FPI Collaborative Projects

FPI researchers have developed disease progression models that characterize the temporal ordering of clinical and biomarker changes in the genetic forms of FTD. These models can be used to facilitate clinical trial development by supporting endpoint selection, analyses of treatment effects, and identification of optimal trial enrollment criteria. Current disease progression models indicate unique progression characteristics between the FTD mutation groups. Model-based simulations of clinical trials suggest that clinical studies in genetic FTD will require global recruitment efforts. Ongoing work in this area is focused on incorporating additional biomarkers, genetic information, and expanding the models to include data from other areas of the world to ensure their generalizability.

Relevant publication:

• Temporal order of clinical and biomarker changes in familial frontotemporal dementia
  • Staffaroni AM, Quintana M, Wendelberger B, Heuer HW, Russell LL, Cobigo Y, Wolf A, Goh SM, Petrucelli L, Gendron TF, Heller C, Clark AL, Taylor JC, Wise A, Ong E, Forsberg L, Brushaber D, Rojas JC, VandeVrede L, Ljubenkov P, Kramer J, Casaletto KB, Appleby B, Bordelon Y, Botha H, Dickerson BC, Domoto-Reilly K, Fields JA, Foroud T, Gavrilova R, Geschwind D, Ghoshal N, Goldman J, Graff-Radford J, Graff-Radford N, Grossman M, Hall MGH, Hsiung GY, Huey ED, Irwin D, Jones DT, Kantarci K, Kaufer D, Knopman D, Kremers W, Lago AL, Lapid MI, Litvan I, Lucente D, Mackenzie IR, Mendez MF, Mester C, Miller BL, Onyike CU, Rademakers R, Ramanan VK, Ramos EM, Rao M, Rascovsky K, Rankin KP, Roberson ED, Savica R, Tartaglia MC, Weintraub S, Wong B, Cash DM, Bouzigues A, Swift IJ, Peakman G, Bocchetta M, Todd EG, Convery RS, Rowe JB, Borroni B, Galimberti D, Tiraboschi P, Masellis M, Finger E, van Swieten JC, Seelaar H, Jiskoot LC, Sorbi S, Butler CR, Graff C, Gerhard A, Langheinrich T, Laforce R, Sanchez-Valle R, de Mendonça A, Moreno F, Synofzik M, Vandenberghe R, Ducharme S, Le Ber I, Levin J, Danek A, Otto M, Pasquier F, Santana I, Kornak J, Boeve BF, Rosen HJ, Rohrer JD, Boxer AL; Frontotemporal Dementia Prevention Initiative (FPI) Investigators. Temporal order of clinical and biomarker changes in familial frontotemporal dementia. Nat Med. 2022 Oct;28(10):2194-2206. doi: 10.1038/s41591-022-01942-9. Epub 2022 Sep 22. PMID: 36138153; PMCID: PMC9951811.
  • https://pubmed.ncbi.nlm.nih.gov/36138153

Early treatment intervention will likely provide the greatest therapeutic benefit for FTD mutation carriers at risk of developing disease. To predict patient conversion to symptomatic disease, FPI researchers are applying statistical models to structural MRI images that have been collected from early-stage FTD mutation carriers. This approach aims to identify the brain regions most vulnerable to degeneration throughout the course of disease progression, and allows for the creation of personalized neurodegeneration maps for each patient. Once these maps are established, FPI researchers will determine their utility to predict FTD symptom onset in patients that have converted from asymptomatic to symptomatic over the course of their research study participation.

