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
Benatar M
(2022)
Preventing amyotrophic lateral sclerosis: insights from pre-symptomatic neurodegenerative diseases.
in Brain : a journal of neurology
Mazzeo S
(2024)
Primary Progressive Aphasia in Italian and English: A Cross-Linguistic Cohort Study.
in Neurology
Chokesuwattanaskul A
(2022)
Primary progressive aphasia: ReADing the clinical GRANularity
in Practical Neurology
Ge Y
(2023)
Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood
in Biological Psychiatry
Samra K
(2023)
Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort
in Journal of the Neurological Sciences
Sevigny J
(2024)
Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results.
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
Benussi A
(2021)
Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia.
in JAMA network open
Sogorb-Esteve A
(2025)
Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.
in Science translational medicine
Drazich-Taylor EHS
(2023)
Q351R MAPT mutation is associated with a mixed 3R/4R tauopathy and a slowly progressive cognitive, behavioural and parkinsonian syndrome.
in Journal of neurology, neurosurgery, and psychiatry
Sattler R
(2023)
Roadmap for C9ORF72 in Frontotemporal Dementia and Amyotrophic Lateral Sclerosis: Report on the C9ORF72 FTD/ALS Summit.
in Neurology and therapy
Mok TH
(2023)
Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease.
in Brain : a journal of neurology
Barbier M
(2021)
SLITRK2 , an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration
in Brain
Russell LL
(2020)
Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort.
in Cortex; a journal devoted to the study of the nervous system and behavior
Tookey SA
(2021)
Specific support needs and experiences of carers of people with frontotemporal dementia: A systematic review.
in Dementia (London, England)
Wilke C
(2022)
Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study.
in Annals of neurology
Gazzina S
(2022)
Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia.
in Neurobiology of aging
Bocchetta M
(2023)
Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative cohort.
in Brain communications
Hardy CJD
(2024)
Symptom-based staging for logopenic variant primary progressive aphasia.
in European journal of neurology
Hardy CJ
(2023)
Symptom-led staging for primary progressive aphasia.
in medRxiv : the preprint server for health sciences
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
Ahmed RM
(2021)
Tackling clinical heterogeneity across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum using a transdiagnostic approach.
in Brain communications
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
Staffaroni AM
(2022)
Temporal order of clinical and biomarker changes in familial frontotemporal dementia.
in Nature medicine
Bocchetta M
(2022)
Thalamic and Cerebellar Regional Involvement across the ALS-FTD Spectrum and the Effect of C9orf72.
in Brain sciences
Chokesuwattanaskul A
(2023)
The architecture of abnormal reward behaviour in dementia: multimodal hedonic phenotypes and brain substrate.
in Brain communications
Jiskoot LC
(2023)
The Benson Complex Figure Test detects deficits in visuoconstruction and visual memory in symptomatic familial frontotemporal dementia: A GENFI study.
in Journal of the neurological sciences
Nelson A
(2022)
The CBI-R detects early behavioural impairment in genetic frontotemporal dementia.
in Annals of clinical and translational neurology
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
Rohrer JD
(2021)
The Frontotemporal Dementia Prevention Initiative: Linking Together Genetic Frontotemporal Dementia Cohort Studies.
in Advances in experimental medicine and biology
Belder CRS
(2022)
The problematic syndrome of right temporal lobe atrophy: Unweaving the phenotypic rainbow.
in Frontiers in neurology
Franklin HD
(2021)
The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort.
in Alzheimer's research & therapy
Zetterberg H
(2023)
The role of neurofilament light in genetic frontotemporal lobar degeneration.
in Brain communications
Yaldiz B
(2023)
Twist exome capture allows for lower average sequence coverage in clinical exome sequencing.
in Human genomics
Scotton WJ
(2023)
Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning.
in Brain communications
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
| 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 |