Podcast – ADPD 2023 Conference Highlights. Part Two

Voice Over:

Brought to you by Dementia Research at .nihr.ac.uk, in association with Alzheimer’s Research UK, Alzheimer’s Society, Race Against Dementia and the Alzheimer’s Association, bringing you research, news, career tips and support.

Dr Anna Mallach:

Hello. Thank you for tuning into the Dementia Researcher Podcast. I’m Dr. Anna Mallach and I’m a research fellow at the UK Dementia Research Institute at UCL. I use spatial transcriptomics to study cellular changes around plaques in Alzheimer’s disease. It’s my pleasure to be hosting this very special podcast recorded on location from the AD/PD conference in Gothenburg. This is the second show in a two-part special, bringing you all the news and highlights from this leading international conference, sharing some of the latest development in neurodegeneration research.

Today we’re going to reflect on the scientific program and the talks that have taken place over the last three days of the event. That could be from Thursday afternoon to Saturday, but who knows? I’m sort of losing track of my days. Joining me to share the highlights are the amazing Dr. Chi Udeh-Momoh, the fabulous Dr. Melissa Scholefield, and the incredible Emily McCann. Hello, everyone.

Dr Melissa Scholefield:

Hi.

Emily McCann:

Hello.

Dr Anna Mallach:

Let’s go around the table and do some proper introduction. Tell us about yourself and what you do.

Emily McCann:

I’m Emily McCann. I’m a final year PhD student at the University of Queensland. My project is about developing cognitive tests to pick up dementia a bit earlier and hopefully trying to relate that to their functional changes that are happening in their brain.

Dr Chi Udeh-Momoh:

So, I’m Dr. Chi Udeh-Momoh and I’m a senior researcher based primarily at Imperial College in London, Karolinska Institutet, Aga Khan University in Kenya. And also, I’m currently doing a fellowship on equity and brain health at the University of San Francisco in California, part of the Global Brain Health Institute. So, my research work program I suppose is translational approaches towards and prediction and prevention of dementia with a focus on diverse populations.

Dr Anna Mallach:

And Melissa?

Dr Melissa Scholefield:

So, I’m Dr. Melissa Scholefield, based at the University of Manchester. I’m a post-doctoral research associate. And we’re performing multiomic analyses across multiple dementias. We’ve already looked at Alzheimer’s and Huntington’s, but we’re extending that to Parkinson’s disease dementia, dementia with Lewy bodies and also Parkinson’s without dementia, with the aim of seeing what similarities and differences there are between diseases and how we can explain why they have different clinical progressions and symptoms. And we’re focusing on metabolomics, metallomics and also proteomics as part of the multiomics network. Yeah.

Dr Anna Mallach:

Very nice. Thank you, everyone. Before we get to your highlights, I should ask if any of you are presenting this week. Tell us about that. So, Emily, you mentioned you gave an online presentation.

Emily McCann:

A lot of my project was having a look at positron emission tomography imaging to have a look at metabolic changes in the back of the brain, particularly for typical Alzheimer’s disease, posterior cortical atrophy, which is a visual variant of Alzheimer’s disease, Parkinson’s with and without dementia, and dementia with Lewy bodies. So, all of those diseases tend to have metabolic changes in the back of the brain sort of reflecting the degeneration. My project was about developing perception tests to target those regions specifically for these kinds of dementias. So yeah, it’s going pretty well so far. We’ve been able to pick up some really early subtle changes in people’s cognition prior to them being picked up on traditional clinical pen and paper tests. So, it’s been interesting to see that and also work with our patients and their clinicians in order to better manage their diseases as well.

Dr Anna Mallach:

Very nice. So, the PhD is slowly wrapping up.

Emily McCann:

Trying to, yeah. Hopefully try and collect as much data as possible over the next few months and yeah, go from there.

Dr Anna Mallach:

Have you given a talk or had a poster?

Dr Melissa Scholefield:

I gave an online talk, so I think it was released on the very first day, on Tuesday actually. So [inaudible 00:04:14] of the pre-conference day, but it was just explaining some of the metabolomics work we’ve done. So based on previous metabolomics we’ve done in Alzheimer’s and Huntington’s, we’ve been quite surprised at the number of similarities that we saw between what two very different diseases are generally. So, we wanted to see, if we looked at the Parkinson’s disease dementia brain, how similar it would look, if it would look more like Huntington’s or Alzheimer’s.

So, we work with postmortem brain tissues, using multiple regions, about nine of them. So, we want to see if changes are localized or if they’re even in regions with low levels of neurodegeneration. We’re quite surprised to see that, for example, changes in glucose, metabolism pathways, really high levels of fructose, which we didn’t really necessarily expect to see in almost every single region that we’re looking at, which suggests that glucose is moving away from glycolysis towards other metabolism pathways. So, polyol pathway, pentose phosphate pathway.

Also, extremely high levels of urea, which-

Dr Anna Mallach:

Wow.

Dr Melissa Scholefield:

Yeah, which you don’t expect to see in the brain. We’re kind of scratching our heads trying to figure out where exactly it’s coming from because, as far as we know, there isn’t a complete urea cycle in the brain. I think there’s been some studies to suggest that exposure of cells to amyloid beta could actually produce a complete urea cycle, which would explain, at least in Alzheimer’s, where it’s coming from, but I’m quite interested in seeing if other proteins would do the same thing.

Dr Chi Udeh-Momoh:

Can I just ask a quick question around that? Maybe they shouldn’t have made it on the menu. No, but I’m just quite intrigued, but how do you look into just ensure the viability of the samples? Could it be because it’s postmortem tissue and I’m just wondering about contaminants.

Dr Melissa Scholefield:

So, we’re very careful about the postmortem delay. So, we’ve gone to extremely long lens to make sure that it’s at least under 24 hours. So, we actually did a study in the wrap brain to look at the effect of postmortem delay on different metabolites. So, the urea, things like the urea and the fructose actually aren’t too bad. Up to 24 hours, they’re fine.

Dr Chi Udeh-Momoh:

I see.

Dr Melissa Scholefield:

Yeah, some metabolites if you go past 24 hours or even by the time, you’re at the 24-hour point, they’re already deep changing. So, you have to be careful depending on what you’re looking at. But we used our previous study to make sure that the things we were looking at were all stable.

Dr Anna Mallach:

And just obviously the question on my mind now, is Parkinson’s more like Huntington’s or Alzheimer’s disease?

Dr Melissa Scholefield:

More like Alzheimer’s.

Dr Anna Mallach:

Interesting.

Dr Melissa Scholefield:

Yeah, so we also looked at metals. We found decreased copper levels in almost every single region that we looked at in the Alzheimer’s and the Parkinson’s, but we didn’t find that in the Huntington’s. We found altered selenium in Huntington’s. So, it seems like those two are closer together and I’m interested in seeing if the dementia with Lewy bodies is in the middle or if it just looks like the Parkinson’s disease dementia. We’re just getting the tissues for those now, but quite interesting.

Dr Anna Mallach:

Are you getting them from the UK brain bank or?

Dr Melissa Scholefield:

From the NIH brain bank in the US.

Dr Anna Mallach:

Okay.

Dr Melissa Scholefield:

Yeah. So, we’ve actually had to get them from two of the brain banks that are apart that network. So, the Harvard brain bank and the Sepulveda brain bank. So, we’ve got quite a big sample size, so it’s 15 versus 15, which isn’t huge, but when you’re working with brain tissues, it’s difficult. And we’re looking at 10 brain regions, so it’s 300 samples. So, we’ve been spending [inaudible 00:07:45] getting these samples of course. So quite excited to finally have them.

Dr Anna Mallach:

Good. And I actually gave a talk as well on the big scary stage downstairs at an industry symposium on Thursday because we’ve been looking at spatial transcriptomics, which is kind of this new and moving field where a lot of companies are now bringing out new tools such as the NanoString CosMx machine and the Xenium from 10x and all of these things. And as part of my research, I had the chance to trial the NanoString CosMx machine ahead of schedule in September. So, we’ve got that data from our mouth sample and we’ve been since then desperately trying to analyze it, which turns out was a bigger job than anticipated.

I don’t know, as a [inaudible 00:08:30]ologist, I thought maybe we’ll just do some analysis. And we started in September and we’re slowly finishing up, but because we’re now slowly finishing up, NanoString invited me to present my work and just kind of show to scientists what you can do with their machine and how it compares to what they advertise because there can be discrepancies between what companies promise you and then what you get once you send your samples in.

Dr Melissa Scholefield:

So do you have a bioinformatician to help you with your analysis?

Dr Anna Mallach:

I have a bioinformatician. We’ve just hired a second one. And I have to say I also learned a lot of bioinformatics since the summer. So we got data from this kind of NanoString CosMx, which is a biased technique, so you only get a thousand genes from your 20,000 cells. It’s actually a relatively small data set. And then we did some unbiased transcriptomics where we have half a million cells and 30,000 genes in total. And that such an unruly dataset that the bioinformatician’s analyzing that because everyone decided I wasn’t qualified, and I get to play with a slightly smaller and manageable dataset. But yeah, I learned a lot of bioinformatics. It’s interesting.

Dr Melissa Scholefield:

Yeah, that’s the fun of doing omics. You kind of have to learn.

Dr Anna Mallach:

You kind of [inaudible 00:09:52], but I also think once you sit down and you have your own project, you do pick it up relatively quickly in a way I find there is who wants to be like, “Oh wow.” And you’re like, now, you just have to. This is pure survival. Just like you learn how to keep cells alive, you learn how to do your own analysis.

Dr Chi Udeh-Momoh:

So I presented data from our landmark FINGER intervental trial, which was on the world’s first multi-domain lifestyle interventions to show any type of therapeutic benefit in terms of cognition, but also functional outcomes, and more recently cost benefits. And so I’m very interested in biomarkers with different context of use. So diagnostic prognostic, but also treatment response, especially with all the advent of the disease modifying therapies. Given that we had an intervention that actually worked, I wanted to see if we could identify a marker, for instance, that would tell us whether people in the intervention groups, what are the biological mechanisms for how they actually performed better than those in the control groups?

And so I’m very interested in HVA access and the marker that I chose was cortisol. And my group have shown that cortisol hyper secretion not only is associated with a predicting cognitive decline, but it also predicts progression from the preclinical state. And because the FINGER participants were at risk or cognitively unimpaired relatively at baseline, it just seemed like a good marker to trial. So went on to do the analysis, did the cortisol samples and that was what I presented, and hypothesized that, yes, so we would see lower levels of cortisol in the intervention group post intervention compared to the control group. Found absolutely no change.

