What has research revealed about frontotemporal dementia?

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By Nicola Williams | Friday 06 October 2023

You may have heard earlier this year, that Die Hard and Pulp Fiction actor Bruce Willis is living with a form of dementia called frontotemporal dementia (FTD).

His diagnosis came after initially having difficulties with speech and being diagnosed with a condition called aphasia in March 2022. But a few months later, Willis’ family gave a heart-breaking update that in fact he has FTD.

But what exactly is FTD, and where are we with finding new treatments?

We caught up with Dr Teresa Niccoli, a Senior Research Fellow with Alzheimer’s Research UK, based at University College London (UCL). Her team are studying some of the underlying causes of FTD, in the hope of opening up new avenues to treat it.

Dr Teresa Niccoli

What is FTD?

“Frontotemporal dementia, or FTD, is really an umbrella term for a spectrum of conditions,” explains Dr Niccoli. “A range of biological disease processes can cause FTD and the symptoms vary from person to person, depending on how the diseases manifest in their brain.”

FTD also tends to affect people earlier than the more common Alzheimer’s disease, usually in a person’s forties to their early sixties (compared to over 65, on average, for Alzheimer’s), although FTD can affect people older or younger than this.

Sadly, there are currently no treatments that can slow, stop or cure the diseases that cause FTD. “We can change this with research,” Dr Niccoli points out. “However, there are many challenges. Because FTD is relatively rare compared to other dementia types, there are critical gaps in our knowledge in terms of understanding the mechanisms driving these diseases.”

What we know about FTD so far

As with many forms of dementia, FTD is linked to the build-up of certain proteins in and around brain cells.

“There are several proteins linked to the development of FTD, such as tau, TDP-43 and FUS,” says Dr Niccoli. “These proteins are part of the cell’s ‘building blocks’ and  healthy brain cells need them to function properly. But in FTD, these proteins build up and form clumps in the brain. This eventually damages nerve cells, preventing them from sending vital messages across our brain and body.”

“But we don’t fully understand how these protein clumps cause the damage to the brain seen in FTD. And if we can understand this more, we might be able to stop it from happening.”

Dr Niccoli is studying a form of FTD caused by a particular change (mutation) in a gene called C9orf72. This mutation is the most common genetic cause of FTD and of a type of motor neurone disease called amyotrophic lateral sclerosis (ALS).

The mutation causes unusual proteins to form in nerve cells, called dipeptide repeat proteins. These proteins are made of a simple sequence of amino acids (the ‘building blocks’ of proteins) which repeats over and over again.

“It’s these repetitive proteins that clump together in nerve cells, which then do not function properly,” Dr Niccoli explains. “But the question is, how can we prevent this damage from happening in the first place?”

How does sugar processing in fruit flies link to FTD?

Dr Niccoli’s latest ground-breaking research into FTD, has been recently published in the scientific journal PLOS Genetics.

Excitingly, the team’s new findings have revealed a major clue in how researchers could counteract the damage caused by dipeptide repeat protein clumps as a result from the C9orf72 mutation.

“We think we may have found a link between how the brain uses a type of sugar called glucose for fuel, and the build-up of proteins in FTD.

“Our brains use 20 % of the body’s energy, which comes from sugar found in the food and drink we consume. It is perhaps not surprising then, that people with dementia show signs of reduced sugar processing in the brain. This can be seen really early in the disease – before symptoms of dementia even begin to appear, the cells in a person’s brain start to consume less sugar for energy. We know there’s plenty of sugar for the brain, it’s just that nerve cells don’t convert as much of it into the essential energy needed for them to survive.

“My team are looking at this drop in sugar processing in more detail. We think that by boosting sugar processing, we might be able to mitigate against some of the damage to brain cells in people with the C9orf72 mutation that causes FTD.”

Dr Niccoli is studying this in fruit flies, which are widely used in medical research and are surprisingly useful for studying age-related diseases like FTD. In fact, they share with us 3 out of 4 genes linked to disease, and have short lifespans – up to 100 days – so researchers can monitor how the disease progresses over a relatively short time period. It turns out that the flies also share similar ways of processing sugar in the brain with humans. The fruit flies the team are studying have been genetically modified to carry the C9orf72 mutation, so they have features of FTD including a build-up of proteins in their brain. They also show behavioural changes, such as sleep disturbances and a shorter lifespan compared to flies without the mutation.

 

 

To find out more about how sugar metabolism affects protein build-up in FTD, the team further genetically altered the flies. First, they made changes so that the flies’ nerve cells took up more glucose, the starting product from which cells obtain energy. However, this had no positive effects on the flies, and they still had the protein build-up characteristic of FTD in their nerve cells.

Investigating another part of the fly brain’s energy pathway, the team then modified the flies to increase their nerve cells’ uptake of a molecule called pyruvate, which our cells get from glucose and use to obtain energy. Previous research suggests that pyruvate may have other important roles in keeping brain cells healthy, aside from being involved in providing the cells with energy.

This time the results were very different.

The modified flies lived longer, even though they carried the mutated C9orf72 gene. They also had less protein build-up in their brain and noticeable improvement in their behaviour and activity. This indicates that boosting pyruvate uptake in the nerve cells could counteract the harmful effects of the C9orf72 mutation.

“What’s really exciting is how much we see a recovery in the fruit flies’ behaviour and lifespan. We saw that the C9orf72 flies only lived for around 20 days, but when their nerve cells take up more pyruvate, they live for about 35 days. Whilst this does not completely restore the flies’ lifespan to that of a healthy fly (around 100 days), increasing pyruvate update nearly doubles the lifespan for flies with this mutation.

“This is the most exciting result we have seen on the project so far.”

What does this mean for people with FTD?

Does this mean that we have a potential new treatment for FTD?

“Unfortunately, not yet,” Dr Niccoli says “It’s very early days and we need a lot more research to understand whether boosting pyruvate intake by nerve cells could indeed counteract the damage caused by FTD.

“Our research is in fruit flies, which have different brains to humans. So, our next steps will use stem cell technology to see whether we see the same thing in lab-grown human nerve cells.”

“We now know that there is something about the way nerve cells take up pyruvate, that may counteract the damage caused by the C9orf72 mutation – but how exactly does it do this? We need to carry out more experiments to truly understand the role of this molecule in the brain.

But Dr Niccoli remains optimistic that this is a new drug discovery avenue.

“If we see the same effect in human nerve cells, then we may have a completely new route to treating FTD cases caused by the C9orf72 mutation in future. Treatments targeting pyruvate uptake might not cure FTD on their own, but we hope that we can at least find new ways to slow down disease progression.”

Intriguingly, Dr Niccoli also saw similar results in fruit flies with features of Alzheimer’s when pyruvate uptake was increased.

“This is really exciting, because we’re discovering new pathways that could be linked to FTD and other dementias. Even with new treatments for Alzheimer’s on the horizon, we need to keep exploring all the different mechanisms behind all types of dementia, so that we can slow, stop and perhaps even reverse the disease that cause them. Ultimately, we want to build a diverse ‘toolkit’ which will help us – one day – cure the devastating condition that affects nearly one million people in the UK.”

If you would like to find out more about FTD, our health information details symptoms, risk factors and how you can access further support.

Or find out more in our Q&A blog: Frontotemporal dementia (FTD) – what is it and how close is a cure?

 

 

Bruce Willis photo credit: Gage Skidmore via Flickr used under a Creative Commons Attribution-ShareAlike 2.0 Generic License.

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Nicola Williams