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VIDEO: Are you curious about the ageing brain? Early-onset dementia

Dr Brigid Ryan has dedicated her scientific research career to helping those diagnosed with early-onset dementia. With the blessing of a local family suffering from the disease, Dr Ryan works with them to learn how to prevent the progressive loss of personality and independence in this devastating disease. By identifying early signs of dementia years or decades before clinical diagnosis, she gives us hope that early intervention is possible.

Enjoy this video interview of Dr Brigid Ryan here or read the transcript to learn more about her and the very special family she works with.

Transcript of interview of Dr Brigid Ryan (BR) by Hayley McLarin (HM)

HM: Hi Brigid, thank you so much for joining us. I'm really excited to catch up with you today because I'm really fascinated by your research. Can you tell me a little bit about what you're doing?

BR: Thanks, Hayley. It's really nice to be here. My research is based on the premise that the key to combating dementia is early detection. What we're trying to do is identify the early signs of dementia before symptoms appear, so that it can be prevented. This is because we know that the brain changes that underlie dementia start many years before people notice symptoms and we also know that trying to treat dementia once symptoms exist, has been unsuccessful so far. So I think that we need to intervene early, and to do this, we need two things. We need treatments that work at this early stage and we also need a way to identify people who are in this early stage. My research is working on the second part - identifying people before they have symptoms.

HM: And how do you go about doing that?

BR: The way we are doing this is we're working with a family who have a type of dementia called genetic frontotemporal dementia.

So genetic testing on healthy members of this family tells us whether they'll develop dementia in the future or not. By studying these people many years before they get symptoms, when they're still healthy, we hope to develop a test - like a blood test for example - that we can then use in the general population to identify this really early dementia. Ultimately, our hope is that this will lead to successful intervention at this early stage to prevent these symptoms from developing in the first place.

HM: How did you find this family and when you do the tests do they then know that they are likely to get dementia later?

BR: That’s a really good question. It’s actually a really interesting part of the study and it started in quite an unusual way. The family that is involved, they actually heard about our research and they had previously had someone in their family who had donated their brain to the Neurological Foundation Human Brain Bank at the University of Auckland. Through that donation, the family became interested in research and they approached researchers at the Centre for Brain Research to ask if they could be involved in any studies and that is why it is quite an unusual way for a study to start.

We are identifying people in this family who carry genetic mutations that will eventually lead to dementia. Because we're doing this in a research capacity rather than a clinical capacity, we don't give this information to our participants. But if they want to find out this information, we do support them to go through the clinical process so that they can find that information out. Some people in the family do want to know if they're carrying this mutation, so they can plan for the future. Some people don't want to know.

HM: So are you looking at just one particular generation, one age group? Or does this traverse quite a few generations?

BR: So our participants age range starts from 25 and that is the youngest person in the study. That's because that's when we think it is the earliest time point we might be able to see these changes starting, so that equates to around about 30 years before we would expect to see symptoms in this family. We know from previous research that it is likely we will see changes happening at that early stage. Really interestingly, this is a common feature of lots of types of dementia that we do get these changes in the brain happening a long time before symptoms are apparent in a person.

What this means is we've got this really amazing opportunity to intervene during this window of change, where there are some things starting to happen in the brain, but it hasn't got to the point yet where it's causing symptoms.

BR: As you can see from this diagram, this is the family tree of the family that's involved in our study.

The black indicates people who have been affected by frontotemporal dementia. The line through the symbols indicates people who have passed away. So as you can see, people have been affected by Frontotemporal dementia through generations of this family. And one of the people in this family, who has passed away, is the woman who first donated her brain to the Neurological Foundation Human Brain Bank and started off this whole project. We have around two thirds of family members who could be involved or who were invited to be involved, that have agreed to be in the study. This means the study is really unique internationally because we have a very large group of people from a single family taking part in the research, and that's a really difficult thing to do, to find a family like this who are generous enough to be involved in research and especially involved in research over the long term.

HM: So how often do you see these family members? What do you look for? What do you do with them?

BR: We're conducting a longitudinal observational study of the family involved in this research. What that means is we're studying them over time with each participant coming into the research clinic once a year and we take lots and lots of measurements of things like thinking ability and sense of smell. We also take a blood sample, which allows us to measure changes in molecules that we can measure in the blood, and we also take images of the brain using MRI. This study is observational, because we're not testing the family in any way, we're just observing what's happening to them over the course of their lives. What we're looking for are changes between the two groups in the family. One group is people in the family who will go on to develop dementia and the second group is people in the family who won't go on to develop dementia. Ultimately, we're hoping the changes we identify will be able to be used to develop a test that can then be used in the general population and we would use this test to identify people who are at risk of getting dementia sometime in the future. That would allow us to intervene before those people develop symptoms.

HM: And have you had any initial findings? Have you seen anything come up that would suggest you can see those changes earlier?

BR: This is a long term project and we started in 2016. So far we've collected data for all of our participants on at least three occasions and for some of them we've collected data five times now. We're currently in the process of analysing our first three years of data and the preliminary results of this are really exciting.

They've shown that we can detect very early changes, for example, in thinking ability, so things like language ability, and also some memory changes we're finding those happening really early on in this family. So we're talking 30 years before symptoms are expected to develop and we can also detect a decline in sense of smell. These early findings are really exciting because they prove that we can see differences many years, and even decades, before people are expected to develop symptoms. They're also really exciting for us because they align with what similar studies are finding overseas. It's demonstrated that even with a single family, in a relatively small group of people, we are able to detect these early changes, which is really encouraging to us.