Dr Anna Mallach:

[inaudible 00:11:44]

Dr Chi Udeh-Momoh:

I did think, why are you going to present negative data? But we’re scientists. That’s what we have to be…

Dr Melissa Scholefield:

You have to say everything.

Dr Chi Udeh-Momoh:

You have to say everything. What I did find though was that, and I’d found this actually previously, and so it was nice to see some consistency showing that at least baseline cortisol was associated with, was able to predict odds of being amyloid positive versus negative, but it was also able to predict longitudinal brain changes, so with gray matter volume particularly and an anti-cortical signature. So that was quite interesting. And I think our next step is because it was a lifestyle intervention, we noted that not everyone was adherent. So not everybody in the intervention group actually adhered to the protocol. So I think that we’re going to check in that adhere group to see whether the hypothesis still stands.

Dr Anna Mallach:

So what were the interventions?

Dr Chi Udeh-Momoh:

So FINGER’s-

Dr Anna Mallach:

Might difficult to attack.

Dr Chi Udeh-Momoh:

So you have physical activity, you have nutritional guidance, cognitive stimulation or cognitive activities. We also have vascular risk monitoring and it’s all embedded within this social engagement framework. So it’s been tested and trialed now, I think we’re now in over 45 countries, so it’s really expanded. The model is been culturally adopted around the world globally. So exciting times.

Dr Anna Mallach:

Why do you think the cortisol didn’t change? [inaudible 00:13:23]

Dr Chi Udeh-Momoh:

So my guess is because there is already existing evidence from single domain trials that show that, say for example with physical activity with yoga and mindfulness, that cortisol cell levels do change in response to these sort of interventions. And I’ve published in this before. So I was expecting a huge, huge, huge significant change. I think that because we looked in such a large sample, and also because we didn’t focus on those who actually adhered to an intervention, we might have missed the actual effect, so there might still be a change. So we really need to do that to really look into whether or not that adherence group have indeed have, their cortisol levels have lowered because then that provides some evidence on a potential biomarker for monitoring treatment response.

Emily McCann:

So you said there was an improvement for single demand studies and you just focused on yoga and mindfulness or whatever that is. Is it just too many things at once for older people that have their life to live and friends to see and family and whatever? It’s like if you’ve got these five massive changes that they’ve got to change for their everyday life. Is it just too many things at once so your adherence is low, do you think?

Dr Chi Udeh-Momoh:

Well, that’s a really good question actually. So what we’ve found was, and the adherence study has been published, so there are various factors that determine adherence. Because the interventions are embedded within a social framework, the feedback actually from participants even within the intervention group was they enjoyed it, they enjoyed the social aspect of things. But of course, I do think that these are elderly individuals, and what surprised me though was there was cognitive benefits. So there was an actual, the primary outcome was met. So it could be that that’s less sensitive and you need a more sensitive increase in the intervention or you need a more sensitive aspect of the intervention to be able to measure biomarker changes.

So we’ve also looked at BDNF as well in this group and found that in the overall intervention cohorts, no change whatsoever. But when we looked in the adherent cohort, BPNF actually there were changes. So it looks like with the biomarkers people do need to actually do the intervention.

Emily McCann:

It’s funny how that works. That does make sense, yeah.

Dr Chi Udeh-Momoh:

Question on that as well by colleague.

Dr Anna Mallach:

Okay. Well, for anyone listening or watching, you know how these shows work. We take turns at talking about our best bits. For this conference, there’ve been quite a few. So let’s go to the highlights.

Dr Melissa Scholefield:

So one of my favorite talks was by Lenora Higginbotham, I think her name is pronounced. I think she’s from Atlanta. So I was quite impressed by her talk because she managed to take some really huge data sets and get them into a 10-minute talk. So actually, one of the data sets that she presented, I presented in a journal club before and it took me the best part of an hour to get through it, so she’s definitely more succinct than me. But she did a network proteomics in Lewis body dementias and Alzheimer’s disease. And what they were doing is they were seeing if the changes in the different network modules were similar or different between Lewis body dementias, including Parkinson’s disease, dementia and DLB, against Alzheimer’s disease. And what they found was that modules associated with things like pre-synaptic signaling and differentiation were different between the two.

They also looked at the type of cells where these changes were happening. So as well as having these huge dataset, they were looking at, say, were they happening in neurons? Were they happening in astroglia? And most of the modules that were changed appeared to be changed in neuronal cells. So the actual, the specificity of the things that they were looking at was quite impressive. And I’m really interested in looking further into the Lewy body dementia data to see how things like Parkinson’s disease dementia and dementia with Lew bodies compare against Parkinson’s without dementia, because I would expect the two of those to look quite similar, but if you can compare them to Parkinson’s without dementia, maybe we can get an idea of what’s contributing to the cognitive symptoms as opposed to the motor symptoms in those diseases. So I’m just quite excited at these kind of data sets, especially the OMEX data sets, and seeing what more they can do with that data.

Dr Anna Mallach:

Cool. Yeah. Do you want to talk about highlight, Chi?

