslegrave:

Yes. That would be true.

Adam Smith:

But CSF, of course, is quite awkward to collect.

Dr Amanda Heslegrave:

And no-one wants to do it and, particularly, what you need always in a study is controlled samples. Now, try getting someone who hasn’t got any disease and isn’t worried about a disease to give you a lumbar puncture. It’s not the easiest thing in the world.

Adam Smith:

From CSF, how reliably can you diagnose different neurodegenerative diseases?

Dr Amanda Heslegrave:

As far as I’m aware, the NHS clinic at the National Hospital is the only one that offers a dementia diagnosis service, and even then, I mean, yes-

Adam Smith:

Using CSF?

Dr Amanda Heslegrave:

Using CSF. And there they-

Dr Elizabeth Coulthard:

We do.

Adam Smith:

Oh, Liz does too.

Dr Amanda Heslegrave:

You do, sorry. Sorry, I didn’t know that.

Dr Elizabeth Coulthard:

There aren’t many centers but, yeah, we do as well, yeah.

Dr Amanda Heslegrave:

Okay. So there they look at the amyloid beta levels in the CSF. It goes down in those people. Well, it goes down, can be an indication of AD. It can go down for other reasons as well, but then you can mitigate that by using ratios. Tau protein tends to go up in the CSF, as does phospho-tau, which is pretty unique to AD in the CSF. But that still… it’s not standalone. They don’t do that and give a diagnosis, you still need the cognitive testing. You still possibly need imaging.

Adam Smith:

Okay.

Dr Amanda Heslegrave:

It’s never definitive.

Adam Smith:

You can’t do a CSF and say, “Right, I can 95% say you have Alzheimer’s, or you have Louis Body dementia,” for example.

Dr Amanda Heslegrave:

No. No, you can’t.

Adam Smith:

Do you think you ever will or is that just not how it works?

Dr Amanda Heslegrave:

Yeah, that’s a difficult question. I don’t know.

Adam Smith:

That’s okay.

Dr Amanda Heslegrave:

Because there’s never, ever going to be, for any of the diseases that we look at, I think, one thing that’s going to give you the correct answer. Not the correct answer, but, you know, the answer.

Adam Smith:

Well, actually you’ve raised an interesting point then as we move on then thinking specifically about blood-based biomarkers. So you’re managing to get to a point now where you can find out the same level of information in blood as you could from CSF. So, how useful is that in diagnosis and at what… Well, how sensitive is it in terms of age I guess is my point? Is it possible then for your fifties you would start to see changes that you might not in other ways?

Dr Amanda Heslegrave:

The most exciting breakthrough recently has been the phospho-tau assays which they can now detect in blood, and looking at the studies that are coming out of that, they’re looking at 15 to 20 years prior seeing rises in this protein. Maybe that is fifties, if you’re going to get in your seventies or something. So this is really quite exciting. That’s only literally a year old this kind of research has been going on now, and they’re looking at different forms of it which could even give us more information. So we have good assays now but they’re going to get better.

Adam Smith:

So I’m going to come to Liz and Josie then. Thinking about how you might practically use this blood test, I can see how it’s actually got various applications because, of course, if you were to apply this blood test to somebody who you would be diagnosing now in their early seventies anyway, I suppose it would help you discount other things that you’ve obviously been trying to do with your other tests you do to make sure that there isn’t something else going on there. But, essentially, is the main point of this that it would be a blood test you could apply to somebody younger to use in different ways? How would you use this? Liz, you go first.

Dr Elizabeth Coulthard:

So we’ve been using CSF biomarkers for a few years, and it is a learning curve. They do transform practice, and once you have the biomarker, you become a slightly different type of clinician because you rely more on a test to tell you and perhaps we’re not doing the thing that Josie says so much, of it’s the history gives you a lot. I think that’s interesting.

Dr Elizabeth Coulthard:

But what we’ve learned is that you have to contextualize the test. If you have someone who has no symptoms but really wants a biomarker test, what are you going to tell them if they’ve got a low CSF amyloid implying that they’ve got amyloid [inaudible 00:35:43] and amyloid plaques in their brain? Do we tell them that plenty of people have amyloid at postmortem and never had dementia during their life? Do we tell them, “Oh, that could mean you’re about to get Alzheimer’s”? Do we tell them, “Oh, you’ve probably got a maximum of 20 years before you get Alzheimer’s”? Does the tau tell us how quickly they’re going to develop Alzheimer’s? Probably not. But does neurofilament light chain, the newer biomarker that’s not in clinical practice for us yet, that might tell us where someone is on… their neurodegenerative is.

Dr Elizabeth Coulthard:

So I think we have to use them very carefully, and really understand what they mean for an individual. It’s a lot more straightforward if someone comes to us with symptoms. Then we can say, “You’ve got cognitive symptoms that look a bit like early Alzheimer’s, and you’ve got a low amyloid and a high tau. That looks like early Alzheimer’s,” and then you can confidently diagnose someone in their fifties, but you wouldn’t just go off the biomarker in that case, and it would be the same with blood.

Dr Elizabeth Coulthard:

But then in five years, 10 years, we’ll know so much more about what the biomarker profiles are, and I think our confidence will grow and we’ll be able to apply them clinically much more easily. But I think they’re going to be transformative, and the way that we can get people into clinical trials will change. Who knows, maybe GPs could be screening with them. I don’t know.

Adam Smith:

I was going to say, that could be where the biggest impact comes, isn’t it? Because I think when the public think about this, they do think of a blood-based biomarker. You see on the tabloid headlines, is, “Blood test to check Alzheimer’s.” The public perceive this that they have memory problems, they can just get a blood test and they’ll say, “Oh, you’ve got Alzheimer’s,” to replace whatever test is already there. Go on, Amanda, you were going to add.

