Developing an evidence base for trials in genetic frontotemporal dementia - measures of disease onset and progression

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Frontotemporal dementia (FTD) is a common cause of young onset dementia. The only known risk factors for FTD at present are genetic with three genes accounting for the majority of familial FTD, called progranulin, tau and chromosome 9 open reading frame 72. There are now promising avenues for treatment of these disorders but we still do not know when drugs should be started or how we should measure the response to treatment. This study plans to investigate people who have genetic FTD, including both people who have developed symptoms and also people who have a risk of developing symptoms in the future because they carry the abnormal genetic mutation. This allows a window into the earliest changes in the disease process. 30 study subjects from families with genetic FTD will have psychology testing, brain imaging, blood tests and spinal fluid collection annually at three time-points in order to investigate the patterns of change in these different tests at different stages of the disorder. Brain imaging will include not only magnetic resonance imaging but also the novel technique of tau positron emission tomography which may be able to identify the presence of tau pathology in the brains of people with tau mutations for the first time during life. The study subjects will be part of a larger multicentre study called the Genetic Frontotemporal dementia Initiative (GENFI) and data will be available for analysis from over 300 subjects who take part in that initiative. The key outcomes of the study will be to develop markers which help identify the disease at its earliest stage as well as markers that allow the progression of the disease to be tracked. These markers can then be used in future clinical trials of drugs in genetic FTD.

Technical Summary

Frontotemporal dementia (FTD) is a common cause of young onset dementia, approximately equal in frequency to Alzheimer's disease in people below the age of 65. Its effect particularly on people of working age with young families represents a major health and economic burden on society. The only known risk factors for FTD are genetic, and around a third of FTD is familial. The aim of the study is to understand the ordering and temporal evolution of imaging and fluid biomarker change in genetic FTD and their clinical associations, forming an evidence base for future clinical trials. In particular, through comprehensive longitudinal phenotyping, the key objectives are to: characterise the earliest neuropsychological and behavioural changes; identify the earliest anatomical changes that occur and how these change over time; evaluate how measures of structural and functional connectivity change over time; examine the role of tau PET imaging as a marker of tau pathology; and correlate changes in CSF and serum markers with changes in neuroimaging. The experimental plan uses cross-sectional and longitudinal measures of behaviour, cognition, neuroimaging and both CSF and serum markers to elucidate the patterns of biomarker change in genetic FTD with the overarching hypothesis being that biomarkers can aid in the identification of disease and tracking of disease progression. The study aims to be the foundation for clinical trials in genetic FTD with the key outcomes being identification of markers of disease onset including those including those indicative of optimal time to start disease-modifying therapy and markers of disease progression that can be used as outcome measures in clinical trials, as well as estimations of the sample sizes necessary for those trials.

Planned Impact

The outcomes of this study will lead to improvement in the recognition and diagnosis of genetic FTD as well as provide improved prognostic information for patients and members of their family in the first instance. This will be important to clinicians and policymakers in that it will allow a better representation of the incidence of genetic FTD in the UK. This study in combination with GENFI will provide a platform for clinical trials in genetic FTD, likely to occur in the next five years: finding a disease-modifying therapy in this disorder will be hugely beneficial both for the patient and their families at risk of the disorder, as well as improving the nation's health and wealth by altering a disease process that affects people generally of working age. Based on the current understanding of the pathophysiology of the disease, it is probable that effective interventions for genetic FTD due to progranulin mutations will become available either by repurposing or from novel agents. Rapid evaluation will support the G8 declaration of a treatment for dementia by 2025. This would have significant UK political benefit building on the UK lead internationally in the G8 dementia summit.

The outcomes of this study in terms of biomarkers of disease onset and progression will feed into pharmaceutical industry-led studies, providing the knowledge required to identify the primary and secondary outcomes used in clinical trials and the timing of when the trials should take place.

Publications

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Fletcher PD (2015) Auditory hedonic phenotypes in dementia: A behavioural and neuroanatomical analysis. in Cortex; a journal devoted to the study of the nervous system and behavior

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Fletcher PD (2016) A physiological signature of sound meaning in dementia. in Cortex; a journal devoted to the study of the nervous system and behavior

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Foiani MS (2018) Plasma tau is increased in frontotemporal dementia. in Journal of neurology, neurosurgery, and psychiatry

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Gordon E (2016) Advances in neuroimaging in frontotemporal dementia. in Journal of neurochemistry

 
Description Novel fluid biomarkers of progranulin-associated FTD
Amount $219,999 (USD)
Organisation Bluefield Project 
Sector Charity/Non Profit
Country United States
Start 01/2019 
End 12/2020
 
Title GENFI XNAT database 
Description Database of biomarker data from the GENFI 1 and GENFI 2 projects (presymptomatic and early symptomatic genetic FTD). 
Type Of Material Database/Collection of data 
Year Produced 2014 
Provided To Others? Yes  
Impact 30 current analyses ongoing across multiple centres within GENFI. 
 
