Podcast – Neuropathology in Focus: Shaping Our Understanding of Dementia

Voice Over:

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

Dr Kamar Ameen-Ali:

Hello, and welcome to the Dementia Researcher Podcast. In this show this week, we’re going to be discussing neuropathology and why this area is essential in dementia research. We’ll hear about how the field helps to identify changes in the brain, how it can help guide developments of targeted treatments, and how our brilliant guests use it to provide critical insights into disease progression to aid diagnosis and therapy advancements.

Hello, I’m Dr Kamar Ameen-Ali. I’m senior lecturer at Teesside University, and it’s a pleasure to be hosting this show. Joining me to talk about their work and what we can learn from neuropathology are three amazing scientists. I’m delighted to welcome Professor Tammaryn Lashley from University College London, Dr Laura Palmer from the University of Bristol, and Dr Daniel Erskine from Newcastle University. Hi, everyone.

Professor Tammaryn Lashley:

Hiya.

Dr Laura Palmer:

Hi.

Dr Daniel Erskine:

Hi.

Dr Kamar Ameen-Ali:

So, let’s start off by doing some proper introductions. So, Tammaryn, let’s start with you. Tell us a little bit about yourself.

Professor Tammaryn Lashley:

So yes, I’m Tammaryn Lashley, based at UCL. So, I’ve been working in the neuropathology field for over 25 years now. Makes me sound really old. So, I started off working as a research technician at Queen Square Brain Bank, and then I’ve done all various roles at the Brain Bank over the years, but then decided to run my research alongside that.

Had a junior and senior fellowship from Alzheimer’s Research UK, all based again around using postmortem tissue to try and understand various neurodegenerative diseases better, and then was promoted to professor of neuroscience three years ago now, so run my own team. I still work closely with Queen Square Brain Bank, but I’m not actually affiliated with Queen Square Brain Bank anymore, but the main focus of my research is still based around the use of postmortem brain tissue.

Dr Kamar Ameen-Ali:

Thanks, Tammaryn. So, Laura, would you like to introduce yourself next?

Dr Laura Palmer:

So I’m Laura. I’m the manager of the Southwest Dementia Brain Bank, based in Bristol. I’ve also been there; this is about to be my 20th year. The Brain Bank is this amazing resource of postmortem brain tissue from people both with dementia but also from other neurological conditions such as Parkinson’s disease, but also from older people who weren’t affected by dementia. The main aim of the Brain Bank and therefore my role is to provide researchers with access to this tissue all in the hopes of understanding dementia better.

Dr Kamar Ameen-Ali:

Thank you, Laura. And finally, Dan, can you go next?

Dr Daniel Erskine:

Hi, I’m Daniel Erskine. I’m at Newcastle University. I’ve been at Newcastle University for quite a long time. I’ve been there for about 12 years now. I did my PhD here. So, a bit like Tammaryn, I had an Alzheimer’s Research UK junior fellowship. I’m now on a senior fellowship, and I also got appointed to senior lecturer relatively recently as well. So, I run my own team at Newcastle, and we are really interested in alpha-synuclein, and Lewy body disease is a particular one. And most of this work is with postmortem brain tissue, which is what, of course, we’re looking forward to chatting about today.

Dr Kamar Ameen-Ali:

Thanks, Dan, and thank you so much to all of you for joining us today. It’s great to have you with us. So, for those who have read my blogs, you’ll understand why I’m hosting today. It’s because this is an area that I’m really passionate about, having worked myself in neuropathology for around 10 years now or so, focusing on dementia-related brain diseases, broadly speaking.

I started off working with animal models of Alzheimer’s disease, looking at neuropathological changes and cognitive impairment associated with the disease. This then led to a focus on using human postmortem brain tissue to look at vascular changes and neuroinflammation and how those things might contribute to the risk of dementia following stroke. I would say in the last four years or so, I’ve developed an interest in the neuropathological changes and, again, specifically neuroinflammation following traumatic brain injury and, again, how this can increase the risk of dementia in later life. So, with introductions done, we can now get down to it.

So, for those who don’t work in labs, it’s probably really important to start off with introducing our listeners to what neuropathology is and to give some background to why it’s particularly useful in researching dementia. So, I would say that pathology can be broadly described as the study of diseases, and this could be using living or postmortem tissue.

But neuropathology specifically is about pathology of brain diseases. And we can kind of separate neuropathology into two categories. So, we’ve got diagnostic neuropathology. This can involve, for example, a tissue biopsy to diagnose cancer in someone who’s living, or it can be postmortem to determine what neurodegenerative disease was the cause of someone’s dementia.

And then we’ve got also experimental neuropathology, which is the other category. It’s what we’re kind of all involved in now or have been at some point in our careers, and that’s more concerned with studying the causes and the mechanisms of specific diseases, as well as adaptations to injury. So now that we have a broad understanding of what neuropathology is, let’s find out about our guests’ specific research areas. So, Tammaryn, let’s start with you. Can you tell us about your research and the specific areas of neuropathology that you’re interested in?

