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The latest research advancements in the field of Frontotemporal Dementia

Today, we bring you highlights from the International Society for Frontotemporal Dementias (ISFTD) Conference in Amsterdam. 

The conference took place in September 2024, and was directed at neurologists, psychiatrists, neuroscientists, and researchers interested in frontotemporal dementia (FTD).

Attended by highly motivated, exceptional researchers from around the world, the conference provided the latest news and insights in the field of FTD research.

Before we dive deeper into the research presented at the conference, we wanted to acknowledge the importance of patient voices at research conferences. 

The ISFTD conference began with a moving speech from Emma Heming Willis, sharing her experience and journey as a caregiver, and talking about the value and significance of research Early diagnosis, support with diagnosis and ensuring  lived experiences  is at the core of all research were some of the most important issues highlighted by both scientists and people personally affected by FTD.

The research and atmosphere at the conference was hopeful, collaborative, and inquisitive. Research will beat dementia, and as attendees at the conference we felt the community was excited about the future of this fast-moving field.

Importance of diversity in FTD

It was incredible to see all the ongoing efforts in making research, diagnostic assessments, and our understanding of the disease mechanisms as diverse as possible. The importance of linguistic and cultural diversity was emphasised by multiple research groups from all around the world.

There is a real need for more understanding of the language variations in FTD and within the different FTD subtypes in real-life settings. When studying the complex symptoms of FTD, which can include language problems, most clinicians and researchers use English language-based assessments. These, however, do not consider the nuances, orthographic, and grammatical rules that many languages in the world use. 

As today’s cognitive and written tests are the backbone of diagnosis, but are often in English, they can only be aimed at and accessed by certain groups of society. 

These tests need to be culturally relevant to reach more people no matter where they live, their educational level, their primary language, or their culture. International working groups have now been set up to create terminology guidelines for clinicians, to help them define terms and symptoms which are more culturally sensitive.

To reflect real-life scenarios, researchers are focusing on understanding how FTD impacts different languages (both spoken and written) and have found that there are distinct differences between them. This is especially true when studying complex languages like Japanese. 

Differences in language and speech processing not only have an impact on diagnostic assessments for individuals with FTD, but also on which areas of the brain are susceptible to atrophy. Yuichi Higashiyama from Yokohama City University in Japan reported differing brain imaging profiles of speech apraxia in Japanese and English speakers with Primary Progressive Aphasia (PPA).

The number of languages a person speaks can also have an impact on FTD. Significant delay of symptom onset (8.26 years in age of onset) was reported in people with FTD who speak two languages compared to monolingual people. However, more long-term data is needed to fully assess this, but this could link to the concept of cognitive resilience - the ability of the brain to resist the effects of disease to preserve and maintain healthy function.

The importance of cultural diversity in FTD research was highlighted by Professor Suvarna Alladi whose research aims to investigate the impact of culture on clinical presentation of dementia. In the case of semantic dementia, once a clinician understood a person’s background and culture, they were able understand the words used by patients to communicate more openly and facilitate a better diagnosis. 

Professor Alladi also discussed the Dementia Design Studio, a clinic using novel ways to diagnose dementias. This clinic is moving away from standard pencil assessments and moving towards performance-based assessments. 

Performance-based cognitive assessments can include real-world problems embedded within instrumental domains, such as cooking, packing, and shopping. So, for example, when faced with a suitcase packing scenario, a person with FTD might pick up the same item repeatedly to pack into a suitcase, whilst a patient with Alzheimer’s disease might be a lot more disorganised and not have a clear focus on an item they want to pack. The Dementia Design Studio can also help to modify a person's environment and find technology-based solutions.

We were inspired by the solutions that are being developed to tackle diversity issues in FTD research, as well as the importance the research community is striving for to ensure representation and diversity in research.

Latest in clinical trials

There was a hopeful message around the topic of clinical trials at ISFTD 2024. Professor Jonathan Rohrer highlighted that although the field of clinical trials is still at early stages in FTD research, it is amazing to see dedicated sessions, posters, and discussions around the topic. Even two years ago, this seemed like light years away. However, with the power of research and collaboration, the field is gaining momentum.

