Unpicking the complexities of frontotemporal dementia

Researchers from University College London are investigating one of the hallmark proteins of frontotemporal dementia.

Researching

Causes

Frontotemporal dementia (FTD) is the second leading cause of dementia in people under the age of 65. Rather than memory loss, people with FTD more commonly experience changes in personality and behaviour, a lack of empathy and social awareness, as well as difficulties with language. Unlike Alzheimer’s disease, the hallmark proteins that cause nerve cell damage in FTD are not the same for all people with the disease; there are different toxic proteins that cause damage in different parts of the brain. This poses a challenge for creating treatments that halt nerve cell damage in FTD – one drug may not work for all forms of the disease.

Dr Tammaryn Lashley will tease apart this complexity, zeroing in on the key changes that cause nerve cells to die. The team is focusing on a particular protein called TDP-43, which is found in the brain in about half of those with FTD. Researchers don’t yet know all the different ways that TDP-43 can cause nerve cell damage, so understanding more about the key steps in the disease will help in the search for new treatments.

Decades of research into Alzheimer’s has enabled scientists to characterise the key hallmark features of the disease; a picture that is much less clear for FTD. Understanding the complex changes in the brain in FTD is crucial in developing new tools for an accurate diagnosis, and targeted treatments to stop the disease in its tracks. While there are some symptomatic treatments that can help manage behavioural symptoms, there are no drugs that halt or slow the progression of the disease.

Because of its complex nature and atypical symptoms, making a diagnosis of FTD is a challenge. Currently, unless FTD is caused by a faulty gene, it isn’t possible to give an exact diagnosis. Developing tools that provide a window into the brain and highlight the hallmark features of the disease will prove invaluable for designing future treatments.

Dr Lashley is studying brain tissue from people who had toxic clumps of TDP-43, comparing these to brain samples from healthy people of a similar age. The team is using a sophisticated microscope to look at TDP-43 from different parts of nerve cells in a variety of brain areas. They can then test how toxic the various forms of this protein are on nerve cells in the laboratory.

As well as studying the impact of TDP-43 on nerve cells, Dr Lashley and her team are looking at its impact on the brain’s immune system. They are focusing on immune cells called microglia – key players in the brain’s inflammatory response to damage. From studies in Alzheimer’s disease, we know that microglia can sometimes cause more harm than good. This fine balance was yet to be extensively studied in FTD, but Dr Lashley is now investigating the brain’s inflammatory response, determining whether different forms of TDP-43 can trigger immune reactions. These investigations will help to unpick the complexity of FTD – something that will guide research into new treatments.

It is also important to refine new tools that can provide an accurate diagnosis of FTD. Dr Lashley will collaborate with experts in brain imaging who have designed a method to study TDP-43 on brain scans. Dr Lashley will test this approach in human brain tissue; an important first step in refining how these scans could be used in people in future.

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Awarded to
Dr Tammaryn Lashley

Institution
University College London

Current Award
£419,995

Dates
1 February 2016 - 31 January 2020

Full project name
Are multiple mechanisms involved in FTLD-TDP pathogenesis: will one drug fit all?

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