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 Milan (Collaboration)
- University of Coimbra (Collaboration)
- Karolinska Institute (Collaboration)
- August Pi i Sunyer Biomedical Research Institute (Collaboration)
- University of California, San Francisco (Collaboration)
- University of Laval (Collaboration)
- University of Limoges (Collaboration)
- Brescia Fatebenefratelli (Collaboration)
- Ludwig Maximilian University of Munich (LMU Munich) (Collaboration)
- Carlo Besta Neurological Institute (Collaboration)
- University of Rouen (Collaboration)
- University of Florence (Collaboration)
- University Hospital Donostia (Collaboration)
- University of Manchester (Collaboration)
- University of Lisbon (Collaboration)
- Erasmus MC (Collaboration)
- University of Brescia (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- McGill University (Collaboration)
- UNIVERSITY OF OXFORD (Collaboration)
- Western University (Collaboration)
- UZ Leuven, Belgium (Collaboration)
- Pitié-Salpêtrière Hospital (Collaboration)
- University of Lille (Collaboration)
- University of Ulm (Collaboration)
- University of Toronto (Collaboration)
- University Hospital Tuebingen (Collaboration)
People |
ORCID iD |
| Jonathan Daniel Rohrer (Principal Investigator) |
Publications
Rohrer JD
(2021)
The Frontotemporal Dementia Prevention Initiative: Linking Together Genetic Frontotemporal Dementia Cohort Studies.
in Advances in experimental medicine and biology
Poos JM
(2021)
Impairment of episodic memory in genetic frontotemporal dementia: A GENFI study.
in Alzheimer's & dementia (Amsterdam, Netherlands)
Russell LL
(2021)
Eye movements in frontotemporal dementia: Abnormalities of fixation, saccades and anti-saccades.
in Alzheimer's & dementia (New York, N. Y.)
Benussi A
(2022)
Conceptual framework for the definition of preclinical and prodromal frontotemporal dementia.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Whiteside DJ
(2023)
Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Tsvetanov KA
(2021)
Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Malpetti M
(2021)
Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Clarke MTM
(2021)
Early anterior cingulate involvement is seen in presymptomatic MAPT P301L mutation carriers.
in Alzheimer's research & therapy
Russell LL
(2021)
Novel instructionless eye tracking tasks identify emotion recognition deficits in frontotemporal dementia.
in Alzheimer's research & therapy
Sogorb-Esteve A
(2022)
Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia.
in Alzheimer's research & therapy
| 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 |