Newswise – Frontotemporal dementia (FTD), a common form of early-onset dementia, is characterized by impairments in behavior, language, and sometimes motor function. Unlike Alzheimer’s disease (AD), researchers and clinicians have not been able to accurately predict the onset of symptoms in people with a familial form of the disease.
While the development of therapies targeting the familial forms of frontotemporal lobe dementia (f-FTD) has increased significantly, there is an urgent unmet need to organize clinical trials to test these therapies given the small number of participants with mutations and the lack of experience with trial therapies in presymptomatic f-FTD mutation carriers.
Although f-FTD is rare, the genes that cause this disease are also heavily implicated in more common neurological diseases such as Alzheimer’s and amyotrophic lateral sclerosis, suggesting that identifying effective f-FTD treatments will accelerate the development of treatments for more common diseases could .
Using biomarkers to reduce the required sample size
In a study published in naturopathy On September 22, 2022, University of California San Francisco researchers Adam Staffaroni, PhD, and Adam Boxer, MD, PhD, combined and harmonized clinical, neuroimaging, and fluid biomarkers from nearly all participants in family FTD clinical research in North America and Europe. Using this data, they developed clinical and biomarker dynamics models to determine the timing of biomarkers and clinical changes in f-FTD before disease progression begins.
Using a sample of over 1,000 members of FTD familial relationships (using data from the comprehensive NIH-funded ALLFTD study in North America and the GENFI study in Europe), they found that brain atrophy and plasma NfL elevations occurred years before the onset of the Symptoms were measurable, paving the way for the use of these biomarkers in clinical trials of therapeutics that could prevent or delay symptoms of f-FTD.
“The models provide a roadmap for the development of new biomarkers and clinical endpoints that may improve the ability to detect treatment effects in presymptomatic disease states,” said Boxer, endowed professor of memory and aging in the Department of Neurology at the Weill Institute of UCSF Neuroscience. “We performed clinical trial simulations to estimate sample sizes for f-FTD clinical trial design, and we found that using combinations of clinical and biomarker data as inclusion criteria can reduce the sample size needed to demonstrate treatment effects said Staffaroni, an assistant professor of neurology at UCSF.
By using multimodal models of f-FTD disease progression that included clinical and neuropsychological longitudinal scores, regional brain volumes, and plasma neurofilament light chains (NfL) in 796 carriers and 412 non-carrier controls, the researchers found that the temporal Order of clinical and biomarker changes differed in C9orf72, GREENand MAP Mutation carriers as individuals who progressed from asymptomatic to symptomatic disease.
Accelerate new treatments
“These results show for the first time that there are clear changes in certain biomarkers that can help clinicians predict if and when a person born with an FTD gene variant will experience 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 accelerate the development of new treatments for this devastating disease.”
Using these models, they were able to estimate clinical trial eligibility criteria and sample size for clinical trials aimed at preventing disease in asymptomatic mutation carriers or treating disease in people who are already mildly affected
In simulations of prevention studies with model-based patient selection, atrophy and NfL were the best study endpoints, whereas clinical measures were potential endpoints in early symptomatic studies.
“These disease progression models will facilitate the planning of f-FTD clinical trials,” said Boxer. “We believe our study underscores the importance of identifying eligible study participants outside of Europe and North America in order to maximize our ability to identify new effective therapies.”
To meet the need for participants in f-FTD clinical research, a global collaboration called the FTD Prevention Initiative was led by Boxer and Professor Jonathan Rohrer at University College London to bring together FTD genetic cohorts from across Europe, North America, South America and Australasia and Asia.