Dr Chi Udeh-Momoh:

Yeah, I’m happy to just give a broad overview of some of the highlights and things that I like, but I have to start with a major caveat. In this sort of conferences, I tend to have loads of meetings and so I had to be very specific about which symposiums, which talks, which process I wanted to attend and view. So I focused on biomarkers because that’s my area of interest and I was quite focused in terms of areas of research, interest areas. I wanted to really understand what this current state is and what the new discoveries were because the menu available was just, it was amazing. Kudos to AD/PD.

So there was so many talks and the state of fluid and major biomarkers with distinct contacts of use, and from way from experimental models to lots of new discoveries, for example, around isotopes of existing markers. I like the tau 3 [inaudible 00:19:22] 396 talk, but I would say my current favorite was one that was beautifully derived by Dr. Thomas Carey, the brain-derived tau. I found that really exciting and it was really interesting to see because, of course, we’re always talking about ATN and working in clinical trials, it’s so important to be able to stratify participants accurately. So we’ve got in blood AT and we total talent not being super specific for N. It was great to see that there’s potentially a new N on the horizon. So please carry on that research.

But I was also interested in methodologies. So for instance, really trying to be specific about the types of the analytes that we’re measuring, but also the fluids that we’re looking at. So I looked into, I went to the exosome symposium and it was great to see they discussed actual methods for isolation of brain-derived exosomal vesicles, which are notoriously impossible to isolate. And I was quite pleased because we’d done our group at the Biofreeze based biomarker here had done a review to see, well, what are the antibodies that we could use to really be specific? And it was great to see people are now looking at extracellular synaptic targets as well. And this was excellently showcased by I think [inaudible 00:20:53] and [inaudible 00:20:55] as well.

And you guys have discussed the physician approaches that we talked about, the multiomic studies. I found those really nice, including the proteomics. But I guess because I work in discovery science, but I’m very interested, my background is translational neuroscience and I’m always thinking how are we going to benefit the patients? So I know I said I was going to start with what I like, but I really want to also highlight that I was encouraged because we’re now at the stage of thinking about real world implementation, and there was a Rush symposium where Dr. [inaudible 00:21:31], she commented to say that we have all of these pieces and you can imagine from all the excellent talks that we’ve gone to, but we really need to start thinking about how we’re going to implement this in real life settings. And Professor [inaudible 00:21:44] gave a really great overview of strategies for implementing this sort of blood-based biomarkers and the applicable context. So I’m going to stop now because-

Emily McCann:

Keep going. Yeah, keep going.

Dr Chi Udeh-Momoh:

I can go on into the things that I think we need to do later or what the conference should focus on later.

Emily McCann:

Yeah, I think the conference has been really broad and diverse. And yeah, you’re absolutely right, there’s so many different pieces of research that are coming together, which is really nice. But I sort of almost feel a little bit like a minority because I actually work with patients, real patients every day. I know my patients are doing and what impacts them, and there’s been just a handful of things that I’ve seen so far because there’s heaps of blood biomarkers and genes and stuff, and that’s been amazing and it’s really good seeing a different side of research that’s really different to my own. But yeah, coming back to how is this going to benefit the patient is really important.

So I thought there’s been a few really interesting talks around one, I think yesterday and potentially maybe the day before, all my days are one now, professor Peter Snyder from the University of Rhode Island. He was looking at retinal biomarkers, which I think is really interesting. My work a lot of the time is in perception and whether our patients are interacting well with their environment, they can identify what they’re looking at, those sort of perceptual issues. I’ve been able to see personally with patients that those sorts of things tend to go a bit earlier and they get missed.

Memory is something you can’t really hide, but perceptual things, like if you accidentally bump into a table or something, it’s you’re clumsy. It’s not, “Oh my god, I’m about to get dementia.” If you start forgetting to make your child up from school or whatever, that’s a problem. So yeah, I thought it was quite interesting coming from actually what’s happening from the eye rather than what’s happening in terms of the pathways that are leading to your visual cortex and how you’re perceiving what’s in front of you.

So yeah, he was really interesting to talk to and he’s totally right, we don’t have these tests for dementia that people do all the time. But you see your optometrist every couple years because your eyes are terrible, and if you’re me, you see them every year and you get new glasses every year. So as we get older, our vision degrades a little bit so you get stronger glasses and you seeing an optometrist or an ophthalmologist every year or two. So having some sort of screening process there to sort of see if there’s anything going on where they can refer you to a neurologist to potentially catch that a bit earlier I think is really exciting.

So he was saying the retina is one of very few exposed tissues we have access to in a person. So if there’s a way that we can have a look at that and have a better idea of what’s happening there, it’ll be important. So in the retina, there’s the plexiform layer I think, is got a cholinergic system within its layer, and cholinergic systems and degeneration in those systems seem to be pointing towards cognitive deficits in a lot of different neurodegenerative diseases. So because there’s some sort of cholinergic input there, there’s something happening.

So he was saying that there’s a decrease in the layer of, the decrease of the thickness of that layer in the [inaudible 00:25:03] in the eye, and that’s happening quite early. And in that later you can sort of see these little inclusion bodies in the peripheral that we have missed, I guess, that a lot of cognitively normal people don’t have.

