On 4th November 2016, researchers and clinicians from across the UK met at the 6th Annual FTD UK Meeting at Wolfson College at the University of Cambridge. The day was full of exciting updates about current and future research for both frontotemporal dementia (FTD) and overlapping conditions such as progressive supranuclear palsy (PSP) and motor neuron disease (MND). Professor Stuart Pickering-Brown from the University of Manchester gave a warm welcome to all present at the start of the meeting.
First up was new brain imaging techniques. Professor James Rowe from the University of Cambridge talked about using a technique called ‘tau PET imaging’ to look at the tau protein in the brain. Tau forms abnormal clumps in brain cells of patients with PSP. Professor Rowe explained that a tracer called ‘AV1451’ is thought to bind to the tau protein, lighting up areas of the brain where there is lots of abnormal tau. As well as being useful for studying PSP, this may be a promising technique to examine the extent and spread of abnormal tau in the brain cells of patients with either familial FTD associated with tau (MAPT) mutations, or patients with sporadic FTD and underlying tau pathology in the brain. However, more research is needed before this technique can be used widely, as it appears the tracer can also bind to other proteins (not just tau), lighting up parts of the brain that don’t contain tau. Dr Martina Bocchetta from UCL then talked about how we can use MRI scans of the brain to look at different patterns of shrinkage within deeper, or ‘subcortical’, areas of the brain in patients with FTD. Patients with different forms of familial FTD (who have either a tau, progranulin or C9ORF72 gene mutation) have different patterns of brain shrinkage in specific subcortical brain areas. Exploring this further might help us to understand more about the cause of different symptoms, such as changes in appetite and food preferences, or altered temperature perception, that patients with FTD often experience.
Genetics was next on the agenda. Dr Jonathan Rohrer from UCL gave us an overview of the current gene mutations known to cause FTD and in particular went through the types of FTD and MND and brain imaging findings that were recently found to be associated with new mutations in genes called ‘TBK1’ and ‘SQSTM1’. He also explained how we can calculate the risk of a person having a familial (also known as genetic, or inherited) form of FTD, based on the number of people within that person’s family who also have, or have had, dementia, and the age at which these relatives first developed symptoms. Research suggests that the risk of having familial FTD is around 5% for a person with FTD who has had no other family members that have been diagnosed with dementia. However, this risk is higher (almost 15%) for patients who have the behavioural variant of FTD, but lower for other forms of FTD such as progressive nonfluent aphasia, and much lower for patients presenting with semantic dementia. As the number of other family members with dementia increases, the risk of having a familial form of FTD also increases. The risk significantly increases if their relative started to have symptoms of dementia at a very young age (onset under 65 years old). This explains why doctors explore a patient’s family history carefully and consider based on this whether their FTD could be familial, and offer genetic testing if felt appropriate. Professor Chris Shaw from King’s College London then gave an overview of all the gene mutations associated with MND (also known as amyotrophic lateral sclerosis, ALS), and how this can cause different symptoms and speed of progression of MND. He also described a family with MND who had a mutation in a new gene which had not been discovered before.
Research was also presented that explored the function of cells in the body in FTD and MND. Dr Jonathan Cooper-Knock from the University of Sheffield talked about his research looking at motor neuron cells produced from skin biopsies collected from patients with a C9ORF72 gene mutation. He uses these to model how this gene mutation causes disease in patients with MND or FTD. He showed that this mutation, when present in one direction in the gene (called the ‘antisense’ direction) is turned into a protein, which forms abnormal clumps in the motor neuron cells. However, this antisense mutation also causes a different protein to clump in ‘granule cells’, which are cells present within a different part of the brain, called the cerebellum. Dr Sarah Ryan from the University of Manchester also showed how injecting different lengths of the C9ORF72 mutation into cells leads to proteins which disrupt the nucleolus, a structure that regulates how efficiently the cell makes new structures inside itself. The longer the mutation, the worse this disruption is. Understanding more about how the C9ORF72 mutation affects brain cells could help scientists design new ‘gene-modifying treatments’ for use in future clinical trials in patients with FTD or MND who have the C9ORF72 mutation. Dr Sean Sweeney from the University of York told us about his research, which explores the impact of rare mutations in the gene ‘CHMP2B’ on brain cell function, using a fly called ‘Drosophila’. His work has suggested these mutations can lead to problems with inflammation and defective debris clearance (autophagy) in the brain, leading to build-up of proteins that then clump up and kill specific brain cells prematurely, leading to FTD.
Finally, we heard about some exciting new drug trials for patients with PSP, and a new observational study of patients with PSP. Dr Irfan Qureshi from the pharmaceutical company Bristol-Myers Squibb explained that they have made a drug which is an antibody that binds to the tau protein while it is floating outside of brain cells but still within the brain tissue. The drug seems to stop tau becoming attached to brain cells, and therefore reduces formation of abnormally clumped tau and its spread from one brain cell to the next. The drug was used in a clinical trial of 64 healthy adults from 2014 to 2016. The drug had no significant side effects so in September 2015 a new drug trial started with 48 patients with PSP in the USA, focusing on examining the safety of the drug, but also its immune system effects in patients. A further trial will also be carried out across the world in selected patients with PSP, starting in 2017. Dr Dirk Beher from pharmaceutical company Asceneuron then talked about how his company has produced a different anti-tau drug which affects how other molecules attach themselves to tau, which can then alter tau’s shape and stickiness. Their drug stops an enzyme in the brain from removing important molecules called glycoproteins from the tau surface. This could stop tau from sticking together and clumping up abnormally. Early non-human trials of this drug have shown promising results and soon it may be used in humans in clinical trials. If trials of these drugs in patients with PSP show good results, potentially they could also be used in future in clinical trials for patients with familial FTD due to MAPT mutations, who also have tau pathology in brain cells.
Continuing with the focus on PSP, Professor Huw Morris from UCL gave an overview of the challenges facing doctors and scientists who see patients with PSP and study this disease. He described a study he is leading called the PROSPECT study. This aims to observe patients with PSP and corticobasal syndrome as well as others forms of atypical parkinsonism over a 7 year period, across 7 UK centres. The study will use different brain imaging techniques, perform clinical and psychology tests and collect blood, DNA, spinal fluid and skin samples from patients for research. Professor Morris explained how this research should lead to better understanding of the cause of these diseases and inform us about earlier indicators of disease, reliable markers that can be used to monitor the disease over time, and new targets for drug treatments.
To finish off the day, Professor Stuart Pickering-Brown, Dr Jonathan Rohrer and Professor James Rowe gave a useful summary of current and future initiatives and collaborations that are specifically focusing on research into FTD, MND, PSP and related disorders across the UK. These include the GENFI study which has now recruited over 600 participants.
All who were present agreed the day was highly informative and that it was very useful to hear about all aspects of research into FTD and related disorders, ranging from right from molecular neuroscience research through to exciting clinical drug trials in patients. We all went away inspired to ensure that our research will continue to contribute to better understanding and new treatments for these devastating disorders and hope for the patients and their families affected by them.