Professor Tammaryn Lashley:

Yeah. Sure. So currently, my research is focused around… Well, my team’s research is focused on frontotemporal dementias and looking at RNA-binding proteins and their involvement in that group of diseases. But over the years, I guess my researchers touched many of the different neurodegenerative diseases, I think because I’ve been quite fortunate to have been in the discipline at the time where lots of things have been discovered.

So, I started out working on familial British and Danish dementias. So, I was working on those brains when the actual mutation was identified, so we could actually see the underlying pathology for the first time, which I find quite exciting. So, you’re the first person to see what is actually causing that disease in that brain, then moving on to… I sort of dabbled a bit with Parkinson’s disease, but unlike Daniel, I don’t find alpha-synuclein that exciting. Sorry, Dan.

So, I moved on to frontotemporal dementia and, again, was working in the area of frontotemporal dementia when tau, TDP, C9, and all the major players in that field were identified. So had the opportunity to review hundreds of cases and bring their differential diagnoses up to date with the current criteria. So, as well as working in the experimental neuropathology, I do have the opportunity to work in looking at more of the diagnostic criteria as well with cases that have been donated to various brain banks, because we get sent different cases from different brain banks depending on what expertise they need to look at those cases as well.

Dr Kamar Ameen-Ali:

Thanks, Tammaryn. That’s really interesting, thinking about diagnostic criteria, because that’s something that clinical neuropathologists, they use in order to be able to make these postmortem diagnoses. And it’s interesting to think about how we have a consensus on what that criterion is for these different diseases, but that it’s important to continually think about updating these in light of information that we have. So that’s interesting that that was something that you’ve been involved in and also something that you continue to be interested in.

Professor Tammaryn Lashley:

Yeah, yeah. Definitely important. And I think people don’t realise that when, say, a brain with Alzheimer’s disease, for example, has been donated 20 years ago, they obviously don’t know, unless we go back and look at it, whether it had co-depositions of TDP-43 and alpha-synuclein for instance. So, there’s that constant going back and looking at these cases to make sure that the right cases are being used for the right scientific research projects.

Dr Kamar Ameen-Ali:

Absolutely. So, Dan, we spent some time working at the same facility at Newcastle University, although we worked in adjacent labs, and it’s been really great to see the progress that you’ve been making in your research and in your career over the past few years, which you’ve already alluded to. Can you tell us a little bit more about your research and the things that you’re interested in at the moment?

Dr Daniel Erskine:

We did, of course, work in the same lab. And likewise, it’s been great to see everything you’ve been doing at Teesside as well, such as your ARUK Day yesterday, which was great to see with Ahmad, who actually supervised my PhD. So, the things that excite me, in contrast to Tammaryn, I think alpha-synuclein is really interesting. So, things that we find interesting are, we have these protein aggregates in a number of different diseases, including in Lewy body diseases like dementia with Lewy bodies and Parkinson’s disease, but we don’t really know what they’re doing.

And the questions we like to ask are, “What exactly is this protein aggregate doing? Is it harming the cell? Is it protecting the cell?” And trying to look beyond the simplicities of protein aggregates and trying to understand things at a more functional level. There are a few things that we’re doing at the minute that I think are really interesting. So, some of the work we’ve been doing has been trying to understand what’s different between a cell that has a Lewy body compared to cells that don’t have Lewy bodies, so trying to understand how they’re actually affecting cells. We do this with single-cell fluorescent microscopy.

We also have questions about what is actually making alpha-synucleins stick together in the first place. What most people may not realise is that most risk genes for Lewy body diseases like Parkinson’s disease encode lysosomal enzymes. These are enzymes that normally break down lipids. So, what can these lipids tell us? And in particular, it’s a class of lipids called sphingolipids, which are waxy, structural lipids, and they could also be involved in signalling as well. And we’re quite interested in what these sphingolipids are doing.

So, something we’ve also been working on is sphingolipid disorders that affect children. So, these are neurodegenerative diseases that occur in children that are linked to Lewy body diseases by a shared gene. So probably, the best example of this is Gaucher disease, which is caused by GBA1, biallelic GBA1 mutations. But heterozygous GBA1 mutations are risk factors for Parkinson’s disease. So, trying to understand the links between these two and, in particular, by studying alpha-synuclein in the brains of children who’ve sadly succumbed to these conditions, we think, can provide new insights. And I’m really excited about this area of work, because the more we look at it, the more we keep finding interesting alpha-synuclein things.

Dr Kamar Ameen-Ali:

Thanks for that, Dan. So, it’s really interesting how you can maybe take things that you’re finding from looking at these, maybe what could be considered as rarer conditions, but can then inform research on conditions like dementia with Lewy bodies, which are more common, and can maybe provide some mechanistic insights into what might be going on.

Dr Daniel Erskine:

Yeah, because, I mean, to some extent, these conditions are… Their cause is much clearer, because we know that there is a loss of function of a particular gene. We can work out what that gene does if we don’t already know, and it provides a tangible link between the dysfunction of a particular process and the accumulation of alpha-synuclein. I kind of think of it as a bit like reverse genetics almost. It’s like instead of we’re looking for genetic risk, we’re actually looking at associations in a biological sense.

