FPI Collaborative Projects
Clinical studies and drug development efforts in rare diseases, such as the genetic forms of FTD, require a compilation of tools that can be utilized by the academic and industry communities. Consortia within the FPI are combining forces to execute research projects to provide the knowledge and understanding required for successful clinical assessments and drug development in genetic FTD. Former and current collaborations are primarily focused on:
- Early disease detection
- Understanding disease progression
- Enhancing data capture, resolution, and interpretation
Unless otherwise noted, the following projects describe collaborations between the ALLFTD and GENFI consortia. Information is current as of June, 2024.
Ongoing Collaborations
Modeling disease progression
FPI researchers have developed disease progression models that characterize the temporal ordering of clinical and biomarker changes in the genetic forms of FTD. These models can be used to facilitate clinical trial development by supporting endpoint selection, analyses of treatment effects, and identification of optimal trial enrollment criteria. Current disease progression models indicate unique progression characteristics between the FTD mutation groups. Model-based simulations of clinical trials suggest that clinical studies in genetic FTD will require global recruitment efforts. Ongoing work in this area is focused on incorporating additional biomarkers, genetic information, and expanding the models to include data from other areas of the world to ensure their generalizability.
Relevant publication:
Modeling disease conversion
Early treatment intervention will likely provide the greatest therapeutic benefit for FTD mutation carriers at risk of developing disease. In order to predict patient conversion to disease, FPI researchers are applying statistical models to structural MRI images that have been collected from early-stage FTD mutation carriers. This approach aims to identify the brain regions most vulnerable to degeneration throughout the course of disease progression, and allows for the creation of personalized neurodegeneration maps for each patient. Once these maps are established, FPI researchers will determine their utility to predict FTD symptom onset in patients that have converted from asymptomatic to symptomatic over the course of their research study participation.
Developing digital assessment tools
Digital assessments can provide significant advantages for FTD drug development efforts by enabling at-home or in-clinic data collection that is more precise, inclusive, comprehensive, and patient-centered. Two remote digital assessment tools have been independently developed and utilized by the GENFI and ALLFTD consortia (Ignite and ALLFTD Mobile App, respectively). FPI researchers are now working together to validate these digital tools across consortia, focusing on assessments useful for FTD diagnosis and disease progression monitoring. Efforts are also underway to expand the capabilities of these assessment tools to include daily activity and sleep monitoring.
Relevant publications:
https://bmjopen.bmj.com/content/12/8/e055211
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2816782
Examining speech and language
Speech and language changes are common symptoms observed across various FTD clinical subtypes and genetic forms. FPI researchers have developed tools to successfully identify speech and language impairments in FTD patients; however, the utility of these measures as potential biomarkers remains unexplored. As a first step, FPI investigators plan to analyze patient’s speech samples to extract metrics that might be useful for early disease detection or clinical trial monitoring.
Determining family relatedness
Understanding patient relatedness allows for improved clinical study design, statistical analysis, and data interpretation for studies utilizing FPI participant data. The genetic forms of FTD may exhibit founder effects, increasing the probability that patients within and among FPI consortia are closely and distantly related. Thus, FPI researchers are using patient genotyping data to identify otherwise unknown relatives who were recruited across FPI study sites.
Past Collaborations
Understanding disease onset and duration
FPI researchers assessed disease age-at-onset, age-at-death, and duration using historic data from over 3,400 genetic FTD patients world-wide. Data from this study suggested that these parameters are influenced by genetic group. Furthermore, the predictive utility of parent and average family data varied across the different FTD genetic groups. Work to identify genetic and environmental factors that modify disease onset and duration is warranted and remains of interest to the FPI. This inaugural study is the first publication to include patient clinical data from multiple FPI consortia.
Relevant publication:
Examining plasma neurofilament light
Neurofilament light chain (NfL) is a protein that is increased in the plasma of individuals suffering from FTD and other neurodegenerative disorders. In this study, FPI researchers used two independent cohorts to investigate the prognostic utility of plasma NfL levels in genetic FTD. The data demonstrated that increased plasma NfL levels were predictive of disease progression within 2 years, even in those mutation carriers who were asymptomatic at the time of NfL measurement. This seminal paper provided strong rationale for the use of NfL as an enrollment criterion or potential endpoint in treatment trials enrolling asymptomatic FTD mutation carriers.
Relevant publication: