Developing an evidence base for trials in genetic frontotemporal dementia - measures of disease onset and progression
Lead Research Organisation:
UNIVERSITY COLLEGE LONDON
Department Name: Institute of Neurology
Abstract
Frontotemporal dementia (FTD) is a common cause of young onset dementia. The only known risk factors for FTD at present are genetic with three genes accounting for the majority of familial FTD, called progranulin, tau and chromosome 9 open reading frame 72. There are now promising avenues for treatment of these disorders but we still do not know when drugs should be started or how we should measure the response to treatment. This study plans to investigate people who have genetic FTD, including both people who have developed symptoms and also people who have a risk of developing symptoms in the future because they carry the abnormal genetic mutation. This allows a window into the earliest changes in the disease process. 30 study subjects from families with genetic FTD will have psychology testing, brain imaging, blood tests and spinal fluid collection annually at three time-points in order to investigate the patterns of change in these different tests at different stages of the disorder. Brain imaging will include not only magnetic resonance imaging but also the novel technique of tau positron emission tomography which may be able to identify the presence of tau pathology in the brains of people with tau mutations for the first time during life. The study subjects will be part of a larger multicentre study called the Genetic Frontotemporal dementia Initiative (GENFI) and data will be available for analysis from over 300 subjects who take part in that initiative. The key outcomes of the study will be to develop markers which help identify the disease at its earliest stage as well as markers that allow the progression of the disease to be tracked. These markers can then be used in future clinical trials of drugs in genetic FTD.
Technical Summary
Frontotemporal dementia (FTD) is a common cause of young onset dementia, approximately equal in frequency to Alzheimer's disease in people below the age of 65. Its effect particularly on people of working age with young families represents a major health and economic burden on society. The only known risk factors for FTD are genetic, and around a third of FTD is familial. The aim of the study is to understand the ordering and temporal evolution of imaging and fluid biomarker change in genetic FTD and their clinical associations, forming an evidence base for future clinical trials. In particular, through comprehensive longitudinal phenotyping, the key objectives are to: characterise the earliest neuropsychological and behavioural changes; identify the earliest anatomical changes that occur and how these change over time; evaluate how measures of structural and functional connectivity change over time; examine the role of tau PET imaging as a marker of tau pathology; and correlate changes in CSF and serum markers with changes in neuroimaging. The experimental plan uses cross-sectional and longitudinal measures of behaviour, cognition, neuroimaging and both CSF and serum markers to elucidate the patterns of biomarker change in genetic FTD with the overarching hypothesis being that biomarkers can aid in the identification of disease and tracking of disease progression. The study aims to be the foundation for clinical trials in genetic FTD with the key outcomes being identification of markers of disease onset including those including those indicative of optimal time to start disease-modifying therapy and markers of disease progression that can be used as outcome measures in clinical trials, as well as estimations of the sample sizes necessary for those trials.
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. This will be important to clinicians and policymakers in that it will allow a better representation of the incidence of genetic FTD in the UK. This study in combination with GENFI will provide a platform for clinical trials in genetic FTD, likely to occur in the next five years: 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. Rapid evaluation will support the G8 declaration of a treatment for dementia by 2025. This would have significant UK political benefit building on the UK lead internationally in the G8 dementia summit.
The outcomes of this study 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 this study 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 / Fellow) |
Publications
Fumagalli Giorgio G.
(2018)
Distinct patterns of brain atrophy in Genetic Frontotemporal Dementia Initiative (GENFI) cohort revealed by visual rating scales
in ALZHEIMERS RESEARCH & THERAPY
Fyfe I
(2016)
Cerebellar atrophy has disease-specific patterns
in Nature Reviews Neurology
Galimberti D
(2019)
Genetic risk factors and role of immune dysfunction in FTLD.
in Nature reviews. Neurology
Galimberti D
(2018)
Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: results from the GENFI study.
in Neurobiology of aging
Gazzina S
(2019)
Education modulates brain maintenance in presymptomatic frontotemporal dementia.
in Journal of neurology, neurosurgery, and psychiatry
Gazzina S
(2022)
Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia.
in Neurobiology of aging
Ge Y
(2023)
Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood
in Biological Psychiatry
Gordon E
(2021)
A comparison of automated atrophy measures across the frontotemporal dementia spectrum: Implications for trials.
in NeuroImage. Clinical
Gordon E
(2016)
Advances in neuroimaging in frontotemporal dementia
in Journal of Neurochemistry
Greaves CV
(2019)
An update on genetic frontotemporal dementia.
in Journal of neurology
Harding SR
(2017)
The TMEM106B risk allele is associated with lower cortical volumes in a clinically diagnosed frontotemporal dementia cohort.
