Transcript
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[Title card: Frontotemporal Dementias | Dementia Australia]
Professor Brodtmann: Hi there. My name's Amy Brodtmann. I'm a Professor of Neurology in Melbourne, Australia, and I run a number of cognitive neurology services here in Melbourne. I've always had an interest in frontotemporal dementias, and so, I'm going to speak to you about this group of conditions in this following video. I'm a Professor at Monash and Melbourne Universities, and my major appointment is at the Department of Neuroscience in the central clinical school at Monash University, and I run a service at the Royal Melbourne Hospital and at Box Hill Hospital. I'm also an honorary medical advisor for Dementia Australia. This talk is mainly directed at people who are loved ones or caregivers of people with frontotemporal dementias, as well as people with lived experience. It might also interest health professionals who are involved in their care. I hope you find it useful. Thanks.
Today, I'm going to talk about the terms and the syndromes that we use for FTD because it is complicated, and the names of the nomenclature is pretty hard to get your head around. I'm going to focus a little bit on the genetic risk because that's something that my patients and their loved ones often ask about, and then I'm going to give a presentation of some case studies. You might recognise yourself or even your loved one in this, and it's just so we can get an idea of the differences and the similarities between these syndromes. I'll talk a little bit about the diagnostic journey, I suppose, to let you know that you've probably not been alone in getting to the diagnosis. It's usually not an easy path. And then a bit about support and care, and trials, because there's a lot happening in this scene.
So, just the background - FTD is a rare disease. It's classified as a rare disease where there's around 15 to 22 per a hundred thousand people. And that's people who are young - 45 to 64. It's a group of diseases that's characterised by a pathology in the frontal and temporal lobes, hence, the reason why it's called frontotemporal dementia. And these are the parts of the brain that determine our behaviour, our speech, and our language.
It's the second commonest cause of young onset dementia after Alzheimer's disease, and we think in Australia, there's between three and a half and 11 and a half thousand Australians, but it's hard to get really good incidents and prevalence data for these diseases. Men are more commonly affected, and they're more commonly diagnosed with something that looks like FTD, but isn't, and we call that a phenocopy syndrome. There are many clinical syndromes, and the three that I'll focus on today are behavioural variant, or behavioural variant FTD. This is the one that a guy called Arnold Pick described back in the 20th century, and he described the pathology of someone whose brain had very severe shrinkage or atrophy in their frontal lobes. The other two forms are also described as progressive aphasia, or primary progressive aphasia, and one of them is non-fluent FTD or primary progressive non-fluent aphasia, or non-fluent variant FTD. And these terms are used interchangeably around the world, despite many efforts to change this and semantic dementia, which is sometimes called semantic variant FTD, but more often in Australia called semantic dementia.
There's a tonne of other conditions that are under this big umbrella of FTD - corticobasal syndrome, progressive apraxia of speech, but I won't speak about those much today. I'll just try to keep it fairly simple. One thing to emphasise, though, is that motor neuron disease and FTD can be associated, and that's something that many people ask about. We know that FTD is associated with a number of pathologies. There's quite a few of them. The commonest one is this TDP-43, which is TAR DNA-binding protein. It's the same protein that we find in the brains of many people with motor neuron disease, and the genes that can cause this protein to be deposited are also the same genes that people with motor neuron disease can have. The other very common protein is tau. Now, tau is a protein that is very important in our brains. It helps to keep the brain's structure of the cells normal and it's a protein that's found in multiple dementias - in Alzheimer's disease, in progressive non-fluent aphasia, often, in Corticobasal syndrome, et cetera. And it's also found in different patterns, in different forms in FTD.
One of the things we often get questioned about is if it's genetic, how do I get tested? And also, do I want to know? I think Australia's really lagged behind the world in trying to get this sorted out, but we now have genetic counselling services throughout Australia at major centres, and it's important for you all to know that these appointments can be via telehealth. In fact, the standard appointment is via telehealth, so you don't need to travel from remote or regional Australia to actually get these testing done. They'll talk you through genetic testing if you've got frontotemporal dementia, and how to get tested if you want to do that. And if you are a family member of someone with frontotemporal dementia, especially if the gene is known, then they'll also talk you through just testing for that.