Authors: Adam M Staffaroni PhD, Melanie Quintana PhD, Barbara Wendelberger PhD, Hilary W Heuer PhD, Lucy L Russell PhD, Yann Cobigo PhD, Amy Wolf MS, Sheng-Yang Matt Goh MS, Leonard Petrucelli PhD, Tania F Gendron PhD , Carolin Heller BSc, Annie L. Clark MS, Jack Carson Taylor MS, Amy Wise BA, Elise Ong BS, Leah Forsberg PhD, Danielle Brushaber BS, Julio C. Rojas MD PhD, Lawren VandeVrede MD PhD, Peter Ljubenkov MD, Joel Kramer PsyD, Kaitlin B Casaletto PhD, Brian Appleby MD, Yvette Bordelon MD PhD, Hugo Botha MD, Bradford C Dickerson MD, Kimiko Domoto-Reilly MD, Julie A Fields PhD, Tatiana Foroud PhD, Ralitza Gavrilova MD, Daniel Geschwind MD PhD, Nupur Ghoshal MD PhD, Jill Goldman MS MPhil, Jonathon Graff-Radford MD, Neill Graff-Radford MD, Murray Grossman MD EdD, Matthew GH Hall MS, Ging-Yuek Hsiung MD MHSc, Edward D. Huey MD, David Irwin MD , MD David T. Jones, MD Kejal Kantarci, MD Daniel Kaufer, MD David Knopman, PhD Walter Kremers, PhD Argentina Lario Lago, MD Maria I. Lapid, Ir ene Litvan MD, Diane Lucente MS, Ian R Mackenzie MD, Mario F Mendez MD PhD, Carly Mester BA, Bruce L Miller MD, Chiadi U Onyike MD, Rosa Rademakers PhD, Vijay K Ramanan MD PhD, Eliana Marisa Ramos PhD, Meghana Rao MPH, Katya Rascovsky PhD, Katherine P Rankin PhD, Erik D Roberson MD PhD, Rodolfo Savica MD PhD, M Carmela Tartaglia MD, Sandra Weintraub PhD, Bonnie Wong PhD, David M Cash PhD, Arabella Bouzigues MSc , Imogen J Swift MSc, Georgia Peakman MSc, Martina Bocchetta PhD, Emily G Todd MRes, Rhian S Convery MSc, James B Rowe PhD, Barbara Borroni MD, Daniela Galimberti PhD, Pietro Tiraboschi MD, Mario Masellis MD PhD, Elizabeth Finger MD, John C. van Swieten MD PhD, Harro Seelaar MD PhD, Lize C. Jiskoot PhD, Sandro Sorbi MD PhD, Chris R. Butler PhD, Caroline Graff PhD RN, Alexander Gerhard MD, Tobias Langheinrich MD, Robert Laforce MD PhD , Raquel Sanchez-Valle MD PhD, Alexandre de Mendonça MD PhD, Fermin Moreno MD, Matthis Synofzik MD, Rik Vandenberghe MD, Simon Ducharme MD, Is Abelle Le Ber MD PhD, Johannes Levin MD, Adrian Danek MD, Markus Otto MD, Florence Pasquier MD PhD, Isabel Santana MD PhD, John Kornak PhD, Bradley F. Boeve MD, Howard J. Rosen MD, Jonathan D. Rohrer FRCP PhD, Adam. L. Boxer MD PhD and Frontotemporal Dementia Prevention 35 Initiative (FPI) investigator*
Financing: Data collection and dissemination of the data presented in this manuscript was funded by the ALLFTD Consortium (U19: AG063911 funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke) and the former ARTFL & LEFFTDS Consortia (ARTFL: U54 NS092089 by the National Institute of Neurological Diseases and Stroke and the National Center for Advancing Translational Sciences; LEFFTDS: U01 AG045390, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke).
This work is also supported by the Association for Frontotemporal Degeneration (including the FTD Biomarkers Initiative), the Bluefield Project to Cure FTD, and the Larry L. Hillblom Foundation [2018-A-025-FEL (AMS)]the National Institutes of Health [AG038791 (ALB), AG032306 (HJR), AG016976 (WAK), AG062677 (RCP), AG019724 (BLM), AG058233 559 (SEL), AG072122 (WAK), P30 AG062422 (BLM), K12 HD001459 (NG), K23AG061253 (AMS), AG062422 (RCP), K24AG045333 (HJR)], and the Rainwater Charitable Foundation. Samples from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD), which receives government support under a collaborative agreement [U24 AG021886 (TF)] awarded by the National Institute on Aging (NIA), were used in this study.
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