I think the important thing is that this kind of work does take a long time, and so the support we've had from AMRF has been really critical to continuing this project. It's not the sort of thing you can complete in three years or even five years. We want to study this family for as long as possible to learn as much as we can about the really early stages of dementia because we have a really unique opportunity to work with this family.

HM: Tell me are there other studies around the world that you can compare yourself to, or is New Zealand really doing something that the world is watching?

BR: One of the great things that's happened recently is that we've had the opportunity to work really closely with similar studies around the world. There are other studies in Europe, America, South America and also studies are emerging in Asia as well that are doing similar work to what we're doing. This is really valuable because for the type of work that we're doing, the more data that we can combine the stronger our findings are going to be. For a relatively rare condition like frontotemporal dementia it really requires an international effort. It requires researchers from across the world to be involved in this effort. What this study has done is really put New Zealand on the map in terms of frontotemporal dementia research. It's allowed us to be involved in that international effort. What's really unique about our study, compared to these international studies, is the size of our single family. These international studies have a lot more people involved but they have people from many different families, with lots of different mutations. It is quite unusual to have a single, large multi-generational family like we have and it's also unusual to have people who are so generous with their time and able to keep coming back year after year to collect that long term data, which is really important.

HM: Where would you hope to take this research? Is it limited to the dementia that you're working in?

BR: I suppose my greatest hope for the research we're doing and research in this field in general, is we will be able to use this work to identify people very early and intervene at that point to prevent dementia symptoms from occurring. Initially, this work is relevant to a particular type of dementia, so frontotemporal dementia, and that in itself would be hugely significant if we were able to contribute to that area of research. The really interesting thing about this particular family, the particular type of frontotemporal dementia that they have, is that it involves a protein called tau which is the same protein that's involved in Alzheimer's disease. So we also hope that the findings from this study may inform research into Alzheimer's disease as well.

HM: What made you want to work in this area? What led you to where you are now?

BR: We know that four out of five New Zealanders know someone with dementia and for me that person was my grandma. She developed dementia when I was younger, and she passed away in 2019. So that experience of seeing her gradually lose her vitality gave me a small insight into what it was like to live with dementia. That was the first thing that got me interested in this as a research field.

After finishing my PhD, I had the opportunity to work with Professor Maurice Curtis at the University of Auckland to establish a project centred around this particular family and working closely with people who are actually affected by dementia really appealed to me.

It was a great opportunity for me to branch out and study a type of dementia that I don't think has had enough research attention previously.

HM: Brigid, you must spend so much time with these people and form a real relationship with them - does that help give you the motivation to keep striving to get to the end?

BR: Absolutely, and that's the thing that I love the most about this project, is being able to get to know this family and develop relationships with them. It's helpful in two ways. I think in the first step, as you've said, is this motivation to really want to work towards treatments for people in their situation in the future and, secondly, it's also given me a real insight to what it's like to experience a condition like frontotemporal dementia. It's so valuable for us as scientists, I think it's quite common to be working on a health condition that you don't actually know a lot about. So having the opportunity to talk to this family and spend time with them over the years has been hugely valuable for my understanding of frontotemporal dementia, dementia in general, and I find it really, really motivating and rewarding. It's also really important to point out that I'm not the only researcher involved in this project. It's a huge team effort. We're taking measurements of many, many different areas and that involves expertise from a large group of researchers and clinicians. Another important aspect of the study as well is that these researchers and clinicians come from different institutions so we have people from both the University of Auckland and the University of Otago working together on this project, which is really valuable.

HM: So you're doing this work and you're able to identify someone who may show signs earlier, but we don't know what those signs are. What treatments, what interventions are available now?

BR: That’s a really great question. There are no treatments or interventions that are available at this point. That's why the research we're doing is really one half of two parts of the wider research that's important in this area. We're working on identifying people really early so we can intervene and a whole lot of other researchers around the world are working on interventions that can be used at that point. I believe that because we are giving these other researchers the opportunity to deliver interventions really early, this is our best chance at preventing or treating dementia. The treatments that have been developed to date have all been used once people are already symptomatic and, unfortunately, those treatments haven't worked to cure or stop the progression of dementia at that point. I believe our greatest hope with preventing dementia is to intervene at this really early point and it might even be the case that some treatments that have been tried when people already have symptoms may actually work if we deliver them earlier. So, it might not be a case of developing new interventions, it might just be a case of repurposing those interventions that have failed at a later time point and trying to use them at a much earlier time.

HM: Wow, that's an amazing thing to think that we might, you and your team might be able to get us to a point of. How phenomenal. Tell me how has AMRF helped in all of this?

BR: The support I've had from AMRF has been really critical to both my career and also to this project. So because this project is longitudinal and it takes place over the long term, it is a difficult project to get funding for because we don't have results within a two or three or even five year timeframe. The support we've had from AMRF has been really valuable and from my point of view as a mid-career researcher, the AMRF Fellowship has been hugely important to my work.

I would also like to acknowledge the Kelliher Charitable Trust for their support which has been in the form of additional funding via an emerging researcher award and also an extension to my fellowship.

Personally, if it wasn't for the AMRF Fellowship, I would have had to seriously think about other career options either outside of science or outside of New Zealand.

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