And yeah, I think it’s an interesting area and I think, most importantly for people affected by dementia, a very… I always think the really important message from this is that it challenges the assumption that dementia is just an inevitable consequence of ageing, because this is a problematic view, because it fosters a spirit of therapeutic nihilism, where it’s almost like there’s nothing we can do because we can’t stop ageing.

But when we observe seed-competent alpha-synuclein pathology in the brain of a baby that was 10 months old with Krabbe disease, that suggests that this is biology that’s dysfunctional, not just a process of ageing, and, of course, something that’s broken we can potentially fix. We probably can’t stop ageing, at least sadly not in my lifetime. So, I think it’s a more realistic goal.

Dr Laura Palmer:

Sure. So, I was lucky enough to join the Brain Bank as a technician in 2004, and I was even luckier still, under the directors of the Brain Bank, to be able to do a part-time PhD, which, I have to say, I didn’t finish until 2014. So, it was eight long years of part-time PhD as well as working in the Brain Bank. It was funnily termed the never-ending thesis, although I’m glad to say it did end at some point.

It was a fascinating project, so at least I found it fascinating. It was on the renin-angiotensin system, which is an important enzyme pathway and signalling system. And the RAS, as we call it, so renin-angiotensin system, is particularly interesting because it’s targeted by antihypertensive drugs, and very little is actually known about those effects on the brain and how they affect people at risk of Alzheimer’s disease or in the early stages of the disease.

But more so now than when I was doing my PhD, there’s a considerable body of evidence suggesting links between vascular risk factors, such as hypertension and Alzheimer’s disease risk, and then there’s also increasing evidence that antihypertensive therapies that target the RAS might be of benefit to cognition even in people who are not experiencing cognitive decline. So those are some really interesting areas.

My role has certainly been incredible in the way it’s developed over the years, obviously doing some research on donated tissue, as well as the main purpose of my role now is really to underpin other people’s research. And I have to say, I feel that I’ve underpinned more research than I could ever have undertaken myself as a research scientist. That is really rewarding. I think in about the last five years, we’ve provided around 37,000 samples to researchers all over the world, and that’s resulted in about 100 publications in peer-reviewed journals. So, it’s quite some output.

A lot of that, I have been lucky enough to be involved in some direct collaboration and some of the science as well, although, as I’m sure my colleagues on the call will say, there’s a lot of science in the process of brain banking itself. What led on from my PhD, which was particularly interesting, but I have to say wasn’t my work. We are really interested in Bristol in what our professor calls the bench-to-bedside approach, so what we are doing in the lab and how that translates to people who are living with these diseases at the moment.

One such drug trial that happened was the RADAR trial in Bristol, which gave people in the early stages of Alzheimer’s disease an antihypertensive drug, a commonly prescribed drug, and then looked at whether or not that affected their cognition or their progression within the disease. So, this earliest work was necessary from donated brain tissue that led to a drug trial in individuals living with Alzheimer’s disease. So, it’s really important to point out to people that although we’re talking about postmortem, deceased donors, this does actually impact people who are living with these diseases today.

Dr Kamar Ameen-Ali:

I think that’s really interesting, Laura, and I think we might mention this later on when we come to some of our later questions. But often, people who do, shall we say, the fundamental research, which might be working on preclinical models or doing cellular work, and if they don’t have any involvement in neuropathology or doing anything with postmortem brain tissue, sometimes it can be quite hard to explain the importance of it, because it’s almost like, “Well, it’s the end stage of the disease. How do you kind of explain how that can inform the cause of the disease, the pathogenesis of it, and the progression of it when we’re looking at end stage?”

And sometimes it’s like, “How do we explain this to people who are basic neuroscientists or fundamental neuroscientists, what we can actually learn from that, and how can that then inform those earlier parts of the processes of biomedical research?” So really interesting to hear how you’ve been involved in those other projects as well.

What we’re going to do now is move on to thinking about what we can learn from neuropathology, the contribution that it can make to helping us understand the causes of neurodegenerative diseases that lead to dementia, and ultimately help us identify new diagnostic markers and develop new therapies. So, Laura, let’s start with you. Without brain banks, it would really be impossible to do any neuropathology research, and I’m really keen to hear more about the importance of brain banking and the process that’s involved. If, for example, somebody wants to donate their brain for research, what’s the process that is involved in that?

Dr Laura Palmer:

So, obviously, I’m slightly biassed, but I think brain banking’s incredibly important, because human brain tissue really has been critical to nearly all of the major advances that we’ve had in dementia research. We are lucky enough in Bristol to have a register of potential donors, so about 650 people at the moment who have committed to donate their brain after they die specifically for dementia research.

And all of the brain banks in the UK, of which there are currently 10, it’s really important that people preregister for brain donation. When I first started at the Brain Bank, we used to accept many, what we now term, ad hoc donations, so donations from people who weren’t part of a clinical cohort or who we didn’t have much information about them as a person and their life. We are realising now that those types of donations, although they have had their place and been very important, they’re not what we need now. What we need is highly characterised cohorts of individuals from which we can provide tissue and data to the research scientists to get the best results.