So it sounds really interesting, exciting, especially because that sort of thing was happening before these people had their amyloid beta and tau deposit sort of coming up on their CSF. It was sort of prior to that in this preclinical stage. So yeah, kind of interesting to see that there’s other things out there that’s kind of pointing towards perceptual things happening earlier than what we thought, which is good. That sort of validates my research project. But yeah, it’s interesting that it’s even happening from the eye before it even gets to the cortex.

So I thought that was really interesting. And yeah, he’s totally right. If we can identify these changes in asymptomatic, potentially amyloid positive people before these symptoms start happening, we can absolutely help them better manage their disease. They can talk to their families and their loved ones and sort of get a plan in place for how they’re going to handle the next few years, which is really important. That’s a real world patient outcome, which is really important.

Dr Anna Mallach:

And I think also then moving into the future, once we have disease modifying therapies, you really want to get them into the patients as soon as you can diagnose them. So I think that’s the other thing where I think at the moment we are catching it so late that there’s a lot going on and there are a lot of comorbidities.

Emily McCann:

Yeah, absolutely.

Dr Anna Mallach:

And in that way, I really enjoyed the plenary session yesterday from Dr. [inaudible 00:26:36]. That was butchered, but okay. We all know who I’m talking about. PD therapies, who very much made a point at the beginning to say there is a lot going on. What we call Parkinson’s is made up of psychiatric symptoms as well as motor symptoms. And so much going on, I’ve been thinking of for a while now, should we at one point maybe drop what we currently call Alzheimer’s disease and Parkinson’s and maybe go more towards a syndrome route of the things of better stratifying the diseases? Because I think that also is a big problem we still have in the field where there is a lot going on and there a lot of comorbidities that really impact.

Emily McCann:

And it helps now that you can go and do a spinal tap, as painful and distressing as that sort of seems to be like, you get your CSF done and you do or you don’t have Alzheimer’s. And if you don’t have it and it’s like, “Okay, well, what’s next? What’s the next step? What’s the next thing we’re looking for?” Because that’s the only thing we can definitely confirm that somebody has or not. Parkinson’s dementia is totally different dementia, Lewy body’s totally different. We don’t have a definite indicator whether somebody’s got it or not. It’s a process of elimination.

Dr Anna Mallach:

Yeah, no, which takes so long.

Emily McCann:

Takes so long, yeah. With the average turnaround for a diagnosis is what, three and a half years? It’s three and a half years too long. Yeah, there’s a lot of change in three and a half years. We have to get it earlier than that.

Dr Chi Udeh-Momoh:

I think that the research with sleep as well around DLB and all of the new sleep type biomarkers and tools, there are some fantastic talks in EEG and sleep. So they sound promising for detecting DLB early potentially.

Dr Melissa Scholefield:

Yeah, I’m looking forward to going to some of those because I think there’s some of those coming up today.

Dr Anna Mallach:

Oh yeah, in the afternoon. Yeah, I know. Highlights are yet to come.

Dr Melissa Scholefield:

Sort of going off what both of you were saying, so firstly seeing inclusions not just in the brain but also in the retina and also talking about not just considering these as diseases but more as syndromes. It’s other things going on. A talk I went to yesterday about [inaudible 00:28:42]. So he was talking about alpha-synuclein inclusions in the heart of people with Lewy body diseases and he found that 88% of them had inclusions in cardiac nerves. Absolutely none of the controllers had it. It was a disease specific thing and it was happening very early on. So even people with brain stem type Lewy body dementia had these inclusions. And not only that, but sudden cardiac death accounted for about half of deaths in these people that they looked up.

So we’ve seen a similar thing in Huntington’s where it’s the second most common cause of death, is cardiac failure. So I think we need to start thinking that these aren’t just brain diseases, these are full body diseases and we need to start looking at them in sort of holistic manner. And it would certainly be very useful if we could get tissues that weren’t just brain or bio fluids. I’d love to have a look at the Huntington’s heart, but I don’t know how to get hold of that tissue without going out, going out to specific patients, and seeing if we can do it that way, but there’s not really banks that cater to that sort of thing. And I think it’s a shame that we’re not collecting other types of tissue when we’re collecting the brain tissue.

Dr Anna Mallach:

Definitely. Never crossed my mind, but yeah.

Dr Chi Udeh-Momoh:

Yeah, that’s quite interesting because I think something I took from that, but also just generally, something that struck me within the conference was the use of personalized medicine approaches because you really need to think about person-centered. Like you’re saying, really think about things as a syndrome because a lot of these present with underlying and additional conditions as well. But it’s really nice to see that they’re starting to think freely and use these personalized medicine approaches with development, for example of AD therapeutics. So I’m quite interested in drug discovery.

So it was nice to go to some of those industry type presentations but also see academics as well being involved in the therapeutics development process. And what I noted was people are no longer just looking across board, but they’re really targeting how you’ve talked about the cardiac… Was it the cardiac myocytes specifically?

Dr Melissa Scholefield:

The cardiac nerves.

Dr Chi Udeh-Momoh:

The cardiac nerves.

Dr Melissa Scholefield:

Yes.

Dr Chi Udeh-Momoh:

So there’s targeting specific profiles as well and it’s showing a lot of promise. So I think one example was there was this trial, I think it was presented by Alzheon’s CEO, and what they’ve done is they’ve used… So they’re targeting precisely targeting subpopulations of people with specific risk profiles. So with Alzheon, they had an [inaudible 00:31:33] enriched cohort and then and they looked and they’re actually seeing, I think what they presented, it was yesterday, yeah, or two days ago now.

