Defining measures of proximity to symptom onset in GENetic Frontotemporal dementia Initiative

Frontotemporal dementia (FTD) is a neurodegenerative disorder commonly caused by genetic 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 assessment of people who carry genetic mutations, including people who are both presymptomatic and symptomatic. 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 biomarkers for future trials. 

Goal

The aim of this study is 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 near to symptom onset, and ii) measurement of disease progression during that period. Also an aim of JPND GENFI-PROX was to demonstrate the earliest changes in the disease process of hereditary FTD using different modalities of neuropsychological examination, blood, CSF and MRI examination.

Approach

The project 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. 

Results

The project has provided insight into the role of neuroinflammatory biomarkers in (hereditary) FTD. This can contribute to the design of therapeutic trials. And ties in with a global initiative to validate these biomarkers within the FTD Prevention Initiative (FPI). A a neuropsychological composite score GENFI-COG has been developed in collaboration with UCL, which could become a very important measure in trials. Also an app has been developed; the IGNITE app (including a Dutch version). This is a user-friendly way to quickly and remotely monitor participants for research, but also for future trials.
Blood biomarkers have been identified that generate knowledge to both understand the disease and predict the onset of the disease. Because we will continue to predict disease better, this will also be used for possible patient selection for clinical trials. Indications for complement activation have been found in both blood and cerebrospinal fluid in both the presymptomatic and symptomatic phases of the disease. This suggests that neuroinflammation plays a role in (genetic) FTD.

Products

• Article'Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia'
• Download the IGNITE App - cognitive assessment tool
• GENFI – The Genetic Frontotemporal Initiative