If you've got FTD and you want to get tested, they'll talk about testing you for all of the major three genes that are associated with the disease. I think it's important to realise now, in 2023, when we're recording this, you don't have to find out the results for yourself. One of the things that people say is, "I don't want to know, but if my family members need to know in the future, is the way that I can actually ensure that they have access to that", and there is - so genetic testing is not just about finding out the gene for you if you have FTD, it could be about finding out the gene for your family members, or even their family members, because there's a way that people who have a known gene in their family can actually be tested and not be told the results if they never want to know, but actually make sure that they don't pass that gene onto their babies should they want to go on and have children. So, I think genetic testing is not something just to find out, "Oh, there's that mutation." It's actually something that can really help give some reassurance to future generations.
So, let's talk about the clinical syndromes. And there's three, as I said. The three major ones are behavioural variant, semantic variant, and progressive non-fluent aphasia. Now, the commonest one, behavioural variant frontotemporal dementia is the one that we sometimes see people with MND, motor neuron disease, develop in their course. And it's the one that people with FTD can actually get MND. There is that association, as I mentioned, through that protein, TDP-43. Now, the reason why I don't get too stuck in the names is one, because they do change sometimes, and also, because people can have overlap syndrome. So, as I said, MND can get FTD, people with this other condition, which is progressive supranuclear palsy, which presents with stiffness, behavioural change, eye movement problems and falls, they're often the people who get non-fluent aphasia, and vice versa. There's lots of complicated names. You might hear your doctor or other health professionals talk about other conditions like corticobasal syndrome, primary progressive apraxia speech, the right temporal variant of FTD, they're all under this umbrella. And so, I think it's useful just to talk about what those major variants are, and then, perhaps, get some more specific information about the variant that you might have.
So, let's talk about some of the people that I've seen over the years. These are kind of a combination of people, I suppose, so they're not identifiable, but let's talk about behavioural variant FTD. This was a man I saw some years ago now who presented with unusual behaviours, he'd been fit and well, all he'd had was a shoulder injury, couple of injuries playing football in his youth, and he's had his appendix out. He was a non-smoker. He'd had a bit of binge drinking in his youth, but really hadn't drunk since then, and actually, had been quite a healthy eater.
What was noticeable is that his family members were concerned because he'd started drinking alcohol again and eating junk food, which was very unlike him. He was a mechanical engineer. He was a really keen fisherman and a boatsman. And he'd presented to the clinic with his ex-wife because he was divorced, had three children, and he'd repartnered, but recently separated from his partner. And those kind of relationship problems, particularly for newer partners are quite common in people who present with this condition. He came along because he'd been strange at work. He was singing all the time, he was talkative. In fact, people said you couldn't shut him up. He had inappropriate remarks to his colleagues and clients, talking about someone's weight, or talking about someone's outfit. And he was starting to neglect his hygiene because he was just a bit apathetic, he didn't care. This is a man who'd been quite fastidious in the past.
He'd also had some altercations with family members, and he'd never been like that, and had a fight on board his boat with his brother. In fact, he threw his brother overboard, which was very uncommon. That hadn't happened before. His ex-wife contacted his ex-partner, and the ex-partner said that, gosh, the reason why they'd split up was because of his behaviour. And when we saw him, he was really disinhibited, and he was really insightless. He didn't think anything was wrong. He was quite childlike in some of his responses, very dismissive of his problems, and really unconcerned by the concerns of others, unconcerned by others' emotions. This is one syndrome of behavioural variant FTD.
Now, everyone has different presentations. Some people are just apathetic. Some people have really significant changes in their eating, but they're all associated with this kind of pathology. So, this is a picture of the brain where this is the front of the head. You can actually see the sinuses at the top of the brain. This is the back of the head. You're lying back in the scanner. So, the black is the fluid around the brain, and the grey and whiteish areas are the brain itself. Now, the back of the brain looks normal. You can see that there's lots of grey matter. It looks like it's really filling up the skull, but as we get to the front of the brain, we can see that there's very significant atrophy. And this is atrophy of the frontal, and to some extent, the temporal lobes. These are the temporal lobes here. You can also see there's some changes in the white matter, and that's actually something we see a lot in people with particularly the tauopathies, that tau, that other protein I spoke about. And so, we can see not only changes in shrinkage patterns, but we can see changes in the actual substance of the brain as well. So this is an example of someone with behavioural variant FTD, quite severe.