Dr Melissa Scholefield:

It’s the one day.

Dr Chi Udeh-Momoh:

Yeah. But what was exciting was you are seeing effect sizes even better than denosumab that we’re all excited about. It’s incredible. And then I also saw another one, I think it was in the same symposium, Actinogen’s 11 beta HSD1 inhibitor. I went there for the Actinogen because it modulates cortisol. But it was great to see efficacy by just targeting those with tau abnormality. And I think that these sort of personalized approaches will be quite useful.

But I would say that one of my favorites, I think, within the talks of attendance so far was Miranda Orr, and she’s an academic and she used, it was translational approaches, but she’s looking not just at AD or PD, she’s looking at senescence with her senolytics. So looking at cellular senescence and it’s a particular pathway that can then be evolved to multiple neurodegenerative diseases. And I think that approach is really fascinating and we need these sort of combinatory therapies.

But I mentioned FINGER, but what I should have said was FINGER’s now being adapted to then add on therapies. So [inaudible 00:33:07], who founded FINGER, she gave her a good presentation on this topic. I think also think they were waiting for the Swedish screen or something to turn off. But they’re combining the lifestyle, lifestyle modification, with an anti-diabetic. And it’s obvious that we need to really start thinking creatively. We’re thinking towards therapies for AD. So it’s great to see that.

Dr Anna Mallach:

Yeah. Thinking about outside of the box, I really enjoyed a talk actually just from this morning from [inaudible 00:33:37]. He looked at, his introduction was the hallmarks of finding hallmarks of cancer and how that can be applied to [inaudible 00:33:48] degeneration. So they did this huge study with 400 patients, single cell RNA, and you just think, what are you going to do with all of this data? And they called out these transcriptional hallmarks to kind of say, “Okay, can we stratify patients? Can we stratify them with that?”

And I found that was such an interesting approach of saying, okay, other diseases, particularly cancer, they are further in terms of treatments. What can we take from them? What can we steal in terms of conceptual aspects? And I really like this idea of can we find hallmarks that connect patients, and that ultimately they found some hallmarks that could correlate with this kind of resilience that was discussed quite a lot this morning kind of saying we have patients with similar loads of pathology without going on to develop dementia.

And I think that was just a really nice way of tying together all of these four brains here and four brains there that have been staying to look at what’s the difference between resilience and controls. And that’s kind of where I come from and to kind of saying, we flip it around instead of going from a resilient patient, can we identify them afterwards?

Dr Melissa Scholefield:

Yeah.

Dr Anna Mallach:

So I thought that was very interesting as well.

Emily McCann:

And it’s really important because patients are so diverse. Especially as you get older, you get more diseases. It’s not just, you don’t just have Alzheimer’s or just have Parkinson’s and that’s it. Everything else is fine and dandy. There’s so many different things that go into it. So yeah, if we can definitely steal something from cancer research and shorten the time it takes to get to the end and fully understand what happens in these elderly people, it’ll go a really long way.

Dr Melissa Scholefield:

I’ve been quite excited find the Amsterdam, the over 100s cohort that they’ve been collecting.

Dr Anna Mallach:

Oh yeah, that was amazing.

Dr Melissa Scholefield:

Yeah, talking about how they differ, their brains differ to those of people that went on to develop AD. And they were talking about how even in healthy people over 100 who had higher, say, tar braak stages, for example, it didn’t correlate with their cognition, but when they looked at the amyloid load it did, and two thirds of them had a lower amyloid beta load than the very lowest AD patient. So it seems to be that when we’re sort of defining the disease and when we’re stratifying it, we will use these sort of traditional staging systems, which are good, but also taking into account other things like amyloid load are probably quite important if we want to have a look at resilience and help people respond to treatment because it seems that other factors are in play here.

Emily McCann:

Exactly, yes. Keep talking about this interior. But yeah, it was, yeah, amazing that they went through all the stuff. They did their cognitive testing, they did this huge protein omic sequence of these people. I don’t know, I’m basic science, but getting to the point where they have younger brains and even though they have an amyloid accumulation which potentially falls somewhere on the normal spectrum, they still had younger brains compared to the other people that were had diseases or whatever because they had less aggregated tau and more protein folding and more neuro filaments and that sort of stuff. So it was, yeah, quite interesting to see that. It’d be cool to see how to age without cognitive decline and make it to 100. Yeah, absolutely. But yeah, it was really interesting. I really enjoyed those talks. Yeah.

Dr Chi Udeh-Momoh:

Yeah. Just going back to your comment about comorbidities, it would be quite important, I don’t think we can ignore that excellent plenary by Professor [inaudible 00:37:30] where she described disparities around blood biomarkers. It was refreshing to see that because I didn’t see a lot of people controlling for this sort of disparities in their own studies. A lot of the talks that I went to anyways. But she talked about it in relation to comorbidities across different ethnic groups. And what struck me even, I was blown by Professor John, I think John Morris’s talk, showing how biomarkers relate to social determinants of health because we always focus on ethno-racial disparities and ignore socioeconomic disparities because that can actually influence blood biomarkers and those are really related to comorbidities.