in Journal of neurology, neurosurgery, and psychiatry
Hardy CJ
(2016)
The Language Profile of Behavioral Variant Frontotemporal Dementia.
in Journal of Alzheimer's disease : JAD
Hardy CJ
(2023)
Symptom-led staging for primary progressive aphasia.
in medRxiv : the preprint server for health sciences
Hardy CJD
(2017)
Behavioural and neuroanatomical correlates of auditory speech analysis in primary progressive aphasias.
in Alzheimer's research & therapy
Hardy CJD
(2017)
Functional neuroanatomy of speech signal decoding in primary progressive aphasias.
in Neurobiology of aging
Hardy CJD
(2019)
Findings of Impaired Hearing in Patients With Nonfluent/Agrammatic Variant Primary Progressive Aphasia.
in JAMA neurology
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
Hardy CJD
(2018)
Sensitivity of Speech Output to Delayed Auditory Feedback in Primary Progressive Aphasias.
in Frontiers in neurology
Hardy CJD
(2018)
Retained capacity for perceptual learning of degraded speech in primary progressive aphasia and Alzheimer's disease.
in Alzheimer's research & therapy
Hardy CJD
(2024)
Symptom-based staging for logopenic variant primary progressive aphasia.
in European journal of neurology
Harper L
(2016)
MRI visual rating scales in the diagnosis of dementia: evaluation in 184 post-mortem confirmed cases.
in Brain : a journal of neurology
Harper L
(2022)
Prenatal gyrification pattern affects age at onset in frontotemporal dementia.
in Cerebral cortex (New York, N.Y. : 1991)
Harrison IF
(2019)
Correction to: Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia.
in Acta neuropathologica communications
Harrison IF
(2019)
Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia.
in Acta neuropathologica communications
Heller C
(2020)
Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia.
in Journal of neurology, neurosurgery, and psychiatry
Heller C
(2020)
Plasma glial fibrillary acidic protein and neurofilament light chain are measures of disease severity in semantic variant primary progressive aphasia.
in Journal of neurology, neurosurgery, and psychiatry
Heywood WE
(2018)
CSF pro-orexin and amyloid-ß38 expression in Alzheimer's disease and frontotemporal dementia.
in Neurobiology of aging
Jabbari E
(2020)
Diagnosis Across the Spectrum of Progressive Supranuclear Palsy and Corticobasal Syndrome.
in JAMA neurology
Jimenez DA
(2020)
Altered phobic reactions in frontotemporal dementia: A behavioural and neuroanatomical analysis.
in Cortex; a journal devoted to the study of the nervous system and behavior
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
Jiskoot LC
(2023)
Addition of the FTD Module to the Neuropsychiatric Inventory improves classification of frontotemporal dementia spectrum disorders.
in Journal of neurology
Jiskoot LC
(2018)
Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study.
in Annals of clinical and translational neurology
Kancheva I
(2024)
Cerebrovascular reactivity impairment in genetic frontotemporal dementia
Kenny J
(2017)
A novel prion protein variant in a patient with semantic dementia.
in Journal of neurology, neurosurgery, and psychiatry
Keshavan A
(2022)
CSF biomarkers for dementia.
in Practical neurology
Koriath C
(2018)
Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series
in Molecular Psychiatry
Koriath C
(2019)
ApoE4 lowers age at onset in patients with frontotemporal dementia and tauopathy independent of amyloid-ß copathology.
in Alzheimer's & dementia (Amsterdam, Netherlands)
Koriath CA
(2017)
The clinical, neuroanatomical, and neuropathologic phenotype of TBK1-associated frontotemporal dementia: A longitudinal case report.
in Alzheimer's & dementia (Amsterdam, Netherlands)
Koriath CAM
(2021)
Genetic testing in dementia - utility and clinical strategies.
in Nature reviews. Neurology
Kuhle J
(2016)
Comment: "If you can't measure it, you can't improve it" (Lord Kelvin).
in Neurology
Lakshmanan R
(2017)
Redefining the phenotype of ALSP and AARS2 mutation-related leukodystrophy.
in Neurology. Genetics
Lamb R
(2019)
A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders.
in Cold Spring Harbor molecular case studies
Lashley T
(2015)
Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations.
in Neuropathology and applied neurobiology
Lashley T
(2018)
Molecular biomarkers of Alzheimer's disease: progress and prospects.
