What happens in the brain in dementia?

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By Dr Laura Phipps | Tuesday 08 March 2016

Not an easy question to answer, but researchers are moving closer to understanding what goes wrong with the circuitry of the brain in diseases like Alzheimer’s, frontotemporal dementia and dementia with Lewy bodies.

In terms of complexity – one disease stands out more than others in the diversity of symptoms people can experience and the challenge in disentangling the many changes that can happen in the brain to cause them.

At the Alzheimer’s Research UK Conference 2016 today in Manchester we’ve heard from researchers who are working tirelessly to unpick this complexity.

‘A chameleon disease’

Frontotemporal dementia (FTD) comes in many guises. While we refer to it as one disease – FTD encompasses a range of different conditions that can affect people in very different ways. Generally, they can be split into three different conditions:

  • Behavioural variant FTD affects personality and behaviour, causing people to behave out of character, lack empathy and social awareness, and struggle with decision making. Research we helped to fund also showed how it can affect a person’s sense of humour.
  • In contrast, progressive non-fluent aphasia is primarily a disorder of language and stops people from being able to get words out and speak fluently.
  • Semantic dementia affects knowledge of what things are or what they mean so people may struggle to use the right words or understand what people are saying.

Some people with FTD develop Parkinson’s-like movement symptoms. Around one in every eight people with behavioural variant FTD will also develop motor neurone disease – characterised by stiff or twitching muscles, muscle weakness and difficulty swallowing.

Although one could easily think these were entirely different diseases, research is showing that they share some common underlying changes in the brain and represent different places on a spectrum.

A local connection

It’s pertinent that we’re talking about this important disease here in Manchester, where much of the founding FTD research took place. In fact, the clinical features of FTD were first described in the ‘Lund-Manchester Criteria’ – a list of symptoms of the disease that still informs diagnoses being made in clinics across the world today.

One of the researchers who led this pioneering work in Manchester back in the early 1990s, Prof David Mann, told the conference today that while we understand more than ever about the disease, the picture of what happens in the brain is becoming ever more complex.

Three main players

Prof Mann explained how brain tissue kindly donated by people with FTD has revealed three proteins that appear to go awry in the brain to cause these conditions – TDP-43, tau and FUS.

Under a microscope, researchers and pathologists have seen clumps of tau protein in the brains of up to half of people with FTD and a similar proportion will have clumps of TDP-43, with FUS present in a smaller number of people.

The different types of FTD tend to associate with different patterns of the three proteins in the brain. Not only does it seem important which proteins are clumping in the brain but where.

Dr Tammaryn Lashley, an Alzheimer’s Research UK-funded Senior Research Fellow at University College London, revealed her latest research into TDP-43 and FUS. The two proteins are part of a group that shuttles between two parts of a cell – like commuters traveling between work and home. Dr Lashley’s research highlights how this process can go wrong in FTD, leaving these proteins stranded in the wrong place inside cells. She’s pinpointed other proteins that seem to also get caught up in this congestion problem, revealing new clues to what’s driving damage in the brain.

However as one protein isn’t solely responsible for one pattern of symptoms, it’s hard to predict exactly what’s happening in the brain in each person with FTD. As drug discovery efforts become more focused on picking out specific proteins to target with new treatments, this could be an important stumbling block for progress in FTD research.

A coordinated push for better diagnosis and new treatments

We heard from Dr Jennifer Whitwell from the Mayo Clinic in the US whose research into brain imaging in FTD is identifying new ways to distinguish between the different types of FTD. On average, people with FTD can wait up to five years for an accurate diagnosis, and reports suggest that almost three quarters of people are initially misdiagnosed. So advances in this area are vital for families affected, as well as helping researchers to improve their approach to studying the disease.

Brain imaging is also a central theme in the Genetic Frontotemporal Dementia Initiative (GENFI), outlined today by Dr Jonathan Rohrer from UCL. This collaborative programme is following hundreds of people whose families are affected by inherited forms of FTD. Using brain scans, the team has already identified particular networks of nerve cells in the brain that are affected differently in FTD caused by different faulty genes.

The study is now entering a second phase with the ultimate aim to map what changes happen in brain, blood and spinal fluid in FTD and when. This will be vital for helping to guide future clinical trials of new treatments in the disease.

As the Alzheimer’s Research UK Drug Discovery Institutes are kick-starting new drug discovery programmes and a Dementia Consortium drug discovery project already focusing on FTD, it’s vital these kinds of initiatives run hand-in-hand.


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Dr Laura Phipps

Team: Science news