So it’s really sad for me, I guess, to see that those sort of important characteristics and still not being fully considered when we’re analyzing data from real world cohorts, and must the cohorts been described, I guess they’re still homogenous in terms of ethnicity, education level, most of them are socioeconomic status, so we’re seeing data from a very small percent of the population, and given the accelerations in drug and biomarker development and validation efforts, I think the field just needs to do better with increasing representation when thinking about these new cohorts. And I’m hoping that these considerations will be integrated and developed in appropriate use criteria and guidelines for how we’re going to use biomarkers for different contexts.

There was a talk earlier just before this session by Dr. Frederico Masa and here he used the Delphi model to define a biomarker based workflow to diagnose different neurodegenerative diseases, and he was using multimodal biomark. But again, the cut points have been developed in very, very homogeneous populations. And for me, that’s a good example of an approach to develop this sort of diagnostic workflows. But until we have enough diversity within our samples, we’re going to get in trouble because we’ll see that, especially with the blood markers where comorbidity has completely changed the picture, socioeconomic status, independent of ethnicity, change the pictures. So we really, really need to…

Dr Melissa Scholefield:

Socioeconomic states in particular, we’ve heard so much about vascular comorbidities and we know how closely those are linked with socioeconomic status.

Dr Chi Udeh-Momoh:

Exactly. Exactly.

Dr Melissa Scholefield:

And the reason it doesn’t get looked at much is because of the type of samples we get and the type of recruitment we have. So hopefully the push is towards getting the representative cohorts actually at least gets looked up.

Emily McCann:

Yeah, I think in one of the… It was a little bit off topic from the cholinergic imaging symposium from yesterday. They were looking at asteroid inhibitors for drugs and that sort of stuff, and one of the questions came up and the presenter couldn’t answer it, but in the last year they changed the recommendations for the dosage for cholinesterase inhibitors because women have more side effects because all of the drug trials and stuff have been on men. So they are getting a big… I know, and that’s only just happened and people weren’t aware of it and it was amazing that it shouldn’t have been missed, but having that lower dose of that medication might have a much better impact on female patients because we aren’t having diverse samples when it comes to drug development. And that’s been a big focus of this conferences, the drug roll out. But how is that actually-

Dr Chi Udeh-Momoh:

Yeah, we’re seeing diversity.

Emily McCann:

Yeah, yeah, the diversity. No, but yeah, there’s every second talk has been about this drug development, but it absolutely comes down to, well, who are you testing? What are you measuring and is it actually working? And it should massively be focused towards personalized medicine because everybody is so different. So yeah, seeing what drugs work for what people is going to be really important. It can’t just be, it’ll work for Alzheimer’s full stop. It needs to go beyond that.

Dr Anna Mallach:

I think that’s a really good point. And I think this is where we’ll slowly think. We’ve talked about our main. That’s what we’ll do next, but we’ll finish this up here. And I think that’s a really good kind of, yeah, conclusion of this, that there is a lot moving in the field now, but we really, researchers, we’re always looking for the next question and we know the next problem that we now need to solve, which is this diversity.

But before we wrap up, I have one last question. Given that all of the talks we’ve seen, is there one tip that you want to share about what makes a good presentation? I think we all have opinions on this now.

Should I start? I think my tip would be assume your audience is ever so slightly less informed and sleepier than you currently think they are. Just break it down. I think I like good introduction slide about Alzheimer’s disease or Parkinson’s at any talk because then roughly where that presenter coming from. So I really like the dumb down, easy to follow talks.

Dr Melissa Scholefield:

Yeah, I think some presentations would benefit on choosing more of a focus. So obviously you can have these huge, really impressive data sets, but you’ve only got so much time to talk about them. So picking out particular bits and really being clear and explaining how they’re relevant to people that don’t work in those fields is really important if you actually want to get your message across clearly.

Dr Chi Udeh-Momoh:

Yeah. And my tip really follows along those lines just because I was late a couple of times for things because I couldn’t get away from talks. And late for really important meetings. So I do think that being very conscious of time and perhaps the moderators not getting too carried away. A lot of the talks I went to, they did fantastic jobs at trying to moderate and explain your coming close to the time. But because when you go over, then people who have critical issues and somewhere to get to, are, one, not able to ask during the session because asking questions that the sessions are really informative. I learned so much from the question sessions.

Emily McCann:

Yeah, the questions. Yeah, absolutely.

Dr Chi Udeh-Momoh:

Not that I didn’t learn from the talks, but it’s really great to really see how people are thinking and a lot of the things that they’re not able to put within the talks, they’re then able to really explain and expand on it and really have a dialogue around it. And I think it’s lessons for both the audience and perhaps even the presenter. So ensuring that you are as close to time as possible. One minute over, we wouldn’t kill you, but 10 minutes over is really difficult for everyone.

Emily McCann:

Yeah. I think… Oh no, you guys might be different, but there’s been a few talks where it’s just all this background, all these methods that potentially aren’t really useful. And then you’ve got one slide at the end that sort of gives you the results. It’s like, no, that’s the interesting part.

Dr Chi Udeh-Momoh:

Yeah.

Emily McCann:

I’m not in genomics and biomarkers. Tell me the basic of what I need to know, and then tell me the important parts of your research and focus on that. Show me the cool graphs and the cool pictures and the histology. Show me that cool stuff and really talk me through that. But before that, just give me the bare minimum I need to understand your graph. I know there’s a lot that goes into a project and for somebody out of field, just tell me the amazing part of your research. That’s what I want to see. That’s what most of your time should be. Not the last two minutes of your 15-minute talk. No, I have so many questions. What did you do next? How does this work? Yeah, absolutely. Tell me the cool part about your research. That’s what I want to hear.

