Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Staffaroni, Adam M.; Quintana, Melanie; Wendelberger, Barbara; Heuer, Hilary W.; Russell, Lucy L.; Cobigo, Yann; Wolf, Amy; Goh, Sheng-Yang M.; Petrucelli, Leonard; Gendron, Tania F.; Heller, Carolin; Clark, Annie L; Wise, Amy B; Ong, Elise; Forsberg, Leah K.; Brushaber, Danielle; Rojas, Julio C.; VandeVrede, Lawren; Ljubenkov, Peter A.; Kramer, Joel H.; Casaletto, Kaitlin B.; Appleby, Brian S.; Bordelon, Yvette; Botha, Hugo; Dickerson, Bradford C.; Domoto‐Reilly, Kimiko; Fields, Julie A.; Foroud, Tatiana; Gavrilova, Ralitza H.; Geschwind, Daniel H.; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathon; Graff‐Radford, Neill R.; Grossman, Murray; Hall, Matthew; Hsiung, Ging-Yuek Robin; Huey, Edward D.; Irwin, David J.; Jones, David T.; Kantarci, Kejal; Kaufer, Daniel I.; Knopman, David S.; Kremers, Walter K.; Lago, Argentina Lario; Litvan, Irene; Lucente, Diane; Mackenzie, Ian R.; Mester, Carly T.; Miller, Bruce L.; Ramos, Eliana Marisa; Rao, Meghana; Rascovsky, Katya; Rankin, Katherine P.; Roberson, Erik D.; Savica, Rodolfo; Tartaglia, Carmela; Wong, Bonnie; Cash, David M.; Bouzigues, Arabella; Swift, Imogen J.; Peakman, Georgia; Bocchetta, Martina; Todd, Emily; Convery, Rhian S.; Rowe, James B.; Borroni, Barbara; Galimberti, Daniela; Tiraboschi, Pietro; Masellis, Mario; Finger, Elizabeth; Swieten, John C. van; Seelaar, Harro; Jiskoot, Lize C.; Sorbi, Sandro; Butler, Chris; Graff, Caroline; Gerhard, Alexander; Langheinrich, Tobias; Laforce, Robert; Sánchez‐Valle, Raquel; Mendonça, Alexandre de; Moreno, Fermín; Synofzik, Matthis; Vandenberghe, Rik; Ducharme, Simon; Ber, Isabelle Le; Levin, Johannes; Danek, Adrian; Otto, Markus; Pasquier, Florence; Santana, Isabel; Kornak, John; Rosen, Howard J.; Rohrer, Jonathan D.; Apostolova, Liana G.; Barmada, Sami; Boeve, Bradley F.; Boxer, Adam L.; Bozoki, Andrea; Clark, David G.; Coppola, Giovanni; Darby, R. Ryan; Dickson, Dennis W.; Faber, Kelley; Fagan, Anne M.; Galasko, Douglas; Grant, Ian; Huang, Eric J.; Kerwin, Diana; Lapid, Maria I.; Lee, Suzee; Léger, Gabriel C.; Masdeux, Joseph C.; McGinnis, Scott; Mendez, Mario F.; Onyike, Chiadi U.; Pascual, María Belén; Pressman, Peter; Rademakers, Rosa; Ramanan, Vijay K.; Ritter, Aaron; Seeley, William W.; Syrjanen, Jeremy; Taylor, Jack C; Weıntraub, Sandra; Sogorb‐Esteve, Aitana; Nelson, Annabel; Greaves, Caroline; Thomas, David L.; Benotmane, Hanya; Zetterberg, Henrik; Nicholas, Jennifer M.; Samra, Kiran; Shafei, Rachelle; Timberlake, Carolyn; Cope, Thomas; Rittman, Timothy; Benussi, Alberto; Premi, Enrico; Gasparotti, Roberto; Archetti, Silvana; Gazzina, Stefano; Cantoni, Valentina; Arighi, Andrea; Fenoglio, Chiara; Scarpini, Elio; Fumagalli, Giorgio; Borracci, Vittoria; Rossi, Giacomina; Giaccone, Giorgio; Fede, Giuseppe Di; Caroppo, Paola; Prioni, Sara; Redaelli, Veronica; Tang‐Wai, David F.; Rogaeva, Ekaterina; Castelo‐Branco, Miguel; Freedman, Morris; Keren, Ron; Black, Sandra E.; Mitchell, Sara; Shoesmith, Christen; Bartha, Robart; Poos, Jackie M.; Papma, Janne M.; Giannini, Lucia; Minkelen, Rick van; Pijnenburg, Yolande A.L.; Nacmias, Benedetta; Ferrari, Camilla; Polito, Cristina; Lombardi, Gemma; Bessi, Valentina; Veldsman, Michele; Andersson, Christin; Thonberg, Håkan; Öijerstedt, Linn; Jelić, Vesna; Thompson, Paul M.; Lladó, Albert; Antonell, Anna; Olives, Jaume; Balasa, Mircea; Bargalló, Núria; Borrego‐Écija, Sergi; Verdelho, Ana; Maruta, Carolina; Ferreira, Catarina; Miltenberger, Gabriel; Couto, Frederico Simões do; Gabilondo, Alazne; Gorostidi, Ana; Villanúa, Jorge; Cañada, Marta; Tainta, Mikel; Zulaica, Miren; Barandiarán, Myriam; Alves, Patricia; Bender, Benjamín; Wilke, Carlo; Graf, Lisa; Vogels, Annick; Vandenbulcke, Mathieu; Damme, Philip Van; Bruffaerts, Rose; Poesen, Koen; Rosa‐Neto, Pedro; Gauthier, Serge; Camuzat, Agnès; Brice, Alexis; Bertrand, Anne; Funkiewiez, Aurélie; Rinaldi, Daisy; Saracino, Dario; Colliot, Olivier; Sayah, Sabrina; Prix, Catharina; Wlasich, Elisabeth; Wagemann, Olivia; Loosli, Sandra; Schönecker, Sonja; Hoegen, Tobias; Lombardi, Jolina; Anderl‐Straub, Sarah; Rollin, Adeline; Kuchcinski, Grégory; Bertoux, Maxime; Lebouvier, Thibaud; Deramecourt, Vincent; Santiago, Beatriz; Duro, Diana; Leitão, Maria João; Almeida, Maria Rosário; Tábuas‐Pereira, Miguel; Afonso, Sónia