The other common presentation that I see in the clinics, and I mean, again, these are rare dementias, but we see it a lot in my clinics because that's what we do. Again, another 58-year-old man who presented this time with difficulty with words. You think that will be a funny thing to present with, but it wasn't that he couldn't think of the word, that episode where we always have, where the word is on the tip of your tongue you can't get it, that's normal. This is something where he'd lost the meaning of the words. He'd had excellent health previously; he'd run his own construction business for more than 30 years. Again, he was married, had three children, and when he presented, he was alone, and he really only presented because his GP twisted his arm. He said, "There's nothing wrong with me." When I was able to speak to his wife and family members, it was revealed that there was actually workplace problems and family issues. And again, he was actually had a lot of problems with his workplace.
His wife said that he was "detached, there's no emotion, he doesn't listen, there's like a brick wall between us." He'd actually been sacked from his own business, which is always a very bad sign. When I examined him, he was completely insightless. He said, "There's nothing wrong with me. I don't know what you're talking about", but his speech was empty, it was missing words, and he was very fixated, he was very rigid in what he did, the same thing again and again - clock watched, things had to be done at the same time, and he was doing some repetitive behaviours, which we call stereotypies. They look a little bit about a tick. Sometimes people rub their nose, or rub their legs, or rub their face, or they can do something with their hand. And that's that kind of repetitive behaviours that are really common in people with these frontotemporal dementias.
He was fine. His mood was good. He was unconcerned by his problems. But when I asked him to name things, he couldn't name quite common things, and he'd lost the context, or meaning, or the semantics of them. He didn't know what an atlas was, and where countries were that he would've known previously. In fact, he'd travelled to them. So, this is semantic dementia. And semantic dementia is a peculiar condition that, unlike the behavioural variant which really affects the frontal lobes, this affects the temporal lobes.
So, the temporal lobes are at our temples, underneath our temples. This is a different way of looking at the brain. The ears would be on the side here. So, these are what we call coronal views, as if you've got a band across your head, and these coronal views are a good way of looking at the temporal lobes. And normally, in these areas here, this would all be full of brain tissue like it is up here, so it would go to the edge of the skull. But you can see what is replacing brain tissue is just the fluid that goes around the brain. So, this man has very severe temporal atrophy on both sides, particularly on the left hand side, although he certainly had bilateral. I've got some other patients who just have left, and there are some people who just have right, and that's called a right temporal variant, or semantic behavioural variant, but as I said, the names are terrible. This condition is peculiar because it really is associated with that loss of understanding of words, but otherwise, they look like someone with behavioural variant FTD because of the behavioural changes.
The third, and again, probably the least commonest aphasia is what we call progressive non-fluent aphasia. This really does present with language and speech problems first. This gentleman, again, had been in extremely good health. He was a retired health professional and had become a lecturer. He had no family history, and he presented with some subtle, getting worse problems with finding words, and also getting the words out. So, unlike the other two people, he was very aware of his problems. He presented with his wife because he was concerned. She'd noticed, his wife, that is some problems with finding words and using the wrong name for something, and said there's lots of replacement words now.
In the last year or so, he'd also developed problems with understanding her. So, when we think of speech and language, we often think of just the production, but obviously, the other big component is understanding. You know, you think of a child when it's learning to speak, it can actually understand a lot of language before it can produce the words. And the reverse happens in people with dementias. Often, it affects the production first, and then the comprehension. She said that when she's in the lounge room and she'll ask for a cup, he could bring anything out of the kitchen. He actually couldn't understand what she was asking for, and when we examined him, his speech was really abnormal, because it was unlike the other two people, really slow, it was really hard to get out. He was very frustrated, very aware of his problems, he was quite depressed, he was very insightful to his problems. And this is progressive non-fluent aphasia, or non-fluent variant.
And the peculiar thing about this condition is that it really affects the left hemisphere. So, X-rays and MRIs left is right and right is left. So, this is the left hemisphere. He's a little bit on the side. Again, these are images where as if you'd imagine that ears are on either side of his head and this is the left hemisphere, and compared to the right, it's atrophic, he's lost brain volume, and it's affecting the frontal lobes and the temporal lobes. And the left hemisphere is usually our language dominant hemisphere. And this uniquely affects the left hemisphere. So, they're the three commonest FTDs. The thing about them is that, you know, word finding difficulties, change in your behaviour, some relationship problems, these are things that probably many of us experience, and it's sometimes it's hard to put this together.