in Disease models & mechanisms
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
| 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 | Novel fluid biomarkers of progranulin-associated FTD |
| Amount | $219,999 (USD) |
| Organisation | Bluefield Project |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 01/2019 |
| End | 12/2020 |
| Title | Additional file 1 of A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers: a GENFI study |
| Description | Additional file 1. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| URL | https://springernature.figshare.com/articles/dataset/Additional_file_1_of_A_panel_of_CSF_proteins_se... |
| Title | Additional file 1 of Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation |
| Description | Additional file 1: Supplementary Figure 1. Mean normalized protein expression values for the chemokines in controls and each of PPA groups in plasma. Significant differences with p values are shown on the graphs. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| URL | https://springernature.figshare.com/articles/dataset/Additional_file_1_of_Differential_chemokine_alt... |
| Title | Additional file 1 of Differential chemokine alteration in the variants of primary progressive aphasia-a role for neuroinflammation |
| Description | Additional file 1: Supplementary Figure 1. Mean normalized protein expression values for the chemokines in controls and each of PPA groups in plasma. Significant differences with p values are shown on the graphs. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2021 |
| Provided To Others? | Yes |
| URL | https://springernature.figshare.com/articles/dataset/Additional_file_1_of_Differential_chemokine_alt... |
| Title | GENFI XNAT database |
| Description | Database of biomarker data from the GENFI 1 and GENFI 2 projects (presymptomatic and early symptomatic genetic FTD). |
| Type Of Material | Database/Collection of data |
| Year Produced | 2014 |
| Provided To Others? | Yes |
| Impact | 30 current analyses ongoing across multiple centres within GENFI. |
| 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 | Annual FTD support group seminar 2016 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Seminar chaired by Jonathan Rohrer (supervisor) with talk by Elizabeth Gordon (PhD studentship) about her PhD work. |
| Year(s) Of Engagement Activity | 2016 |
| Description | British Science Festival |
| 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 young onset dementia and presymptomatic neurodegenerative disease highlighting the work of the GENFI project as part of the national British Science Festival - around 70 people attended with both a panel discussion and personal questions afterwards. |
| Year(s) Of Engagement Activity | 2015 |
| URL | https://thelittleboxoffice.com/bsa/event/view/26635 |
| Description | Contribution to online learning module about dementia (MOOC) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Videoed talk and written information provided for an online learning tool about dementia - highlighting my research and work on GENFI project. Over 10,000 people currently signed up for course (official start March 2016). |
| Year(s) Of Engagement Activity | 2016 |
| URL | https://www.futurelearn.com/courses/faces-of-dementia |
| Description | FTD support group meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | ~70 people attended, mainly carers but also professionals, to hear about the latest research, with a question and answer session afterwards including discussion of patient involvement in future study design. |
| Year(s) Of Engagement Activity | 2018 |
| 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 | Familial FTD support group |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Talk to around 100 people as part of the familial FTD support group annual day - discussion about GENFI and current research; questions and discussion about research from family members and those at risk of developing genetic FTD. |
| Year(s) Of Engagement Activity | 2015 |
| URL | https://www.ucl.ac.uk/drc/support-groups/fFTD-support-group |
| Description | Meet the researcher Youtube video |
| 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 | Video made to inform people about research at UCL - interview about work on FTD. |
| Year(s) Of Engagement Activity | 2014,2015,2016,2017 |
| URL | https://www.youtube.com/watch?v=8oMe4bgSHoY&feature=youtu.be |
| Description | Pint of Science 2019 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | 120 attendees at a Pint of Science event describing our research work - lots of questions and engagement in interactive activities from the audience. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://pintofscience.co.uk/event/speechless |
| 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 |
| Description | Pint of Science Festival |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Around 100 people attended an event as part of the national Pint of Science Festival - discussion regarding young onset dementias and the work we are doing to find biomarkers and an evidence base for clinical trials - lots of questions and discussion afterwards and personal feedback from audience regarding how much they learned about the area. |
| Year(s) Of Engagement Activity | 2015 |
| Description | Talk at FTD support group annual seminar 2017 |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Increased awareness of FTD research and the work we are doing to FTD support group consisting mainly of carers. |
| Year(s) Of Engagement Activity | 2017 |
| Description | Talk to event for UK magistrates |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Talk on frontotemporal dementia to a UK magistrates event to inform them about forensic nature of symptomatology of FTD and how our research is exploring this further - long discussion afterwards about how this might inform the work of magistrates, particularly in considering dementia as a underlying problem with people who have been involved in crimes and therefore may change their practice. |
| Year(s) Of Engagement Activity | 2015 |
| Description | The Science Museum - Science Lates - Dementia |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Organised and presented at a section of the Science Museum 'Science Lates' evening in April 2016. My section had 5 stands (manned by 10 of my team) each focused on different parts of clinical and imaging dementia research that represented our current research work, particularly focusing on young onset and genetic dementias. >4000 people attended the event. Many people said that their views and understanding about dementia changed as a result of visiting our section. |
| Year(s) Of Engagement Activity | 2016 |