Dr Melissa Scholefield:

On theme, it’s something that’s come up at previous conferences where obviously everyone’s doing different things. You have your own specialization, but you also have clinical and you have basic scientists, and they so often have very little knowledge of how each other’s type of science works. So giving all these really detailed explanations doesn’t help. You need to explain it in a way that someone who doesn’t do what you do understands.

Emily McCann:

Yeah. Exactly.

Dr Anna Mallach:

It’s a very different thing to writing a paper online.

Emily McCann:

I have found with this, because I’m obviously not a basic scientist, and they’re like, “Hey, we’ve shown that this is correlated with cognitive impairment and this is done whatever.” I’m like, “Cool. So what’s your measure of cognitive impairment?” “Oh, we just did a test.” I’m like, “Cool. What test?” This is what I do. I’m actually interested. I want to know how you’re measuring this stuff. And like, “Oh yeah, it’s called a something, something, something.” And I’m like, “All right.” Yeah, they don’t what it is. The cognitive stuff is what the patients actually care about. That’s their everyday day-to-day stuff. So even if it correlates with whatever your cognitive impairment measure is, it needs to be a good one. It can’t just be a really hard test that everybody’s going to fail. It needs to be something that’s specifically and targeted to their cognitive ability.

Dr Melissa Scholefield:

There’s a converse as well where if you’re a basic scientist, you obviously know some of the cognitive tests, but sometimes you just get an acronym.

Emily McCann:

Yeah, exactly.

Dr Melissa Scholefield:

And it’s like, what kind of cognition is this?

Emily McCann:

It definitely set in that way because you’re like, “Yeah, we just run the whatever.” And it’s like, “Cool, well, what is that? We don’t use that in Australia. Tell me what it is.” And like, “Oh, well it gives you a global sense of their cognition.” I’m like, “Yeah, I get that, but what are they actually doing?” Yeah, it’s absolutely, you’re totally right. It’s that next step. Exactly, just pull it all together. Yeah.

Dr Anna Mallach:

Exactly. That you would never normally.

Emily McCann:

Exactly.

Dr Anna Mallach:

Last time I read a biomarker paper might have been a while ago. Someone spoon-fed [inaudible 00:47:16] and you’re like, yes, 50 minutes. That’s why.

Emily McCann:

Yes, yes. I’m an expert now. Yeah.

Dr Anna Mallach:

I feel like I know what’s happening in the field now without having read.

Emily McCann:

Yeah, yeah. That’s exactly right. Yeah.

Dr Chi Udeh-Momoh:

Can I just share one observation though, just because there’s been multiple papers now, I’m talking about gender balanced panels and how they actually affect questions during sessions and engagement from audience. So for the ones, most of the panels that I attended, I did note a gender balance, and I did note ECRs asking questions on women asking questions, which is different to The Lancet paper where they actually looked at it and then provided recommendations for gender balance. So it sounds like AD/PD might have read the paper and then did something about it, and it’s actually works, though I don’t know if they’ll be able to check those metrics, but it was quite interesting to see something I’d read in the paper as a gap and then actually see it work real time was really fascinating. And I love the question and answers during presentation. I’m still in that tape because you’ve asked for what one advice is, to really engage, because presentations and you’re right, some of them are super early. I’m not a morning person anymore.

[inaudible 00:48:34] in t he morning, right? You’re trying so hard. Maybe you haven’t had a coffee or you just managed to get, you’re trying to finish your coffee. But when you engage people with those, I think they had the interactive sessions where you got to vote, I always woke up at those times. That really helped.

Emily McCann:

Yeah, that’s exactly. Yeah. It’s going to be entertaining, sort of bring you all in.

Dr Chi Udeh-Momoh:

Yeah.

Emily McCann:

Yeah.

Dr Melissa Scholefield:

I was upset at one of the forums that I went to and I think they forgot to actually look at the audience questions.

Emily McCann:

Oh no.

Dr Chi Udeh-Momoh:

Oh no.

Emily McCann:

I’m ready, I’m ready.

Dr Chi Udeh-Momoh:

I’m here for that.

Dr Melissa Scholefield:

It’s your discussion is interesting, but those questions-

Emily McCann:

Yeah, that’s it. Yeah, I’m ready. Tell me if I’m right. Yeah, yeah, it’s been quite good.

Dr Anna Mallach:

So that’s all we have time for. I hope you’ve enjoyed listening or watching, and if you want to find out more about any of the research we discussed, head over to the AD/PD website. The online portal’s open for another 30 days. I didn’t know this. [inaudible 00:49:40] Wow. Cool. Thank you to my fabulous guests. This has been so much fun. We had Dr. Chi Udeh-Momoh. I’m learning. Fabulous. Dr. Melissa Scholefield and the incredible Emily McCann. Thank you, everyone.

Emily McCann:

Thank you.

Dr Melissa Scholefield:

Thank you.

Emily McCann:

And I’m Dr. Anna Mala, and you’ve been listening to the Dementia Researcher Podcast.

Voice Over:

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

END