The UK GENetic Frontotemporal dementia Initiative (UK GENFI)

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

Abstract

Frontotemporal dementia (FTD) is a common cause of young onset dementia. Its effect on people of working age with young families represents a major health and economic burden on society. The only known risk factors for FTD at present are genetic with abnormalities (mutations) in 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 investigates people who have genetic (inherited) FTD, including both people who have developed symptoms and also their first-degree relatives who are at 50% risk of carrying the genetic mutation and therefore developing symptoms in the future. By studying individuals who carry the disease mutation and are thus destined to develop the disease we can understand the development from the very earliest changes, which would be the best time to start any treatment whilst the person remains well. A pilot phase of the study between 2011 and 2014 has created a common platform for studying genetic FTD and a standardized testing protocol. This study builds on the pilot phase by creating a UK-wide study of genetic FTD (at University College London, University of Cambridge, University of Manchester and the University of Oxford) over the next five years. It is expected that 200 participants will be seen, being assessed three times in total. Study participants will have psychology testing (tests of memory, language, behaviour etc.), brain imaging, blood tests and spinal fluid collection (by lumbar puncture) in order to investigate the patterns of change in these different tests at different stages of the disorder. The key outcomes of the study are to (1) improve understanding of how brain systems break down in genetic FTD and how this breakdown relates to the underlying behavioural and cognitive symptoms, (2) develop markers which help identify the disease at its earliest stage, and (3) develop markers that allow the progression of the disease to be tracked. The eventual aim will be to use these markers in future clinical trials of drugs in genetic FTD. The results of this project will also lead to improvement in the recognition and diagnosis of genetic FTD as well as provide improved information about prognosis for patients and members of their family.

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 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. There are currently no treatments that can delay the onset or prevent the progression of genetic FTD but there are now potential disease-modifying therapies in development. However, there are still no biomarkers of genetic FTD that can confidently predict when disease-modifying therapy should be initiated or how the response to it should be monitored. By studying participants who carry a mutation and are thus destined to develop the disease we can explore the entire disease pathway, using mutation negative first-degree relatives as controls. A pilot study has created a common methodological platform to study genetic FTD. This follow-on study aims to capitalize on the work of the pilot, extending both the platform and expertise generated to a UK-wide study of genetic FTD. Specifically, we will establish a UK-wide familial FTD cohort of 200 participants which will (1) lead to greater understanding of the biological underpinning of the cognitive and behavioural deficits seen in FTD; (2) permit large-scale cohesive and integrated longitudinal biomarker studies of familial FTD with the specific remit of informing clinical trial design; and (3) provide a "readiness" cohort of patients for disease-modifying drug trials. The experimental plan includes longitudinal clinical and neuropsychological assessments, neuroimaging and both blood and spinal fluid sampling, with the key outcomes including improved understanding regarding the selective vulnerability of the specific neural systems affected in FTD, robust biomarkers of disease onset and progression, and estimation of sample sizes required for trials.

Planned Impact

The outcomes of UK GENFI 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. UK 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 UK GENFI 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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Bocchetta M (2016) The habenula: an under-recognised area of importance in frontotemporal dementia? in Journal of neurology, neurosurgery, and psychiatry

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Warren JD (2016) Binary reversals in primary progressive aphasia. in Cortex; a journal devoted to the study of the nervous system and behavior

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Meeter LH (2016) Neurofilament light chain: a biomarker for genetic frontotemporal dementia. in Annals of clinical and translational neurology

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Kenny J (2017) A novel prion protein variant in a patient with semantic dementia. in Journal of neurology, neurosurgery, and psychiatry

 
Description Development of a methodological framework of presymptomatic clinical trials
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Bluefield Project Grants - Developing a GENFI Biobank
Amount $148,222 (USD)
Organisation Bluefield Project 
Sector Charity/Non Profit
Country United States
Start 03/2016 
End 04/2018
 
Description Developing a platform trial for frontotemporal dementia
Amount $490,988 (USD)
Organisation Milken Institute 
Sector Charity/Non Profit
Country United States
Start 03/2024 
End 02/2026
 
Description JPND - Working Groups to Inform Cohort Studies in Neurodegenerative Disease Research
Amount € 34,178 (EUR)
Organisation EU Joint Programme - Neurodegenerative Disease Research (JPND) 
Sector Public
Country European Union (EU)
Start 09/2014 
End 05/2015
 
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 Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study 
Description Additional file 1. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL https://springernature.figshare.com/articles/dataset/Additional_file_1_of_A_panel_of_CSF_proteins_se...
 
Title Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study 
Description Additional file 1. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL https://springernature.figshare.com/articles/dataset/Additional_file_1_of_A_panel_of_CSF_proteins_se...
 
Title Additional file 1 of Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation 
Description Additional file 1: Supplementary Figure 1. Mean normalized protein expression values for the chemokines in controls and each of PPA groups in plasma. Significant differences with p values are shown on the graphs. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL https://springernature.figshare.com/articles/dataset/Additional_file_1_of_Differential_chemokine_alt...
 
Title Additional file 1 of Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation 
Description Additional file 1: Supplementary Figure 1. Mean normalized protein expression values for the chemokines in controls and each of PPA groups in plasma. Significant differences with p values are shown on the graphs. 
Type Of Material Database/Collection of data 
Year Produced 2021 
Provided To Others? Yes  
URL https://springernature.figshare.com/articles/dataset/Additional_file_1_of_Differential_chemokine_alt...
 
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. 
 
Title [Supp. Mat.] Spatiotemporal Analysis For Detection Of Pre-Symptomatic Shape Changes In Neurodegenerative Diseases: Initial Application To The Genfi Cohort 
Description Supplementary tables and figure of paper Spatio-temporal analysis for detection of pre-symptomatic shape changes in neuro-degenerative diseases: initial application to the GENFI cohort, for testing different number of clusters of the spatio-temporal regression. The supplementary materials shows results for 2 4 6 8 12 14 and 16 clusters. The 10 clusters analysis is in the paper. 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
URL https://zenodo.org/record/1324233
 
Description Frontotemporal dementia Prevention Initiative - FPI 
Organisation University of California, San Francisco
Department Memory and Ageing Centre UCSF
Country United States 
Sector Academic/University 
PI Contribution This is a collaboration of the GENFI study led by me with other international studies - ARTFL/LEFFTDS in the US and DINAD in Australia. I jointly lead the initiative
Collaborator Contribution The PIs of the studies jointly run this collaboration - we have developed shared guidelines for academic-pharma partnerships for future clinical trials in FTD as well as a shared dataset.
Impact The collaboration has developed guidelines for academic-pharma partnerships which will be used in upcoming trials.
Start Year 2017
 
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. There is an active blog about my research.
Year(s) Of Engagement Activity 2014,2015,2016,2017,2018,2019,2020,2021
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 Patient and carer workshop - Ask the Doctor about FTD (Cambridge GENFI group - led by Prof James Rowe) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Standalone PPI group for FTD within the Rowe Lab in Cambridge. By inviting patients and their carers we looked at development of research studies and ethical issues within them.
Year(s) Of Engagement Activity 2020
 
Description Pint of Science 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact 120 attendees at a Pint of Science event describing our research work - lots of questions and engagement in interactive activities from the audience.
Year(s) Of Engagement Activity 2019
URL https://pintofscience.co.uk/event/speechless
 
Description Pint of Science 2022 
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 our FTD research work as part of the Pint of Science annual meeting in 2022 - to ~140 members of public.
Year(s) Of Engagement Activity 2022
 
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