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
Sogorb-Esteve A
(2021)
Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation.
in Journal of neuroinflammation
Sogorb-Esteve A
(2021)
Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation.
in Journal of Alzheimer's disease : JAD
Sogorb-Esteve A
(2025)
Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.
in Science translational medicine
Sogorb-Esteve A
(2022)
Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia
in Alzheimer's Research & Therapy
Staffaroni AM
(2022)
Temporal order of clinical and biomarker changes in familial frontotemporal dementia.
in Nature medicine
Street D
(2023)
Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials.
in Brain : a journal of neurology
Swift IJ
(2024)
Differential patterns of lysosomal dysfunction are seen in the clinicopathological forms of primary progressive aphasia.
in Journal of neurology
Swift IJ
(2021)
Variable clinical phenotype in TBK1 mutations: case report of a novel mutation causing primary progressive aphasia and review of the literature.
in Neurobiology of aging
Tavares TP
(2020)
Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration.
in Journal of neurology, neurosurgery, and psychiatry
Taylor B
(2025)
Data-driven neuroanatomical subtypes of primary progressive aphasia.
in Brain : a journal of neurology
Tookey SA
(2021)
Specific support needs and experiences of carers of people with frontotemporal dementia: A systematic review.
in Dementia (London, England)
Tregidgo HFJ
(2023)
Accurate Bayesian segmentation of thalamic nuclei using diffusion MRI and an improved histological atlas.
in NeuroImage
Tse NY
(2023)
Distinct hypothalamic involvement in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum.
in NeuroImage. Clinical
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
Ullgren A
(2023)
Altered plasma protein profiles in genetic FTD - a GENFI study.
in Molecular neurodegeneration
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
Valentino RR
(2023)
Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease.
in medRxiv : the preprint server for health sciences
Van Der Ende EL
(2022)
A data-driven disease progression model of fluid biomarkers in genetic frontotemporal dementia.
in Brain : a journal of neurology
Van Der Ende EL
(2022)
Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study.
in Journal of neuroinflammation
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
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
Wilke C
(2022)
Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study.
in Annals of neurology
Wilson K
(2022)
Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72 -associated frontotemporal dementia and amyotrophic lateral sclerosis
in Journal of Neurology, Neurosurgery & Psychiatry
Woollacott I
(2020)
Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration
in Journal of Neuroinflammation
Woollacott IOC
(2022)
CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia.
in Annals of clinical and translational neurology
Yaldiz B
(2023)
Twist exome capture allows for lower average sequence coverage in clinical exome sequencing.
in Human genomics
Zetterberg H
(2023)
The role of neurofilament light in genetic frontotemporal lobar degeneration.
in Brain communications
Ćijerstedt L
(2022)
Practice effects in genetic frontotemporal dementia and at-risk individuals: a GENFI study.
in Journal of neurology, neurosurgery, and psychiatry
| 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 |