[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-393839-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-393839-en":131},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","temporal-order-of-clinical-and-biomarker-changes-in-familial-frontotemporal-dementia","Temporal order of clinical and biomarker changes in familial frontotemporal dementia","","Familial frontotemporal dementia (f-FTD) presents a major obstacle for prevention trials because presymptomatic mutation carriers cannot have symptom onset accurately predicted. The study builds multimodal, genotype-specific progression models using longitudinal clinical/neuropsychological scores, regional brain volumes, and plasma neurofilament light chain (NfL) from 796 carriers and 412 controls. Temporal ordering of clinical and biomarker changes differs across C9orf72, GRN, and MAPT mutations. Simulations indicate atrophy and NfL are best endpoints for prevention trials, while clinical measures may fit early symptomatic studies. Global recruitment is likely required.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/temporal-order-of-clinical-and-biomarker-changes-in-familial-frontotemporal-dementia/393839/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/temporal-order-of-clinical-and-biomarker-changes-in-familial-frontotemporal-dementia/393839.png","ImageObject",300,407,{"name":42,"@type":43},"Aurelia","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-03","2026-09-26",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why is predicting symptom onset a hurdle for f-FTD prevention trials?","Question",{"text":63,"@type":64},"Unlike familial Alzheimer’s disease, presymptomatic f-FTD mutation carriers cannot be predicted accurately for symptom onset. This complicates identifying eligible participants and designing prevention studies.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What data were used to build the multimodal f-FTD progression models?",{"text":68,"@type":64},"The models used longitudinal clinical and neuropsychological scores, regional brain volumes, and plasma neurofilament light chain (NfL). Data came from 796 carriers and 412 noncarrier controls.",{"name":70,"@type":61,"acceptedAnswer":71},"Which endpoints performed best in prevention-trial simulations?",{"text":72,"@type":64},"Model-based simulations using patient selection indicated brain atrophy and NfL as the best endpoints. Clinical measures may be more suitable endpoints in early symptomatic trials.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},393839,1790702837,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":140,"language":141,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":12,"update_tm":145,"read_time":146,"preview_page_count":4},1099514068365,"https://ap-avatar.wpscdn.com/avatar/10000253d8d9f28188e?_k=1776742907772140068","Articles  \n[https://doi.org/10.1038/s41591-022-01942-9](https://doi.org/10.1038/s41591-022-01942-9)  \nTemporal order of clinical and biomarker changes in familial frontotemporal dementia  \nAdam M. Staffaroni 1 ✉, Melanie Quintana 2, Barbara Wendelberger 2, Hilary W. Heuer1, Lucy L. Russell 3, Yann Cobigo 1, Amy Wolf1, Sheng-Yang Matt Goh1, Leonard Petrucelli4, Tania F. Gendron 4, Carolin Heller 3, Annie L. Clark1, Jack Carson Taylor 1, Amy Wise1, Elise Ong1, Leah Forsberg5, Danielle Brushaber6, Julio C. Rojas1, Lawren VandeVrede 1, Peter Ljubenkov1, Joel Kramer1, Kaitlin B. Casaletto1, Brian Appleby7, Yvette Bordelon8, Hugo Botha 5, Bradford C. Dickerson9, Kimiko Domoto-Reilly 10, Julie A. Fields11,  \nTatiana Foroud 12, Ralitza Gavrilova5, Daniel Geschwind 8,13, Nupur Ghoshal 14, Jill Goldman15, Jonathon Graff-Radford5, Neill Graff-Radford16, Murray Grossman17, Matthew G. H. Hall1, Ging-Yuek Hsiung 18, Edward D. Huey15, David Irwin17, David T. Jones 5, Kejal Kantarci5, Daniel Kaufer19, David Knopman 5, Walter Kremers6, Argentina Lario Lago1, Maria I. Lapid 11, Irene Litvan 20, Diane Lucente9, Ian R. Mackenzie21, Mario F. Mendez 8, Carly Mester6,  \nBruce L. Miller1, Chiadi U. Onyike22, Rosa Rademakers 4,23,24, Vijay K. Ramanan 5,  \nEliana Marisa Ramos8, Meghana Rao5, Katya Rascovsky17, Katherine P. Rankin1, Erik D. Roberson 25, Rodolfo Savica5, M. Carmela Tartaglia 26, Sandra Weintraub27, Bonnie Wong9, David M. Cash 3, Arabella Bouzigues 3, Imogen J. Swift3, Georgia Peakman 3, Martina Bocchetta 3, Emily G. Todd3, Rhian S. Convery3, James B. Rowe 28, Barbara Borroni29, Daniela Galimberti 30,31, Pietro Tiraboschi32, Mario Masellis33, Elizabeth Finger34, John C. van Swieten35, Harro Seelaar 35, Lize C. Jiskoot35, Sandro Sorbi 36,37, Chris R. Butler38,39, Caroline Graff40,41, Alexander Gerhard 42,43,  \nTobias Langheinrich 42,44, Robert Laforce 45, Raquel Sanchez-Valle 46, Alexandre de Mendonça47, Fermin Moreno48,49, Matthis Synofzik50,51, Rik Vandenberghe52,53,54, Simon Ducharme55,56,  \nIsabelle Le Ber57,58,59, Johannes Levin60,61,62, Adrian Danek 60, Markus Otto63, Florence Pasquier 64,65,66, Isabel Santana67,68, John Kornak69, Bradley F. Boeve 5, Howard J. Rosen1, Jonathan D. Rohrer3, Adam. L. Boxer 1 ✉ and Frontotemporal Dementia Prevention Initiative (FPI) Investigators*  \nUnlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, includingthe selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.  \nFrontotemporal dementia (FTD), marked by impairments in  \nbehavior, language and sometimes motor function, is a common form of early-onset dementia1. Approximately 20–30% of FTD is caused by autosomal dominant mutations (familial, orf-FTD), usually in one of three genes: chromosome 9 open reading  \nframe 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT)2. FTD is uniformly fatal, and there are no approved therapies; however, a growing number of new treatments targeting C9orf72, GRN and MAPT are moving into clinica","cbCaiirIjp7IskWB","https://ap.wps.com/l/cbCaiirIjp7IskWB","pdf",19627278,26,"English","# Introduction\n## Background on FTD and familial forms\n## Treatment rationale and need for prevention trials\n## Challenges in designing f-FTD clinical trials\n# Methods and Models\n## Multimodal progression modeling\n## Endpoints and trial simulation approach\n# Results Overview\n## Genotype-specific temporal ordering\n## Endpoint performance across trial stages\n# Conclusion\n## Feasibility and recruitment considerations for prevention trials","[{\"question\":\"Why is predicting symptom onset a hurdle for f-FTD prevention trials?\",\"answer\":\"Unlike familial Alzheimer’s disease, presymptomatic f-FTD mutation carriers cannot be predicted accurately for symptom onset. This complicates identifying eligible participants and designing prevention studies.\"},{\"question\":\"What data were used to build the multimodal f-FTD progression models?\",\"answer\":\"The models used longitudinal clinical and neuropsychological scores, regional brain volumes, and plasma neurofilament light chain (NfL). Data came from 796 carriers and 412 noncarrier controls.\"},{\"question\":\"Which endpoints performed best in prevention-trial simulations?\",\"answer\":\"Model-based simulations using patient selection indicated brain atrophy and NfL as the best endpoints. Clinical measures may be more suitable endpoints in early symptomatic trials.\"}]","Temporal order of clinical and biomarker changes in familial frontotemporal dementia | PDF",1790394326,66]