So, we ask people to preregister by contacting their local brain bank. We then put some primary checks in place and, of course, are hopefully notified at the time of a donor’s death. Brain banks have a really important role at the time of a donor’s death. A lot of the time, I feel that we’re making someone’s last wishes come true. We’re helping them make a difference. And it’s also really important to families, I think, to know that their loved one’s death perhaps has some additional meaning. It can give people quite a lot of comfort.

We handle all of the arrangements at the time of a donor’s death. So, we would liaise with their GP if they died in the community, or the doctor or consultant if they died in a hospital setting. We work with the family-appointed funeral director, and we make all of the arrangements associated with the donation to try to limit the impact that it has on the family at an already difficult time. We have to get all of our brain donations within 72 hours, and we request from local mortuaries all over the Southwest that we receive the brain whole, and we also receive a sample of cerebrospinal fluid, which can be really important later on for researchers for biomarker studies.

When we receive the brain, we perform a dissection. Half of the brain is dissected and frozen, rapidly frozen, to start with at -150 degrees Celsius, and then later, long-term storage at -80. The other half of the brain, we fix in formalin, and that’s the tissue that’s really important for us to be able to obtain this neuropathological diagnosis, which we have to have on every single donor before that tissue is made available to researchers.

Dr Kamar Ameen-Ali:

It sounds quite similar to the processes that we used when I worked at the Glasgow Brain Injury Research Group, and part of my role there was involved in managing the brain bank that we had there. And it sounds like there’s very similar processes. Do you take brain donations from across the UK, or is it just within the region that’s close to where the hospital is?

Dr Laura Palmer:

So, we in Bristol actually cover quite a large geographical region. So, we do cover the whole of the Southwest. We don’t cover the whole of the UK. We have tried to keep it to within about a 200-mile radius of Bristol. The main reason for that is because most researchers want postmortem-delayed tissue to have the shortest possible delay.

So, we are an entirely charity-funded resource. Our staff members use their own vehicles to transport brain tissue back to our hospital in Bristol. So, we can’t go too far afield because it would result in longer postmortem delays, increased costs, and potentially be detrimental to the quality of the tissue if we weren’t able to get it back in time and kept, in certain conditions, for cold storage prior to dissection.

Dr Kamar Ameen-Ali:

That’s certainly one of the challenges we had, because we received brains from all over the UK, because we were specifically looking at brain injury cases. And because of a lot of media coverage particularly around repeated head injuries in contact sports, we started to get a lot of registered interest in brain donations, particularly from former athletes who were elderly and had gone on to develop dementia or their family members contacted us about that.

So, we would potentially get brains from anywhere in the UK, and there was a whole process of, as you said, thinking about the postmortem delay. We would have to request that the tissue was stored for up to two weeks in formalin before it then be sent to us. And sometimes that would lead to that variability in tissue quality, as you mentioned, and then that can have knock-on effects later down the line when you’re processing the tissue, staining the tissue, and then quantifying the proteins and things like that afterwards.

So, all these little steps along the process are really, really important and need to be thought about, not just for diagnostics, but also if you’re using the tissue for experimental reasons as well. So I think that one of the interesting things about neuropathology is, as we’re working with postmortem tissue, we’re typically looking at late-stage disease, as I mentioned earlier, but our objective is usually, or at least our long-term research objective is to try and understand what’s happening at the beginning of the disease process as well as the progression of it, whatever the disease or condition is that we’re interested in.

So, it’s almost like with neuropathology, the end is where we start from. So, Tammaryn, can you tell us a little bit about the potential for neuropathology research to translate into promising biomarkers for early diagnosis of neurodegenerative diseases or any potential clinical therapies?

Professor Tammaryn Lashley:

Yeah. Sure. So, as we’ve highlighted, it is the end stage of the disease we are looking at. But I think looking at the actual human brain that has the disease is vitally important for us to look at the proteins, look at the lipids, look at everything else that is going on in the human brain for the diseases, but also to recognise that this is just a piece in the puzzle.

So, for us at UCL, we work with the clinicians at the Dementia Research Centre, and most of the people that they sign up for brain donation are donated to Queen Square Brain Bank. But having that complete circle, as Laura has mentioned, having that clinical workup where we have the detailed clinical history of these cases. We have in-life biofluid samples, either plasma, CSF, or the imaging as well that they’ve had during life. They then donate their brain at postmortem for research.

We have that full story of that individual that we can then reflect back on once we have the underlying diagnosis, because often, what they’re diagnosed with in life is not what we see in the brain, particularly with the frontotemporal dementias. If somebody’s diagnosed with behavioural variant, it’s one of three, maybe four different types of pathologies, so until we get that definitive diagnosis. We can obviously look at the imaging. We can look at potential biomarkers of the samples that are taken during life. But I think we won’t know, until we get a big enough cohort of patients with that definitive diagnosis, what we can actually do or make the most of the in-life studies that are being done.

