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.
People |
ORCID iD |
| Jonathan Daniel Rohrer (Principal Investigator) |
Publications
Magen I
(2023)
microRNA-based predictor for diagnosis of frontotemporal dementia.
in Neuropathology and applied neurobiology
Samra K
(2023)
Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales.
in Journal of neurology, neurosurgery, and psychiatry
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
Mok TH
(2023)
Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease.
in Brain : a journal of neurology
Chokesuwattanaskul A
(2023)
The architecture of abnormal reward behaviour in dementia: multimodal hedonic phenotypes and brain substrate.
in Brain communications
Swift IJ
(2024)
Differential patterns of lysosomal dysfunction are seen in the clinicopathological forms of primary progressive aphasia.
in Journal of neurology
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
Ulugut H
(2024)
Clinical recognition of frontotemporal dementia with right anterior temporal predominance: A multicenter retrospective cohort study.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Bouzigues A
(2024)
Disruption of macroscale functional network organisation in patients with frontotemporal dementia
in Molecular Psychiatry
Hardy CJD
(2024)
Symptom-based staging for logopenic variant primary progressive aphasia.
in European journal of neurology
Kancheva I
(2024)
Cerebrovascular reactivity impairment in genetic frontotemporal dementia
O'Connor A
(2024)
Genetic testing in dementia.
in Practical neurology
Feldman HH
(2024)
A framework for translating tauopathy therapeutics: Drug discovery to clinical trials.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Sevigny J
(2024)
Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.
in Nature medicine
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
Coppieters R
(2024)
A systematic review of the quantitative markers of speech and language of the frontotemporal degeneration spectrum and their potential for cross-linguistic implementation.
in Neuroscience and biobehavioral reviews
Benussi A
(2024)
Diagnostic accuracy of research criteria for prodromal frontotemporal dementia.
in Alzheimer's research & therapy
Seddighi S
(2024)
Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.
in Science translational medicine
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
Mulroy E
(2024)
Binary reversals: a diagnostic sign in primary progressive aphasia.
in Journal of neurology, neurosurgery, and psychiatry
Serpente M
(2024)
Long Non-Coding RNA Profile in Genetic Symptomatic and Presymptomatic Frontotemporal Dementia: A GENFI Study.
in Journal of Alzheimer's disease : JAD
Hardy CJD
(2024)
Symptom-led staging for semantic and non-fluent/agrammatic variants of primary progressive aphasia.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Mazzeo S
(2024)
Primary Progressive Aphasia in Italian and English: A Cross-Linguistic Cohort Study.
in Neurology
Sexton CE
(2024)
Novel avenues of tau research.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Liu X
(2024)
Frontoparietal network integrity supports cognitive function in pre-symptomatic frontotemporal dementia: Multimodal analysis of brain function, structure, and perfusion.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Fahy N
(2025)
The experience of "at-risk" status for familial frontotemporal dementia (fFTD) and its impact on reproductive decision-making: A qualitative study.
in Journal of genetic counseling
Taylor B
(2025)
Data-driven neuroanatomical subtypes of primary progressive aphasia.
in Brain : a journal of neurology
Sogorb-Esteve A
(2025)
Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.
in Science translational medicine
Dellar ER
(2025)
Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.
in Annals of neurology
| 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 | 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 | 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 |