doi:10.1038/s41591-022-01942-9

Cited by 55 publications

(38 citation statements)

References 63 publications

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“…Recent estimates suggest that f‐FTD clinical trials will require global recruitment to achieve sufficient power. 11 Decentralized trials may be necessary to overcome recruitment barriers and will require new tools to enable remote data collection.…”

Section: Introductionmentioning

confidence: 99%

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research

Taylor

Heuer

Clark

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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Introduction Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD‐mApp). Methods A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC‐FTLD = 0 [ N = 101]; prodromal: 0.5 [ N = 49]; symptomatic ≥1 [ N = 51]; not measured [ N = 13]) were asked to complete ALLFTD‐mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys. Results It was feasible for participants to complete the ALLFTD‐mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered the time commitment acceptable (98% of respondents). Greater disease severity was associated with poorer performance across several tests. Discussion These findings suggest that the ALLFTD‐mApp study protocol is feasible and acceptable for remote FTD research. HIGHLIGHTS The ALLFTD Mobile App is a smartphone‐based platform for remote, self‐administered data collection. The ALLFTD Mobile App consists of a comprehensive battery of surveys and tests of executive functioning, memory, speech and language, and motor abilities. Remote digital data collection using the ALLFTD Mobile App was feasible in a multicenter research consortium that studies FTD. Data was collected in healthy controls and participants with a range of diagnoses, particularly FTD spectrum disorders. Remote digital data collection was well accepted by participants with a variety of diagnoses.

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Section: Introductionmentioning

confidence: 99%

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research

Taylor

Heuer

Clark

et al. 2023

Alz & Dem Diag Ass & Dis Mo

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“…Data from progranulindeficient mouse models indicates that progranulin-boosting therapeutics can correct behavioral, biochemical, and neuropathological abnormalities even after onset, but initiating treatment after symptoms emerge would be limited by the fact that FTD-GRN progresses rapidly once it becomes symptomatic. In disease progression models, FTD-GRN had the fastest decline among the three major genetic etiologies of FTD [151]. The ideal timeframe for treatment initiation is probably a few years before symptom onset, and identifying patients at this stage will likely be enabled by plasma biomarkers.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