Description GENFI2 
Organisation August Pi i Sunyer Biomedical Research Institute
Department Hospital Clinic of Barcelona
Country Spain 
Sector Hospitals 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation Brescia Fatebenefratelli
Country Italy 
Sector Hospitals 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation Carlo Besta Neurological Institute
Country Italy 
Sector Public 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation Erasmus University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation Ludwig Maximilian University of Munich (LMU Munich)
Department University Clinic of Munich
Country Germany 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation McGill University
Country Canada 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation Pitié-Salpêtrière Hospital
Country France 
Sector Hospitals 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation UZ Leuven, Belgium
Country Belgium 
Sector Hospitals 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University Hospital Donostia
Country Spain 
Sector Hospitals 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University Hospital Tuebingen
Country Germany 
Sector Hospitals 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Brescia
Country Italy 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Coimbra
Country Portugal 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Florence
Country Italy 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Laval
Country Canada 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Lille
Country France 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Limoges
Country France 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Lisbon
Country Portugal 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Milan
Country Italy 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Rouen
Country France 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Toronto
Country Canada 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation University of Ulm
Country Germany 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description GENFI2 
Organisation Western University
Country Canada 
Sector Academic/University 
PI Contribution I have led this multicentre international biomarkers study of genetic frontotemporal dementia, which has been co-ordinated from UCL.
Collaborator Contribution Partners are recruiting sites within the study.
Impact Publications - Lancet Neurology 2015; Annals of Clinical and Translational Neurology 2016; Presentations - International Conference on FTD 2014; International Conference on FTD 2016
Start Year 2015
 
Description Annual FTD support group seminar 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Seminar chaired by Jonathan Rohrer (supervisor) with talk by Elizabeth Gordon (PhD studentship) about her PhD work.
Year(s) Of Engagement Activity 2016
 
Description British Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk on young onset dementia and presymptomatic neurodegenerative disease highlighting the work of the GENFI project as part of the national British Science Festival - around 70 people attended with both a panel discussion and personal questions afterwards.
Year(s) Of Engagement Activity 2015
URL https://thelittleboxoffice.com/bsa/event/view/26635
 
Description Contribution to online learning module about dementia (MOOC) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Videoed talk and written information provided for an online learning tool about dementia - highlighting my research and work on GENFI project. Over 10,000 people currently signed up for course (official start March 2016).
Year(s) Of Engagement Activity 2016
URL https://www.futurelearn.com/courses/faces-of-dementia
 
Description FTD support group meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact ~70 people attended, mainly carers but also professionals, to hear about the latest research, with a question and answer session afterwards including discussion of patient involvement in future study design.
Year(s) Of Engagement Activity 2018
 
Description FTD talk website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I have set up and run a public engagement website dedicated to frontotemporal dementia (FTD talk) - it aims to provide information to the public about FTD, and particularly lay updates about research.
Year(s) Of Engagement Activity 2014,2015,2016,2017
URL http://www.ftdtalk.org
 
Description Familial FTD support group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Talk to around 100 people as part of the familial FTD support group annual day - discussion about GENFI and current research; questions and discussion about research from family members and those at risk of developing genetic FTD.
Year(s) Of Engagement Activity 2015
URL https://www.ucl.ac.uk/drc/support-groups/fFTD-support-group
 
Description Meet the researcher Youtube video 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Video made to inform people about research at UCL - interview about work on FTD.
Year(s) Of Engagement Activity 2014,2015,2016,2017
URL https://www.youtube.com/watch?v=8oMe4bgSHoY&feature=youtu.be
 
Description Pint of Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Around 100 people attended an event as part of the national Pint of Science Festival - discussion regarding young onset dementias and the work we are doing to find biomarkers and an evidence base for clinical trials - lots of questions and discussion afterwards and personal feedback from audience regarding how much they learned about the area.
Year(s) Of Engagement Activity 2015
 
Description Talk at FTD support group annual seminar 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Increased awareness of FTD research and the work we are doing to FTD support group consisting mainly of carers.
Year(s) Of Engagement Activity 2017
 
Description Talk to event for UK magistrates 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact Talk on frontotemporal dementia to a UK magistrates event to inform them about forensic nature of symptomatology of FTD and how our research is exploring this further - long discussion afterwards about how this might inform the work of magistrates, particularly in considering dementia as a underlying problem with people who have been involved in crimes and therefore may change their practice.
Year(s) Of Engagement Activity 2015
 
Description The Science Museum - Science Lates - Dementia 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Organised and presented at a section of the Science Museum 'Science Lates' evening in April 2016. My section had 5 stands (manned by 10 of my team) each focused on different parts of clinical and imaging dementia research that represented our current research work, particularly focusing on young onset and genetic dementias. >4000 people attended the event. Many people said that their views and understanding about dementia changed as a result of visiting our section.
Year(s) Of Engagement Activity 2016