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
Poos JM
(2022)
Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort.
in Neurology
Bocchetta M
(2021)
Looking beneath the surface: the importance of subcortical structures in frontotemporal dementia.
in Brain communications
PĆ©rez-Millan A
(2023)
Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers: a GENFI study.
in Journal of neurology
Woollacott I
(2020)
Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration
in Journal of Neuroinflammation
Magen I
(2023)
microRNA-based predictor for diagnosis of frontotemporal dementia.
in Neuropathology and applied neurobiology
Seddighi S
(2024)
Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.
in Science translational medicine
Panman JL
(2021)
Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia.
in Journal of neurology, neurosurgery, and psychiatry
Samra K
(2023)
Motor symptoms in genetic frontotemporal dementia: developing a new module for clinical rating scales.
in Journal of neurology
Manera AL
(2021)
MRI data-driven algorithm for the diagnosis of behavioural variant frontotemporal dementia.
in Journal of neurology, neurosurgery, and psychiatry
Shafiei G
(2023)
Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia.
in Brain : a journal of neurology
Finger E
(2023)
Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers.
in Brain : a journal of neurology
Chelban V
(2022)
Neurofilament light levels predict clinical progression and death in multiple system atrophy.
in Brain : a journal of neurology
Meda FJ
(2023)
Neurofilament light oligomers in neurodegenerative diseases: quantification by homogeneous immunoassay in cerebrospinal fluid.
in BMJ neurology open
Shribman S
(2022)
Neuroimaging Correlates of Cognitive Deficits in Wilson's Disease.
in Movement disorders : official journal of the Movement Disorder Society
Samra K
(2023)
Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales.
in Journal of neurology, neurosurgery, and psychiatry
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
Sexton CE
(2024)
Novel avenues of tau research.
in Alzheimer's & dementia : the journal of the Alzheimer's Association
Russell LL
(2021)
Novel instructionless eye tracking tasks identify emotion recognition deficits in frontotemporal dementia.
in Alzheimer's research & therapy
Mahoney CJ
(2021)
Pathophysiology and Treatment of Non-motor Dysfunction in Amyotrophic Lateral Sclerosis.
in CNS drugs
Rojas JC
(2021)
Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.
in Neurology
Ćijerstedt L
(2022)
Practice effects in genetic frontotemporal dementia and at-risk individuals: a GENFI study.
in Journal of neurology, neurosurgery, and psychiatry
Harper L
(2022)
Prenatal gyrification pattern affects age at onset in frontotemporal dementia.
in Cerebral cortex (New York, N.Y. : 1991)
| 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 |