2023

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Heterozygous loss-of-function mutations in progranulin (GRN) cause frontotemporal dementia (FTD), a leading cause of early-onset dementia characterized clinically by behavioral, social, and language deficits. There are currently no FDA-approved therapeutics for FTD-GRN, but this has been an active area of investigation, and several approaches are now in clinical trials. Here, we review preclinical development of therapies for FTD-GRN with a focus on testing in mouse models. Since most FTD-GRN-associated mutations cause progranulin haploinsufficiency, these approaches focus on raising progranulin levels. We begin by considering the disorders associated with altered progranulin levels, and then review the basics of progranulin biology including its lysosomal, neurotrophic, and immunomodulatory functions. We discuss mouse models of progranulin insufficiency and how they have been used in preclinical studies on a variety of therapeutic approaches. These include approaches to raise progranulin expression from the normal allele or facilitate progranulin production by the mutant allele, as well as approaches to directly increase progranulin levels by delivery across the blood–brain barrier or by gene therapy. Several of these approaches have entered clinical trials, providing hope that new therapies for FTD-GRN may be the next frontier in the treatment of neurodegenerative disease.

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“…Direct comparisons of these groups across the whole genetic FTD spectrum may, however, be limited because of considerable gene-related heterogeneity. 11,12,17,18 Variability in NfL longitudinal trajectories in individuals who convert appears related to the variant-carrying gene and partly to the clinical course. We found different trajectories of NfL levels in FTD genetic groups, characterized by a steep rapid increase after conversion in C9orf72, a steady increase in GRN, and a gradual increase followed by a plateau in MAPT, in line with previous research showing different NfL trajectories between genetic groups.…”

Section: Discussionmentioning

confidence: 99%

“…12 This time window is, however, too broad for clinical trials because these aim to recruit participants in closer proximity of symptom onset. Another large recent study found genotype-specific trajectories of biomarkers changes, including NfL, relative to estimated prodromal onset, 18 yet it had limited resolution on the clinical implications of these changes, such as their predictive and diagnostic value for the prodromal stage in the individual patient.…”

Section: Introductionmentioning

confidence: 99%

Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia

et al. 2023

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Background and Objectives:Elevated serum neurofilament light chain (NfL) is used to identify carriers of genetic frontotemporal dementia (FTD) pathogenic variants approaching prodromal conversion. Yet, the magnitude and timeline of NfL increase are still unclear. Here, we investigated the predictive and early diagnostic value of longitudinal serum NfL for the prodromal conversion in genetic FTD.Methods:In a longitudinal observational cohort study of genetic FTD pathogenic variant carriers, we examined the diagnostic accuracy and conversion risk associated with cross-sectional and longitudinal NfL. Time periods relative to prodromal conversion (>3, 3-1.5, 1.5-0 years before; 0-1.5 years after) were compared to values of participants who did not convert. Next, we modeled longitudinal NfL and MRI volume trajectories to determine their timeline.Results:We included 21 participants who converted (5C9orf72, 10GRN, 5MAPT, 1TARDBP) and 61 who did not (20C9orf72, 30GRN, 11MAPT). Participants who converted had higher NfL levels at all examined time periods before prodromal conversion (median values 14.0-18.2 pg/mL; betas=0.4-0.7, standard error [SE]=0.1, p<0.046) than those who did not (6.5 pg/mL), and showed further increase 0-1.5 years after conversion (28.4 pg/mL; beta=1.0, SE=0.1, p<0.001). Annualized longitudinal NfL change was only significantly higher in participants who converted (vs. participants who did not) 0-1.5 years after conversion (beta=1.2, SE=0.3, p=0.001). Diagnostic accuracy of cross-sectional NfL for prodromal conversion (vs. non-conversion) was good-to-excellent at time periods before conversion (AUC range: 0.72-0.92), improved 0-1.5 years after conversion (0.94-0.97), and outperformed annualized longitudinal change (0.76-0.84). NfL increase in participants who converted occurred earlier than frontotemporal MRI volume change, and differed by genetic group and clinical phenotypes. Higher NfL corresponded to increased conversion risk (hazard ratio: cross-sectional=6.7 [95%CI 3.3-13.7]; longitudinal=13.0 [95%CI 4.0-42.8]; p<0.001), but conversion-free follow-up time varied greatly across participants.Discussion:NfL increase discriminates individuals who convert to prodromal FTD from those who do not, preceding significant frontotemporal MRI volume loss. However, NfL alone is limited in predicting the exact timing of prodromal conversion. NfL levels also vary depending on underlying variant-carrying genes and clinical phenotypes. These findings help to guide participant recruitment for clinical trials targeting prodromal genetic FTD.

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Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Cited by 55 publications

References 63 publications

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research

Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations

Clinical Value of Longitudinal Serum Neurofilament Light Chain in Prodromal Genetic Frontotemporal Dementia

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