Summary: Researchers used neuroimaging and fluid biomarkers from people with the familial form of frontotemporal dementia (f-FTD) to build models of clinical and biomarker progression. These models reveal the likely temporal sequence of brain, fluid, and cognitive changes that occur before symptom onset and help define practical endpoints and enrollment strategies for prevention and early-treatment clinical trials.
Source: UCSF
Frontotemporal dementia (FTD) is a leading cause of early-onset dementia, producing changes in behavior, language, and sometimes motor function. Predicting when symptoms will begin in people who carry familial FTD gene mutations has been difficult, creating a major obstacle to designing prevention trials for this disorder.
Although familial FTD (f-FTD) is rare, the genes responsible overlap with those implicated in more common neurodegenerative diseases such as Alzheimer’s disease and amyotrophic lateral sclerosis. That overlap means discoveries in f-FTD biomarkers and therapies can have broader implications for neurodegenerative disease research and drug development.
Using biomarkers to reduce clinical trial size and improve trial design
In a large, harmonized analysis published in Nature Medicine, investigators at the University of California, San Francisco combined clinical, neuroimaging, and fluid biomarker data from nearly all available familial FTD research cohorts in North America and Europe. The study pooled data from more than 1,000 members of f-FTD families, drawing on the ALLFTD consortium in North America and GENFI in Europe to construct multimodal disease-progression models.
These models incorporated longitudinal clinical and neuropsychological assessments, regional brain-volume measurements from MRI, and plasma neurofilament light chain (NfL) levels. By comparing 796 mutation carriers with 412 noncarrier controls, the team mapped how biomarker and clinical changes unfold as carriers transition from asymptomatic to symptomatic stages.
The analysis showed that measurable brain atrophy and elevations in plasma NfL can appear years before clinical symptoms. Importantly, the sequence and timing of these changes differed across genotypes: C9orf72, GRN, and MAPT mutation carriers displayed distinct patterns of biomarker progression and clinical decline. This genotype-specific ordering has direct consequences for selecting trial endpoints and for identifying the right participants for prevention versus early treatment trials.
Clinical trial simulations based on the models indicated that using biomarker-informed inclusion criteria can substantially reduce the number of participants needed to detect a treatment effect. In prevention-trial simulations, regional brain atrophy and plasma NfL performed best as primary endpoints, while cognitive and behavioral clinical measures were better suited as endpoints for trials in early symptomatic individuals.
These findings provide a practical roadmap for trial designers: combining neuroimaging and fluid biomarkers for participant selection and endpoint choice can increase statistical power and make f-FTD prevention trials more feasible. The authors emphasize that global recruitment will be necessary to achieve sufficient sample sizes for robust prevention trials.
Implications for accelerating treatments
By clarifying which biomarkers change first and how those changes vary by gene, the models give clinicians and trialists tools to predict if and when a presymptomatic carrier is likely to develop behavioral or cognitive symptoms. That predictive ability can focus enrollment on those most at risk of short-term progression, improving the efficiency of trials testing therapies aimed at delaying or preventing symptom onset.
Investigators note that these multimodal progression models will help determine optimal endpoints and enrollment criteria, support planning of international prevention and early-treatment trials, and guide development of new biomarkers that further increase trial sensitivity.
About this dementia research news
Author: Press Office
Source: UCSF
Contact: Press Office – UCSF
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Original Research: Closed access. “Temporal order of clinical and biomarker changes in familial frontotemporal dementia” by Adam M. Staffaroni et al., Nature Medicine.
Abstract
Temporal order of clinical and biomarker changes in familial frontotemporal dementia
Accurately forecasting symptom onset in presymptomatic familial FTD mutation carriers has been a central challenge that limits disease prevention trials. To address this, the researchers developed multimodal progression models for C9orf72, GRN, and MAPT mutation carriers using longitudinal clinical and neuropsychological scores, regional MRI brain volumes, and plasma neurofilament light chain (NfL) levels from 796 carriers and 412 noncarrier controls.
The models revealed genotype-specific temporal orderings of biomarker and clinical changes. In simulated prevention trials that applied model-based participant selection, MRI-measured atrophy and plasma NfL proved to be the most powerful endpoints. For early symptomatic trials, clinical measures remain important candidate endpoints. The work concludes that prevention trials for f-FTD are feasible but will likely require coordinated global recruitment and carefully chosen biomarker-informed enrollment criteria to maximize power to detect treatment effects.