So, from my point of view, working with the clinicians and looking at everything as pieces of the puzzle, working with the clinicians, working with people taking the skin biopsies to work up the iPS cells, working with the people working on the biofluids, working with bioinformaticians that we need more and more now for large data sets. I think the neuropath analysis of the brain is essential, but it is only a key to being able to solve these diseases.

Dr Kamar Ameen-Ali:

I think that’s a good way of putting it, almost like a piece of the puzzle. We’ll be coming onto this shortly. But I mean, one of the starkest things that I found was, as you mentioned, that sometimes that disparity between what someone’s been diagnosed with in life, not matching up to them, what you see in the neuropath analysis. So, we’ll come onto that in a second.

But I just want to come over to you, Dan, if that’s okay, because as we mentioned about you are being now well-established as an independent researcher, you’ve obtained successive research fellowships. I’m really keen to know, within your research, what has been probably, would you say, the most surprising or the most interesting findings about the pathological mechanisms of Lewy body diseases that you’ve come across?

Dr Daniel Erskine:

I think it’s a really good question. The problem I think that I have is that I find so many things interesting that it’s very, very hard to sort of distil it into one or two points. I mean, I think research is a journey in many ways, and I think there are a couple of different moments that come across that really alter your direction on things.

I think for me, it was probably quite a long time ago, but I think the most interesting thing, and it’s kind of, I suppose, set the scene for the rest of my career really, is when I sat… I used to do a technique called stereology, which you may be familiar with. It’s a method where you can sequentially section areas of the brain. You count a subset of cells, and then you can estimate the total number of cells within a given region. Ahmad, who works with Kam, is an expert in this.

So, I was doing my PhD. I had a fairly, I would say, straightforward worldview. Lewy bodies cause cell death. Cell death equals symptoms. But I was doing stereology in all these brain regions, and we could never find any relationship whatsoever between Lewy bodies and the loss of neurons in these regions. So, this just meant that we looked harder, and we looked at more and more different things. We would look at specific types of cells and try and correlate them, but I think the difficulty was that we were trying to maybe put a square peg into a hole, as it were. It’s very difficult because it didn’t seem that there was any relationship at all.

And if you look in the literature as well, nobody really finds any relationship. And yet, the majority of drugs that are currently in development for Lewy body diseases are typically antibodies that target the aggregation of alpha-synuclein. So, I say this was probably the biggest moment. It wasn’t just one study. It was a number of studies that we did over time, and also cell loss in regions that didn’t have any Lewy bodies and preservation of cells in regions with Lewy bodies. So, I think this is probably the biggest bit, because it’s set the scene for everything we’ve done since, and it’s, I suppose, given us the reason, the rationale to investigate these things further. So that would be my answer to that.

Dr Kamar Ameen-Ali:

Thanks, Dan. And do you still use stereology in your research? Because it’s quite a time-consuming process, isn’t it? Even though I often hear people talking about it being gold standard, but I don’t really know that many people that use it.

Dr Daniel Erskine:

Yeah. I mean, I’m sort of eager not to disagree too much with Ahmad, but I guess that I… No, we don’t, is the short answer. We are increasingly moving towards slide scanning, so we slide-scan images. We can use AI-based pipelines, which can quantify things like neuronal density. To date, I have never done stereology on a single brain region and found a different result than what I got from looking at one slide and measuring the density of cells.

So, I think it is probably gold standard, but a luxury that probably few can afford in terms of time, because, of course, time is the greatest investment that you make, particularly if you have good students. It’s a lot of their PhD is taken up. So, I’m very glad I did it. I’m very glad I understand it, but it’s not something we routinely use. No.

Dr Kamar Ameen-Ali:

I love slide scanners as well. It just saves so much time, doesn’t it? Okay. So, let’s move on then. So having worked myself in neuropathology labs, involved in both diagnostics and research, I know that for a big motivation for people to donate their brains, usually it can be for family members to be able to get confirmation of which brain disease might have caused their loved one’s dementia.

As we know, and as we’ve kind of mentioned, neurodegenerative diseases like Alzheimer’s, they can only be confirmed postmortem, and that’s not something that is routinely done. So, I just want to ask Laura, what are your thoughts on how someone may have been clinically diagnosed with something during their life, as we mentioned earlier, that can often be quite different to the neuropathological diagnosis postmortem? And then maybe, Tammaryn, you can jump in on this one as well.

Dr Laura Palmer:

Yeah. I completely agree. I mean, we find approximately 40% of the cases that we receive in the Brain Bank do not… The neuropathological diagnosis does not match the clinical diagnosis. And in some cases, it’s an entirely different cause. But in a lot of cases, our staggeringly more cases nowadays, we find mixed pathology, and really significant mixed pathology. Very complicated cases with maybe four different types of contributing pathology.

And that becomes really difficult to unpick if you’re not going to involve neuropathology and research. When you start to look at these cases, I think you can really start to understand perhaps why we’re having so many problems with developing drugs to either prevent or treat dementia, or dementias, I should say. I mean, I’m dreaming now, but when we are looking at clinical trials in the future, I’d love to see a brain banking element introduced into those trials with the ability to actually go back and reanalysed the results of trials.

I realise it would be probably a significant time later, but I think we’re missing a trick in terms of drugs that we may potentially have missed or that we’re on the cusp of showing differences or benefits to people with dementia. If you think about the clinical trial setting, if perhaps up to 40% of the people that you’ve recruited for an Alzheimer’s disease trial either don’t have Alzheimer’s disease or have contributing pathology that perhaps may change the outcomes or change the outcomes looked at within that trial, I think you can start to see the challenges in treating these diseases.

We’re also really interested in Bristol in the lifestyle factors at the moment, which seems to be of increasing interest to many people, with some recent papers being shown that large numbers of cases of dementia could potentially be preventable, but cognitive decline could be dramatically slowed with lifestyle changes that we could all make now. I’m really interested in seeing those types of changes that even somebody can make after having a diagnosis of, say, Alzheimer’s disease or dementia to find that they still see benefits.

Those are the types of things that I’m really interested in that could make a difference to people now, without drugs, with very basic interventions, with diet, with lifestyle, with modifying risk factors such as those that I was really interested in in my PhD, so midlife hypertension, hypercholesterolemia, all of these things we are trying to look at in our donors as well. So, it gives us a bit of an advantage. So, we’re not just looking at brain tissue or not just looking at cerebrospinal fluid.

We in Bristol are part of the national Brains for Dementia Research project, which is a cohort of individuals from whom we collect data, so cognitive data, but lifestyle data as well for many years in advance of their death and their eventual brain donation. And that’s proven to be a really interesting cohort in terms of the types of work that can be done looking both just at the data but the data in conjunction with tissue later. And Tammaryn’s point as well, we also try to take blood samples from this living cohort so that that can also be applied both to their data and to their tissue later.

Dr Kamar Ameen-Ali:

Thanks, Laura. And sometimes I find myself thinking about things like mixed pathologies. And I’m wondering, as you mentioned about clinical trials and developing of new drug treatments, and I wonder whether if people have these mixed pathologies that are progressing at maybe different rates or to different extents, if you were to treat, say, one, does that mean that potentially, yes, you might slow down or delay the progression of that disease?

Will that allow another one to then develop and progress at a faster rate, and potentially that then becomes the dominant pathology that then is driving the dementia in that individual? And how would you get the balance then of having these different drugs that you’d have to treat for these potential different disease pathologies? And I think that those complexities are going to be the real challenges around treating any of these diseases that we’re talking about that lead to dementia.

Professor Tammaryn Lashley:

I think I can respond to that one. I guess the answer is we just don’t know how the co-pathologies affect each other from a seeding point of view. Does one initiate the other? And that’s where neuropathology helps as well, is to look at where the different pathologies start. So, we know with Alzheimer’s, with Parkinson’s disease, they start in different brain regions. And even with Alzheimer’s disease, the Abeta and the tau start in different brain regions completely.

But also, there’s two aspects, I think, it would be good to mention, is that we’re looking at the pathologies we know. We don’t know what we are not seeing yet. So, in 20 years’ time, what will we be screening all these brains for again? So, we know from the RNA-binding proteins, we see a lot of pathologies with the RNA-binding proteins across the different neurodegenerative diseases.

Are they having an impact on the clinical manifestations? Obviously, we don’t know at the moment. And just to touch on which we’ve not really mentioned, is the number of cases that we receive that are cognitively normal in life, but actually have a huge amount of these pathologies in their brains as well. To look at the difference between those and the cognitively impaired cases, I think, is very understudied at the moment.

Dr Kamar Ameen-Ali:

And I guess through collaborating with other people from other disciplines, it’s going to help a lot with that. And if we’re wanting to develop things like new methods, new technologies, often we need that cross-disciplinary work in order to do that. And Tammaryn, I know that throughout your career, you’ve collaborated with people in other disciplines, including clinicians and biochemists as two examples. So, whilst we’re on this, can you talk a little bit about how combining neuropathology with other fields can really help to advance dementia research?

Professor Tammaryn Lashley:

Yeah. Sure. I mean, I think it’s essential. As all three of us have mentioned, it’s essential that we do collaborate with other disciplines or the clinicians in the field as well that see these patients during life. Nobody can do it single-handedly. We need different inputs. We need different perspectives.

And even speaking with members of the charity, lay members that give you a different insight, a different perspective of these diseases could often trigger something that you’ve thought about but not actually connected it with the research as well. So, I always find speaking to the lay members really important. But we are, in neuropathology, in… I think we’re all on the same page, is essential, but it’s not going to be the magic key to unlocking these diseases. We need to all work together to find a cure for these diseases.

Dr Kamar Ameen-Ali:

Thanks, Tammaryn. And my final question in this section is for you, Dan. So, thinking about some of those challenges around mixed pathologies and these things that we’ve talked about, what recent advancements in neuropathological techniques do you think could significantly impact dementia research or even just neuropath research more broadly? Is there anything that you think might be able to help to determine the presence of these pathologies that we’ve been talking about and the extent to which they might be contributing to the progression of someone’s dementia?