Relevant publications:

• Individualized Atrophy-Based Prediction of Dementia Progression in Familial Frontotemporal Lobar Degeneration With Bayesian Linear Mixed-Effects Modeling
  • Dutt S, Leichter D, Cobigo Y, Wolf A, Kornak J, Clark A, Russell LL, Bouzigues A, Cash DM, Bocchetta M, Olzinski M, Appleby B, Bayram E, Borroni B, Bozoki A, Butler CR, Clark D, Convery RS, Darby RR, de Mendonça A, Dickerson B, Domoto-Reilly K, Ducharme S, Ferry-Bolder E, Finger E, Foster PH, Galasko DR, Galimberti D, Gerhard A, Ghoshal N, Graff C, Graff-Radford N, Grant IM, Hales CM, Honig LS, Hsiung GY, Huey ED, Irwin D, Jiskoot LC, Kremers W, Kwan JY, Laforce R, Le Ber I, Léger GC, Levin J, Litvan I, Mackenzie IR, Masellis M, Mendez MF, Moreno F, Onyike C, Otto M, Pascual B, Pressman P, Rademakers R, Ramos EM, Ritter A, Roberson ED, Rowe JB, Sanchez-Valle R, Santana I, Seelaar H, Snyder A, Sorbi S, Synofzik M, Tartaglia MC, Tiraboschi P, van Swieten JC, Vandebergh M, Vandenberghe R, Heuer HW, Miller BL, Seeley WW, Gorno-Tempini ML, Kramer JH, Forsberg L, Kantarci K, Boeve BF, Boxer AL, Rohrer JD, Rosen HJ, Staffaroni AM; FTD Prevention Initiative (FPI) investigators. Individualized Atrophy-Based Prediction of Dementia Progression in Familial Frontotemporal Lobar Degeneration With Bayesian Linear Mixed-Effects Modeling. Ann Neurol. 2026 May;99(5):1315-1326. doi: 10.1002/ana.78167. Epub 2026 Jan 29. PMID: 41608854; PMCID: PMC12950279.
  • https://pubmed.ncbi.nlm.nih.gov/41608854

Digital assessments can provide significant advantages for FTD drug development efforts by enabling at-home or in-clinic data collection that is more precise, inclusive, comprehensive, and patient-centered. Two remote digital assessment tools have been independently developed and utilized by the GENFI and ALLFTD consortia (Ignite and ALLFTD Mobile App, respectively). FPI researchers are now working together to validate these digital tools across consortia, focusing on assessments useful for FTD diagnosis and disease progression monitoring. Efforts are also underway to expand the capabilities of these assessment tools to include daily activity and sleep monitoring.

Relevant publications:

• Study protocol: computerised cognitive testing in a cohort of people with frontotemporal dementia
  • Moore K, Convery RS, Rohrer JD
  • Study protocol: computerised cognitive testing in a cohort of people with frontotemporal dementia
  • BMJ Open 2022;12:e055211. doi: 10.1136/bmjopen-2021-055211
  • https://bmjopen.bmj.com/content/12/8/e055211
• Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration
  • Staffaroni AM, Clark AL, Taylor JC, et al. Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration. JAMA Netw Open. 2024;7(4):e244266. doi:10.1001/jamanetworkopen.2024.4266
  • https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2816782
• Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study
  • Paolillo EW, Casaletto KB, Clark AL, Taylor JC, Heuer HW, Wise AB, Dhanam S, Sanderson-Cimino M, Saloner R, Kramer JH, Kornak J, Kremers W, Forsberg L, Appleby B, Bayram E, Bozoki A, Brushaber D, Darby RR, Day GS, Dickerson BC, Domoto-Reilly K, Elahi F, Fields JA, Ghoshal N, Graff-Radford N, G H Hall M, Honig LS, Huey ED, Lapid MI, Litvan I, Mackenzie IR, Masdeu JC, Mendez MF, Mester C, Miyagawa T, Naasan G, Pascual B, Pressman P, Ramos EM, Rankin KP, Rexach J, Rojas JC, VandeVrede L, Wong B, Wszolek ZK, Boeve BF, Rosen HJ, Boxer AL, Staffaroni AM; ALLFTD Consortium. Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study. JMIR Aging. 2024 Jun 26;7:e52831. doi: 10.2196/52831. PMID: 38922667; PMCID: PMC11237775.
  • https://pubmed.ncbi.nlm.nih.gov/38922667

Speech and language changes are common symptoms observed across various FTD clinical subtypes and genetic forms. FPI researchers have developed tools to successfully identify speech and language impairments in FTD patients; however, the utility of these measures as potential biomarkers remains unexplored. As a first step, FPI investigators plan to analyze patient’s speech samples to extract metrics that might be useful for early disease detection or clinical trial monitoring.

