JPND - Defining measures of proximity to symptom onset in the GENetic Frontotemporal dementia Initiative
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Frontotemporal dementia (FTD) is a highly heritable neurodegenerative disorder with the majority of that heritability accounted for by autosomal dominant mutations in three genes: progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72). The Genetic FTD Initiative (GENFI) is a European and Canadian multicentre natural history study of genetic FTD with detailed phenotyping of both presymptomatic and symptomatic mutation carriers. In the absence of treatments that can delay the onset or prevent the progression of genetic FTD, the aim of GENFI has been to identify robust biomarkers for future trials. However, with trials imminent, it will be critically important to identify biomarkers of proximity to symptom onset, identifying on an individual basis those who are likely to progress to clinical FTD over the next 5 to 10 years. The aim of this study is therefore to characterize the prodromal period of genetic FTD, establishing cognitive, imaging and fluid biomarker measures that allow i) stratification of individual presymptomatic carriers into a stage proximal to symptom onset, and ii) measurement of subsequent disease progression during that proximal period. In particular, the work will extend the results found on a group basis in the prior GENFI studies to identify measures and patterns of change on an individual basis, thus paving the way for a precision medicine approach to FTD. It will make use of data from at least 950 participants already in the current GENFI studies with biomarker data acquired longitudinally (>2000 visits so far). It will focus on those likely to be in proximity to symptom onset, following 500 participants over time, with cognitive, neuroimaging, and fluid biomarker assessment as well as genomic, proteomic and transcriptomic profiling of participants. Integration of these approaches will allow stratification of genetic FTD, delineating an individualized disease profile that identifies those in proximity to symptom onset and their subsequent progression. This will be fundamental to rational trial design involving presymptomatic participants over the next few years - such trials will not be possible without this.
Technical Summary
Frontotemporal dementia (FTD) is a highly heritable neurodegenerative disorder with the majority of that heritability accounted for by autosomal dominant mutations in three genes: progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72). The Genetic FTD Initiative (GENFI) is a European and Canadian multicentre natural history study of genetic FTD with detailed phenotyping of both presymptomatic and symptomatic mutation carriers. With trials imminent, it will be critically important to identify biomarkers of proximity to symptom onset, identifying on an individual basis those who are likely to progress to clinical FTD over the next 5 to 10 years. The aim of this study is therefore to characterize the prodromal period of genetic FTD, establishing cognitive, imaging and fluid biomarker measures that allow i) stratification of individual presymptomatic carriers into a stage proximal to symptom onset, and ii) measurement of subsequent disease progression during that proximal period. In particular, the work will extend the results found on a group basis in the prior GENFI studies to identify measures and patterns of change on an individual basis, thus paving the way for a precision medicine approach to FTD. It will make use of data from at least 950 participants already in the current GENFI studies with biomarker data acquired longitudinally (>2000 visits so far). It will focus on those likely to be in proximity to symptom onset, following 500 participants over time, with cognitive, neuroimaging, and fluid biomarker assessment as well as genomic, proteomic and transcriptomic profiling of participants. Integration of these approaches will allow stratification of genetic FTD, delineating an individualized disease profile that identifies those in proximity to symptom onset and their subsequent progression.
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. GENFI-prox will provide a platform for clinical trials in genetic FTD: 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.
The outcomes of GENFI-prox 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.
The outcomes of GENFI-prox 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.
Organisations
- University College London (Lead Research Organisation)
- University of Coimbra (Collaboration)
- Karolinska Institute (Collaboration)
- University of California, San Francisco (Collaboration)
- August Pi i Sunyer Biomedical Research Institute (Collaboration)
- University of Laval (Collaboration)
- University of Limoges (Collaboration)
- University of Brescia (Collaboration)
- Brescia Fatebenefratelli (Collaboration)
- Carlo Besta Neurological Institute (Collaboration)
- Ludwig Maximilian University of Munich (LMU Munich) (Collaboration)
- University of Florence (Collaboration)
- University Hospital Donostia (Collaboration)
- University of Milan (Collaboration)
- University of Manchester (Collaboration)
- McGill University (Collaboration)
- University of Lisbon (Collaboration)
- University of Ulm (Collaboration)
- Erasmus MC (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- Western University (Collaboration)
- UZ Leuven, Belgium (Collaboration)
- Pitié-Salpêtrière Hospital (Collaboration)
- University of Lille (Collaboration)
- University of Toronto (Collaboration)
- University Hospital Tuebingen (Collaboration)
- University of Rouen (Collaboration)
People |
ORCID iD |
Jonathan Daniel Rohrer (Principal Investigator) |
Publications
Ge YJ
(2023)
Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood.
in Biological psychiatry
Zetterberg H
(2023)
The role of neurofilament light in genetic frontotemporal lobar degeneration.
in Brain communications
Chokesuwattanaskul A
(2023)
The architecture of abnormal reward behaviour in dementia: multimodal hedonic phenotypes and brain substrate.
in Brain communications
Street D
(2023)
Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.
in Brain : a journal of neurology
Ducharme S
(2024)
Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry.
in The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry
Benussi A
(2024)
Diagnostic accuracy of research criteria for prodromal frontotemporal dementia.
in Alzheimer's research & therapy
Volkmer A
(2024)
'Communication is difficult': Speech, language and communication needs of people with young onset or rarer forms of non-language led dementia.
in International journal of language & communication disorders
Sexton CE
(2024)
Novel avenues of tau research.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Seddighi S
(2024)
Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.
in Science translational medicine
Linnemann C
(2024)
NfL reliability across laboratories, stage-dependent diagnostic performance and matrix comparability in genetic FTD: a large GENFI study.
in Journal of neurology, neurosurgery, and psychiatry
Hardy C.J.D.
Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia
in Alzheimer's and Dementia
Sattler R.
Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit
in Neurology and Therapy
Ullgren A.
Altered plasma protein profiles in genetic FTD - a GENFI study
in Molecular Neurodegeneration
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 | 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 MC |
Country | Netherlands |
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 | 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 | 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 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 | 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 | 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 |