Dr Daniel Erskine:

I think there are a number of levels to that. The first thing I would say is just as an addition to what everyone else said. I mean, of course, neuropathology is so important. And I think one of the things that really underlies why neuropathology is so important is because we don’t know what causes these diseases. If you want to model a genetic disease, it’s not that difficult to do, because basically, you can genetically modify a mouse or you can genetically modify a cell line, or you can take a cell from that person and convert it to pluripotency and turn it into something else.

The problem is, we don’t have that luxury with most of these diseases. If we want to make a model, we have to know what causes the disease to recapitulate it in that model. We don’t know what causes these diseases in almost every case. So that’s the great challenge. And that’s where I think why neuropathology is vital because you can look at any processes you want in a cell. It doesn’t necessarily mean that’s what’s happening in the brain, and you need to then take it back to confirm what you do see.

And I honestly think that the field has been held back to some extent in some cases by observations and model systems that simply do not occur in the human brain, and that’s why neuropathology, for me, will always be absolutely vital. In terms of the advances that I think… And I mean, there are so many advances, I think, that have really, really helped. It’s probably not something funders want to hear, but I honestly think one of the most valuable things we could do aside from… Sorry, let me go back one step.

I think we’re already doing some of those things now. The collection of large cohorts that are clinically really well-characterised, that is huge. The number of cases that we have from a long time ago that we knew virtually nothing about, we need to get better at this. And we need to understand, as Laura said, getting this rich clinical information. As Tam said, biomarkers through life.

And then what I also think is also new advancements in terms of techniques. So, I know Tammaryn, for example, has used things like proteomics. I don’t think funders want to hear this, but sometimes I think one of the best things we could do is go in without a hypothesis and literally just see what’s different. Stratify cases on a number of different levels and see what is different. Take an absolutely a hypothetical view.

Hypothesis-driven research is superb, but sometimes if we really want to crack something, I think that a large cohort that is really, really deeply phenotyped within a shotgun-type technique like that, I think, would advance the field more than lots of hypothesis-driven studies, in my opinion.

Dr Kamar Ameen-Ali:

Thanks, Dan. And I’m interested to know what you think about… I mean, we talked a little bit about slide scanning, and that obviously lends itself well to digital pathology. I’m still in two minds, and quite a lot of people that work in pathology are very much in two minds about how digital pathology can really help speed up a lot of processes, but the accuracy of it can never really replace some of the more traditional methods that we use to do image analysis, quantifying cells, quantifying the presence of protein.

So where do you kind of sit on that? And I guess I’m seeing more of this kind of software’s that are introducing AI as well, and I’m a little bit sceptical about the specificity of some of these software’s. So, I’m just keen to hear what you think about that, and anybody else that wants to jump in.

Dr Daniel Erskine:

I kind of think there’s a number of different levels to that. So, on the one hand, do I think that AI in the near future will replace a hospital pathologist to render a diagnosis? Almost certainly not. In fact, I would say a categorical no in the near future, especially when judgments have to be made. Any of these systems is good at saying something is something or is not. Can it form a holistic picture of something and make a judgement on that basis? Probably not, and probably not in the near future.

If it can determine the amount of a particular area that’s brown, yes, it’s quite good at that. So, if you’re using DAB staining and you want to know the percentage area that is positive with DAB staining, it’s probably okay at that. If you wanted to determine the number of neurons within a region that have been stained with NeuN, for example, it’s probably quite good at that.

So, I guess in a research context, would it enable us to have much, much, much larger cohorts quantifying something relatively simple, like immunohistochemistry, percentage areas stained? I think it probably can be used for that. In terms of rendering diagnoses or making complex judgments based on a number of different variables, probably not, and probably not in the near future either.

Professor Tammaryn Lashley:

If I can just add to that as well, I think it’s important to look at… Yes, I think it’s a good idea, the AI, and the digital images that we produce from the stained slides. But if we think about the clinical field, a patient will go in for an MRI scan. That MRI scan is stored for multiple researchers to use for various research projects. But from a brain bank point of view, and Laura can agree or disagree, but will probably agree, is that we hand tissue out for various projects.

We could have 10 people with 10 hippocampal slices stained in a H&E, an Abeta, or a tau, whereas if we digitise these slides, we can then give the images out, which saves the brain tissue, saves time. So, I think there’s different aspects to the digital world that we can look at, which will be beneficial for neuropath research. But I agree with Dan. I think for the diagnosis, no. But I think for the research, pushing the research forward and speeding up research, I think it will be essential to drive that aspect of the research.

Dr Kamar Ameen-Ali:

So, before we go, I just have a question that might help some of the newer scientists who might be listening to the show. So, anybody that kind of wants to jump in and give an answer to this, then you’re very welcome. What advice would you give to young scientists who might be interested in neuropathology and might be interested in either pursuing research in this area or other roles that’s like Laura’s, either as a technician and then progressing through to being a manager of a brain bank? What advice would you give to them? Laura, yes.