Dr Amanda Heslegrave:

Yeah, no, I was going to add that we’re doing a really interesting study at the moment where they’re going to combine the blood biomarkers; so neurofilament light, phospho-tau, [inaudible 00:37:42], amyloid-beta 42, amyloid-beta 40, with individual polygenic risk scores that have been worked out by someone who’s an expert in that, and I’m not, but to see how these can inform each other and perhaps come out with a better… Maybe we can come out with a score and say to someone when they’re 40, “Okay. So you need to do this to mitigate your risk of getting Alzheimer’s in later life,” or something. So make it real individual, personalized medicine, isn’t it?

Dr Josie Jenkinson:

Yeah.

Dr Amanda Heslegrave:

This is the way we’re heading, I guess.

Adam Smith:

Personalized medicine. We’ve talked about that before as well. I guess this is where trials like Prevent come in really, where they’re trying to take people over the age of 40 to collect all these biomarkers over a long period of time so that you can get better at predicting the presence of these biomarkers at earlier age increases… so they can get a better likelihood of you diagnosing this and make then whatever changes to lifestyles. Or, more importantly, that you’ve said that these biomarkers can be used in the short-term is in identifying study trial participants for certain drug trials, which is where you can see an immediate benefit.

Adam Smith:

I’ve worked on various drug trials myself over the last few years and you know that they’re looking for people with certain risk factors, and the screen fail rates for those are really high, they’re a big impact on drugs. So, how do you think this will help you with drug trial, study trial participants? I’m making a big meal of that, Liz.

Dr Elizabeth Coulthard:

Oh, if we get blood biomarkers it would be brilliant because… When we’re doing our own research, having to pay for an amyloid PET is £1,500, and then even CSF testing costs about £600, and trying to persuade people to get it done is not always easy, often it’s the main factor putting someone off a trial. So if we could diagnose with blood biomarkers and then track progress with blood biomarkers, that will be a huge change in our ability to run large-scale trials.

Dr Amanda Heslegrave:

The phospho-tau looks very much like an amyloid marker. So, perfect.

Adam Smith:

So, overall, are we looking at what’s going to be the best outcome here is actually not any single biomarker but actually a combination of biomarkers? Because what we’ve not talked about now, and we see at conferences all the time, is that there are so many other biomarkers being considered, whether that’s gait analysis, conversation analysis, eye tracking technologies, all these different ways to try and differentiate between certain different types of dementias. But a combination of a blood-based biomarker with some of these other things would allow maybe for some better typing earlier diagnosis, and maybe something we skipped talking about earlier, but something that’s easier to deliver in a world when physical, face-to-face clinics might be a challenge?

Adam Smith:

Everybody’s just nodding. My challenge with some of those things is, of course, I’ve seen lots of talks about these other biomarkers that technically already exist there but none of them… Liz, it sounds like you’re pretty cutting-edge when it comes to these different ways to look at… like conversation analysis, like gait [crosstalk 00:41:05]

Dr Josie Jenkinson:

We don’t have access to that at the moment, but it’s really exciting to see all of the different areas that are developing. I think, like most areas of medicine, things get ever more complex the more we research and understand them. I think we can’t even conceive of the solutions that are going to emerge in 10 years’ time because it’s going to be so dependent on things like machine-learning and algorithms and using huge [inaudible 00:41:36] of different bits of information that are much easier to get because of more sophisticated technologies.

Dr Josie Jenkinson:

We can’t quite conceive of it yet, but I suspect it will be getting huge amounts more information than we get at the moment via various different means, via measurements on scans, biomarkers, gait analysis, all these different things, and putting it all together to come up with probabilities and answers, is where I think we’re probably headed, these ever more complicated routes that most people actually won’t understand, but it may be protocol driven. So people will get a battery of information and tests and then we’ll come with an answer based on those.

Adam Smith:

I suppose it’s interesting to see that the blood-based biomarker in itself is going to transform certain areas sooner than others. So, clearly it’s going to be particularly helpful in the short-term with recruitment to certain trials, particularly being able to see whether amyloid is there without having to do expensive PET scans or CSF and things that potential volunteers-

Dr Amanda Heslegrave:

It’s pretty specific for AD. So you can rule out other things. And there’ll be other ones that will rule out more; I know there will, that’s just a matter of time.

Adam Smith:

So that’s the brilliant short-term goals, and then as we gather more information and more data and can start to see what those predictors are at an earlier age, I guess is working towards a point where at age 50 you’re offered a screening test like you are for other things in the future. Maybe that’s still a way off. But, as you’ve all said, this technology, this research is moving on so rapidly. It’s brilliant.

Adam Smith:

This has been a really interesting topic, and it’s one that I’ve wanted to talk about for quite some time. We didn’t spend as much time talking about the effects of the pandemic on diagnosis care pathways.

Dr Josie Jenkinson:

That’s a whole podcast in itself, Adam.

Adam Smith:

It is. You’re entirely right. Having looked at the numbers, we know that the numbers fell in the last year. I think there were 35,000 fewer people diagnosed this year at one point. It looks like things are starting to catch back up now potentially.

Adam Smith:

So it’s time to end today’s show. I’d like to thank my guests, Dr. Amanda Heslegrave, Dr. Josie Jenkinson, and Dr Liz Coulthard. We have profiles of all of today’s panelists on the website, including details of their Twitter accounts. So you can please look them up, and do reach out if you’ve been affected by any of the topics we’ve discussed in today’s podcast. There’ll also be lots of other content on our website as well which will help anybody interested in this field.

Adam Smith:

Finally, please do remember to subscribe in whichever app you’re listening to. Thank you very much, and goodbye. Thank you for listening.

Voice Over:

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

END