In this multicenter cohort, clinical presentations of behavioral variant FTD (bvFTD) were examined to ask why sporadic cases of bvFTD show a higher male prevalence, while genetic bvFTD affects men and women equally. Researchers found that women with sporadic bvFTD exhibit worse compulsive behavior and language impairments—alongside less severe parietal gray matter loss—compared to those with genetic bvFTD. These atypical clinical symptoms in non-genetic female patients may lead to misdiagnosis, helping explain the observed difference in sex distribution between sporadic and genetic cases.

Relevant publications:

• Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia
  • Liu X, de Boer SCM, Cortez K, Poos JM, Illán-Gala I, Heuer H, Forsberg LK, Casaletto K, Memel M, Appleby BS, Barmada S, Bozoki A, Clark D, Cobigo Y, Darby R, Dickerson BC, Domoto-Reilly K, Galasko DR, Geschwind DH, Ghoshal N, Graff-Radford NR, Grant IM, Hsiung GR, Honig LS, Huey ED, Irwin D, Kantarci K, Léger GC, Litvan I, Mackenzie IR, Masdeu JC, Mendez MF, Onyike CU, Pascual B, Pressman P, Bayram E, Ramos EM, Roberson ED, Rogalski E, Bouzigues A, Russell LL, Foster PH, Ferry-Bolder E, Masellis M, van Swieten J, Jiskoot L, Seelaar H, Sanchez-Valle R, Laforce R, Graff C, Galimberti D, Vandenberghe R, de Mendonça A, Tiraboschi P, Santana I, Gerhard A, Levin J, Sorbi S, Otto M, Pasquier F, Ducharme S, Butler CR, Ber IL, Finger E, Rowe JB, Synofzik M, Moreno F, Borroni B, Boeve BF, Boxer AL, Rosen HJ, Pijnenburg YAL, Rohrer JD, Tartaglia MC; ALLFTD Consortium and the GENFI Consortium. Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia. Alzheimers Dement. 2025 Apr;21(4):e14608. doi: 10.1002/alz.14608. PMID: 40277074; PMCID: PMC12022892.
  • https://pubmed.ncbi.nlm.nih.gov/40277074

FPI researchers assessed disease age-at-onset, age-at-death, and duration using historic data from over 3,400 genetic FTD patients world-wide. Data from this study suggested that these parameters are influenced by genetic group. Furthermore, the predictive utility of parent and average family data varied across the different FTD genetic groups. Work to identify genetic and environmental factors that modify disease onset and duration is warranted and remains of interest to the FPI. This inaugural study is the first publication to include patient clinical data from multiple FPI consortia.

Relevant publication:

• Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study
  • Moore KM, Nicholas J, Grossman M, McMillan CT, Irwin DJ, Massimo L, Van Deerlin VM, Warren JD, Fox NC, Rossor MN, Mead S, Bocchetta M, Boeve BF, Knopman DS, Graff-Radford NR, Forsberg LK, Rademakers R, Wszolek ZK, van Swieten JC, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Snowden JS, Saxon J, Jones M, Pickering-Brown S, Le Ber I, Camuzat A, Brice A, Caroppo P, Ghidoni R, Pievani M, Benussi L, Binetti G, Dickerson BC, Lucente D, Krivensky S, Graff C, Öijerstedt L, Fallström M, Thonberg H, Ghoshal N, Morris JC, Borroni B, Benussi A, Padovani A, Galimberti D, Scarpini E, Fumagalli GG, Mackenzie IR, Hsiung GR, Sengdy P, Boxer AL, Rosen H, Taylor JB, Synofzik M, Wilke C, Sulzer P, Hodges JR, Halliday G, Kwok J, Sanchez-Valle R, Lladó A, Borrego-Ecija S, Santana I, Almeida MR, Tábuas-Pereira M, Moreno F, Barandiaran M, Indakoetxea B, Levin J, Danek A, Rowe JB, Cope TE, Otto M, Anderl-Straub S, de Mendonça A, Maruta C, Masellis M, Black SE, Couratier P, Lautrette G, Huey ED, Sorbi S, Nacmias B, Laforce R Jr, Tremblay ML, Vandenberghe R, Damme PV, Rogalski EJ, Weintraub S, Gerhard A, Onyike CU, Ducharme S, Papageorgiou SG, Ng ASL, Brodtmann A, Finger E, Guerreiro R, Bras J, Rohrer JD; FTD Prevention Initiative. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol. 2020 Feb;19(2):145-156. doi: 10.1016/S1474-4422(19)30394-1. Epub 2019 Dec 3. Erratum in: Lancet Neurol. 2020 Feb;19(2):e2. doi: 10.1016/S1474-4422(19)30483-1. PMID: 31810826; PMCID: PMC7007771.
  • https://pubmed.ncbi.nlm.nih.gov/31810826

Neurofilament light chain (NfL) is a protein that is increased in the plasma of individuals suffering from FTD and other neurodegenerative disorders. In this study, FPI researchers used two independent cohorts to investigate the prognostic utility of plasma NfL levels in genetic FTD. The data demonstrated that increased plasma NfL levels were predictive of disease progression within 2 years, even in those mutation carriers who were asymptomatic at the time of NfL measurement. This seminal paper provided strong rationale for the use of NfL as an enrollment criterion or potential endpoint in treatment trials enrolling asymptomatic FTD mutation carriers.

Relevant publication:

• Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration
  • Rojas JC, Wang P, Staffaroni AM, Heller C, Cobigo Y, Wolf A, Goh SM, Ljubenkov PA, Heuer HW, Fong JC, Taylor JB, Veras E, Song L, Jeromin A, Hanlon D, Yu L, Khinikar A, Sivasankaran R, Kieloch A, Valentin MA, Karydas AM, Mitic LL, Pearlman R, Kornak J, Kramer JH, Miller BL, Kantarci K, Knopman DS, Graff-Radford N, Petrucelli L, Rademakers R, Irwin DJ, Grossman M, Ramos EM, Coppola G, Mendez MF, Bordelon Y, Dickerson BC, Ghoshal N, Huey ED, Mackenzie IR, Appleby BS, Domoto-Reilly K, Hsiung GR, Toga AW, Weintraub S, Kaufer DI, Kerwin D, Litvan I, Onyike CU, Pantelyat A, Roberson ED, Tartaglia MC, Foroud T, Chen W, Czerkowicz J, Graham DL, van Swieten JC, Borroni B, Sanchez-Valle R, Moreno F, Laforce R, Graff C, Synofzik M, Galimberti D, Rowe JB, Masellis M, Finger E, Vandenberghe R, de Mendonça A, Tagliavini F, Santana I, Ducharme S, Butler CR, Gerhard A, Levin J, Danek A, Otto M, Sorbi S, Cash DM, Convery RS, Bocchetta M, Foiani M, Greaves CV, Peakman G, Russell L, Swift I, Todd E, Rohrer JD, Boeve BF, Rosen HJ, Boxer AL; ALLFTD and GENFI consortia. Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration. Neurology. 2021 May 4;96(18):e2296-e2312. doi: 10.1212/WNL.0000000000011848. Epub 2021 Apr 7. PMID: 33827960; PMCID: PMC8166434.
  • https://pubmed.ncbi.nlm.nih.gov/33827960