The clinical trial space in FTD faces issues around set-up and management. FTD is considered a rare disease, where genetics often play a large role, however genetic testing is not the standard of care for FTD, leading to difficulties with diagnosis and participant recruitment. 

This adds to the complexity of setting up clinical trials. To address these challenges, ‘platform trials’ were discussed as a way forward to allow efficient testing of multiple therapies at once. Platform trials test multiple candidates simultaneously and combine placebo (untreated) groups so that results can be pooled. 

This trial set-up has been reported to potentially take 50% less time, cost 40% less, and would require 40% less participants. This could help a trial become more successful.

Other barriers to participation have also been reported according to a survey carried out by FTD Disorders Registry. It was noted that the biggest barrier was trial logistics. Travel was one of the biggest issues, including cost for participants. 

Other research reported at the conference suggested the idea of developing at-home assessments for participants, so that they can contribute to data gathering from the comfort of their own homes, which would eliminate some of the issues faced by participants. There is also a need to understand the fundamentals and mechanisms of the disease, and critically develop and validate biomarkers to drive earlier and more accurate diagnosis.

The potential solutions that might be needed to enable clinical trials are:

• tools to design trials with fewer participants;
• broadening access to clinical research;
• expanding to diverse communities;
• better approaches to collaboration;
• FTD prevention initiative;
• FTD registries;
• improving processes to run trials in academic settings.

Some of the current clinical trials for FTD aim to restore progranulin protein levels, which is an important protein in a genetic form of FTD (FTD-GRN).

The ongoing FTD clinical trials include Latozinemab (Phase 3), which aims to reduce progranulin interactions with Sortilin. Other candidates in earlier phase trials (Phase 1/2) include PBFT02, PR006, and AVB-101, which investigates AAV-progranulin gene therapy for FTD, as well as a Phase 1 trial of Verdiperstat in svPPA.

There are also drug repurposing candidates, such as a Phase 2 clinical trial of intranasal oxytocin for apathy in FTD, and a clinical trial investigating noradrenaline treatment of apathy and impulsivity in PSP. Some attention was also given to non-drug therapy trials, such as Communication Bridge 1, which is speech-therapy based trial for PPA.

We are looking forward to reporting on the results of these exciting trials when they are available.

We must also remember that all trials are an opportunity to learn, even if they have failed, as they teach us about new mechanisms and processes in disease, as well as teach us about how to set up better trials in the future, ultimately advancing the field.

Translational and fundamental research

There were many fantastic talks touching upon the latest fundamental and translational research in FTD.

Professor Rosa Rademakers from the University of Antwerp, gave us an insight into the research of her group, which identified a new major genetic risk factor for a rare sub-type of FTD, FTD-U. This disease is characterised by severe FTD and psychiatric changes. 

Looking at the DNA of people with FTD-U, the researchers found that more than 60% of people had a genetic risk variant located on chromosome 15, which might be implicated in the disease. The specific allele mentioned revealed to be a new repeat expansion 500-1000 base pairs long, however, the extra sequence can be different in every individual. Professor Rademakers emphasised this is a risk factor, so it won’t always cause disease, however it might be an important new development in FTD.

Other talks reported on investigating MRI biomarkers and using deep learning to differentiate between FTD subtypes, helping with more accurate diagnosis, and many talks focused mostly on proteins: TDP43, Annexin 11, TMEM106B, UNC13A, and tau. 

Huge efforts are being made to understand the fundamental mechanisms of different subtypes of FTD, and a lot of results implicated vesicles and damaged protein machinery in the mechanisms. Equally, a lot of talks explored risk factors, and research was presented across many FTD subtypes. There were multiple talks highlighting the need to develop robust biomarkers for the different subtypes of FTD.

For more highlights about the ISFTD conference, please visit Dementia Researcher to listen to the podcast we recently featured on, and follow us on X (@AlzSocResearch) to hear about more highlights from our funded researchers themselves!