University of California San Francisco researchers combined and harmonized clinical, neuroimaging, and fluid biomarkers to develop models of clinical and biomarker dynamics and determine the temporal sequence of biomarker and clinical changes in frontotemporal lobe dementia (f-FTD) before disease progression begins.
Adam Staffaroni, PhD, and Adam Boxer, MD, PhD, used a sample of over 1,000 members of familial FTD kindreds (with data from the comprehensive NIH-funded ALLFTD study in North America and GENFI study in Europe). They found that brain atrophy and plasma NfL elevations were measurable years prior to the onset of symptoms, paving the way for the use of these biomarkers in clinical trials of therapeutics that could prevent or delay symptoms of f-FTD. Their research was published in Nature Medicine.
Although f-FTD is rare, the genes that cause this disease are also strongly implicated in more common neurological disorders such as Alzheimer’s Disease and Amyotrophic Lateral Sclerosis, suggesting that identification of effective f-FTD treatments could speed the development of treatments for more common diseases.
“The models provide a roadmap for development of new biomarkers and clinical endpoints that may improve power to detect treatment effects in pre-symptomatic stages of disease,” said Dr Boxer, endowed professor in memory and aging in the department of neurology at UCSF’s Weill Institute of Neurosciences. “We conducted clinical trial simulations to estimate sample sizes for planning f-FTD clinical trials, and we found that using combinations of clinical and biomarker data as inclusion criteria can reduce the sample size required to detect treatment effects,” said Staffaroni, an assistant professor of neurology at UCSF.
By using multimodal models for f-FTD disease progression that included longitudinal clinical and neuropsychological scores, regional brain volumes, and plasma neurofilament light chain (NfL) in 796 carriers and 412 non-carrier controls, the researchers found that the temporal ordering of clinical and biomarker changes differed in C9orf72, GRN, and MAPT mutation carriers as individuals transitioned from asymptomatic to symptomatic disease.
“These results show for the first time that there are distinct changes in certain biomarkers which may help clinicians predict if and when a person who is born with an FTD gene variant will start experiencing the behavioral and cognitive problems associated with the disease,” said John K Hsiao, MD, program director at the NIH’s National Institute on Aging. “The results could speed the development of new treatments for this devastating disorder.”
Using these models, they were able to estimate clinical trial enrollment criteria and sample sizes for clinical trials to prevent disease in asymptomatic mutation carriers or to treat disease in people who are already mildly affected
In prevention-trial simulations employing model-based patient selection, atrophy and NfL were the best study endpoints, whereas clinical measures were potential endpoints in early-symptomatic trials.
“These disease progression models will facilitate the planning of f-FTD clinical trials,” said Dr Boxer. “We believe our study highlights the importance of identifying eligible trial participants outside of Europe and North America to maximize our ability to identify new effective therapies.”Back To Top
Study Uses Biomarker Data to Better Predict Frontotemporal Lobe Dementia. Appl Radiol.