We know that in Australia, it's between four and seven years before someone gets referred to see someone who can make the diagnosis. We've obviously got an interest in my clinics about seeing people with FTD, but we looked at our clinical audit, almost 60% of our patients attend three specialists beforehand, and 35%, more than a third, had seen four or more. Some people attend five, six people. So, you can imagine the stress, well, I don't think you need to imagine the stress that that leads to. Almost two thirds have been given an alternative diagnosis, you know, depression, marital discord, other conditions before they had the diagnosis of an FTD made. About half, particularly people with behavioural variant FTD were given a psychiatric diagnosis of depression because of the apathy, even though they weren't depressed. And I think that it's really important that the diagnosis is made by experienced clinicians, or specialist clinics, and there's many around Australia.
Brain imaging is absolutely essential, ideally with MRI and a PET scan. Now, PET scans of the brain are now have been available on Medicare for over a year now. And I think that they're really, really helpful in FTD to say yes or no, because if you've got a normal PET scan, it's very unlikely to be FTD. Neuropsychological assessments, particularly for the language onset ones, semantic, non-fluent, really helpful. Behavioural variant patients can have completely normal neuropsychological assessments. So, I think it's important these are behavioural changes that we're focusing on. We're really trying to get better biomarkers, and we lack a clinically validated blood test for neurodegeneration, but there's a lot of work in this space. There's studies that we are doing in Melbourne, the NAVAIDD study, looking at a protein called NfL, studies being done in other centres, mind study in Sydney, et cetera, so I think that this is something that, in a few years’ time, will be available.
So, where to now? You've got the diagnosis, you've been through the diagnostic odyssey, and you're there. The mainstay of treatment is still support. Support for you if you have FTD, your loved ones, and for all family members, and I think that that's really essential. We know that the prognosis, how things are going to change, is really variable. Some people can have a very rapidly progressive disease, and actually, from time of diagnosis to death be only a couple of years. We've had patients who have been followed up for more than 20 years, so very variable. We know that people who are carers for someone with FTD endorse high levels of care burden. The diagnostic delays are the biggest reasons why, and then the unique issues because of the behavioural problems. So, it's really essential to emphasise there are support groups available right throughout Australia.
We've got support groups that initially were set up by the Australian FTD Association, and they're now organised via Dementia Australia. There are online support groups for people who live in rural and remote areas, as well as some support groups actually in those regional areas. I think that, I can't emphasise that enough, some people just aren't group people, but if you are needing support, getting some support one-on-one is great. Otherwise, the Dementia Australia, obviously, helpline is really essential. I think that COVID has actually helped in the sense that we've set up more online groups for rural and remote carers, and I think you should access these if you need to. There is also new hope. We've got FTD treatments and trials that are in the pipeline or available. There's a nutritional drink called Souvenaid, which actually has been demonstrated to help in clinical trials. It's a nutritional supplement so it's not on Medicare or PBS. And that's actually available at Chemist Warehouse and other places. Some people find it benefits; some people don't think it helps. I would advise trying it.
There are more than 300 studies listed on what is the biggest worldwide register clinicaltrials.gov, and there's over a hundred that are actually trials of treatments. Some of them are symptomatic, that is, they're treating the symptoms, trying to improve behaviour or sleep, or agitation, or apathy. Some of them are what we call disease modifying, they're drugs that we actually hope to slow down the progression of the disease, or even prevent it for people with genetic FTD. And this is everything from tablets to actually remove the tau from the brain, that selenite study that's running in Melbourne and Sydney, to infusions to try to remove the brain proteins or dampen down inflammation. The first wave of gene specific therapies has been done in Australia. At the moment, it's only present for people with granular mutations, so that's one of those three common mutations I mentioned, and we're really awaiting those results with interest, because we're hoping that next year, that we'll get a readout, but our hope is that that will be of benefit.
The toolkit that we have on the ECDC website has a list of some of the genetic FDD trials that are running in Australia and in our clinic, and also in FTD trials, so take a look at that if you need to. And we know that there's about three drugs that were presented just this year that some did slow the disease progression. Some are showing great signs, but we haven't got the readout yet. And I think that whilst it's terrible that Bruce Willis was diagnosed with this condition, his wife and his family members are really advocating for a lot of funding in this area, and there has been considerably more funding in this space since he was diagnosed. So, I think that there is cause for hope. So, in summary, these are rare but devastating diseases. The nomenclature and the symptoms are confusing. The diagnostic journey is not straightforward, but help is out there, with large national and international communities that you can access. Treatments are on the horizon, but we're not there yet, and I'll just emphasise the Dementia Australia hotline is your friend if you need it. Thanks a lot.
[Title card: No matter how you are impacted by dementia or who you are, we are here for you.]
[Title card: Dementia Australia. National Dementia Helpline 1800 100 500. Dementia.org.au]
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