Dr Laura Palmer:

I can definitely start with this one. So, my advice in a nutshell is to make the most of every single training and development opportunity that comes your way, and that’s both in the workplace and outside of it, because my personal experience is that skills are transferable no matter how random they might seem. I had the weirdest range of work experience before I joined the Brain Bank, ranging from working in a chip shop to… I did eight years in Tesco, which I also carried on alongside my technical role when I first joined the Brain Bank.

But as part of that, I did some training in pharmacy dispensing, and I used to work in the pharmacy. And I actually found a lot of those skills, talking to people perhaps when they weren’t feeling very well, confidentiality, dealing with people who might be distressed, dealing with confidential information. All of those skills were really very transferable to my role in the Brain Bank, which is, although it centres around postmortem brain tissue, my role really is about dealing with people.

It’s about dealing with potential donors, putting their fears to rest, reassuring their families, counselling them through the process of brain donation, and then feeding back this end diagnosis, and also working with researchers. So, there are lots and lots of people elements in science that I think sometimes if you’re at the bench a lot, you can forget a little. So yeah, that’s my advice. All experience doesn’t matter what it is, you can bring something new to your role or to your career progression. Hopefully, that’s useful.

Dr Kamar Ameen-Ali:

Thanks, Laura. And I would second that because I actually used to work as a dispenser in a pharmacy as well.

Dr Laura Palmer:

There were a lot of us. There were a lot of us. I’ve met a few people actually who, yeah, that’s been an inroad for them.

Dr Kamar Ameen-Ali:

Yeah. And I can totally see how a lot of those skills can translate to research or at other roles within academia and within research as well. Tammaryn, I’ll go over to you next.

Professor Tammaryn Lashley:

Yeah. I didn’t work in a pharmacy, and I can’t see how transferable my skills were from McDonald’s. I’ve just wanted to say that I can’t really come on a neuropath podcast without mentioning the British Neuropath Society. So, scientists or people wanting to embark on a career in neuropathology, it’s a good place to start. We have a website. I’ll be taking over the presidency in the beginning of February, which I’m mightily scared about, but I do want to increase the profile of the Society for younger scientists, neuroscientists.

It’s not a society just for neuropathologists. It’s for everybody working in the neuropath field that can come together, share skills, and just enable the research to progress, really. So, if you are a young scientist looking to come into this field, then reach out and we can put you in contact with a researcher working in your area that may be able to allow work placement, work shadowing, or even just have a conversation about how they got into the field. So do reach out.

Dr Kamar Ameen-Ali:

Thanks, Tammaryn, and the BNS meeting in two weeks’ time, I think.

Professor Tammaryn Lashley:

Yes. Yes. It’s all going to plan so far, the organisation. So, fingers crossed it goes okay.

Dr Kamar Ameen-Ali:

Yeah. I’ve ran an event yesterday, and I know everything that goes into these things. And it can be very stressful, but the feeling afterwards is great. So, fingers crossed it’ll all go well.

Professor Tammaryn Lashley:

Thank you. Sorry, just to say, the symposia on neurodegeneration as well.

Dr Kamar Ameen-Ali:

And that’s on Wednesday, isn’t it?

Professor Tammaryn Lashley:

Yup. Yup.

Dr Kamar Ameen-Ali:

Yup. Dan, anything that you want to add.

Dr Daniel Erskine:

I’m not really sure of anything unique. I mean, I would definitely echo Tammaryn’s comments about the British Neuropathological Society. I can honestly say, of all the academic conferences that exist, it’s the only one I will definitely go to every year. It is that good. It’s not like AD/PD, the Alzheimer’s Disease and Parkinson’s Disease Conference, where it’s large and overwhelming and you can’t see everything, you want to see. It’s one session. Everyone’s working on a very similar area. And they’re all using the techniques that you use, so it feels like every talk is definitely relevant.

So, I mean, I’m just echoing, I guess, that. And also just, do not be afraid to reach out to people, because you find most people in this field are really friendly, really supportive, and they want to help if they can. So, I would not be at all afraid to do that. And I’d also really recommend that anyone listening does it, because it’s the best thing I’ve ever done. And hopefully, it will be for anyone listening as well, if it’s something they’re interested in.

Dr Kamar Ameen-Ali:

Really, really great advice. Thank you. And a nice little plug for the BNS as well. Maybe from this, we’ll get some partnerships between Dementia Researcher and the BNS going forward, or we can have maybe a series of podcast episodes that might have been birthed from this one. But thank you all for that great advice.

I’m afraid that is all we have time for today. If you just can’t get enough of this topic, visit the Dementia Researcher website, where you will find a full transcript, biographies of our guests, blogs, and much more on the topic. I would like to thank our incredible guests, Daniel Erskine, Laura Palmer, and Tammaryn Lashley. I’m Kamar Ameen-Ali, and you’ve been listening to the Dementia Researcher Podcast.

Professor Tammaryn Lashley:

Bye.

Dr Kamar Ameen-Ali:

Bye.

Voice Over:

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

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