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1. Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia

Author

Benussi, A. (Alberto), Premi, E. (Enrico), Gazzina, S. (Stefano), Brattini, C. (Chiara), Bonomi, E. (Elisa), Alberici, P. (Paola), Jiskoot, L.C. (Lize), Swieten, J.C. (John) van, Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, C. (Carmela), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Le Ber, I. (Isabelle), Pasquier, F. (Florence), Peakman, G. (Georgia), Todd, E. (Emily), Bocchetta, M. (Martina), Rohrer, J.D. (Jonathan), Borroni, B. (Barbara), Benussi, A. (Alberto), Premi, E. (Enrico), Gazzina, S. (Stefano), Brattini, C. (Chiara), Bonomi, E. (Elisa), Alberici, P. (Paola), Jiskoot, L.C. (Lize), Swieten, J.C. (John) van, Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, C. (Carmela), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Le Ber, I. (Isabelle), Pasquier, F. (Florence), Peakman, G. (Georgia), Todd, E. (Emily), Bocchetta, M. (Martina), Rohrer, J.D. (Jonathan), and Borroni, B. (Barbara)

Abstract

Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, Setting, and Participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main Outcomes and Measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of

Published
2021
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2. Disease-related cortical thinning in presymptomatic granulin mutation carriers

Author

Borrego-Écija, S. (Sergi), Sala-Llonch, R. (Roser), Swieten, J.C. (John) van, Borroni, B. (Barbara), Moreno, F. (Fermin), Masellis, M. (Mario), Tartaglia, C. (Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Laforce, R. (Robert), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), Tagliavini, F. (Fabrizio), De Mendonça, A. (Alexandre), Santana, I. (Isabel), Synofzik, M. (Matthis), Ducharme, S. (Simon), Levin, J. (Johannes), Danek, A. (Adrian), Gerhard, A. (Alex), Otto, M. (Markus), Butler, C. (Chris), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Heller, C. (Carolin), Bocchetta, M. (Martina), Cash, D.M. (David M), Convery, R.S. (Rhian S), Moore, K.M. (Katrina M), Rohrer, J.D. (Jonathan), Sánchez-Valle, R. (Raquel), Rossor, M.N. (Martin N.), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Greaves, C. (Caroline), Neason, M. (Mollie), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Nicholas, J. (Jennifer), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Thornton, A.S. (Andrew), Pijnenburg, Y.A.L. (Yolande), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), TaintaMD, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (David), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini MD, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Maruta, C. (Carolina), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giorgio), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro, D. (Diana), Rosario Almeida, M. (Maria), Castelo-Branco, M. (Miguel), João Leitão, M. (Maria), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Flanagan, T. (Toby), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), Anderl-Straub, S. (Sarah), Borrego-Écija, S. (Sergi), Sala-Llonch, R. (Roser), Swieten, J.C. (John) van, Borroni, B. (Barbara), Moreno, F. (Fermin), Masellis, M. (Mario), Tartaglia, C. (Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Laforce, R. (Robert), Rowe, J.B. (James), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), Tagliavini, F. (Fabrizio), De Mendonça, A. (Alexandre), Santana, I. (Isabel), Synofzik, M. (Matthis), Ducharme, S. (Simon), Levin, J. (Johannes), Danek, A. (Adrian), Gerhard, A. (Alex), Otto, M. (Markus), Butler, C. (Chris), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Heller, C. (Carolin), Bocchetta, M. (Martina), Cash, D.M. (David M), Convery, R.S. (Rhian S), Moore, K.M. (Katrina M), Rohrer, J.D. (Jonathan), Sánchez-Valle, R. (Raquel), Rossor, M.N. (Martin N.), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Greaves, C. (Caroline), Neason, M. (Mollie), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Nicholas, J. (Jennifer), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Thornton, A.S. (Andrew), Pijnenburg, Y.A.L. (Yolande), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), TaintaMD, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (David), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini MD, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Maruta, C. (Carolina), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giorgio), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro, D. (Diana), Rosario Almeida, M. (Maria), Castelo-Branco, M. (Miguel), João Leitão, M. (Maria), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Flanagan, T. (Toby), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), and Anderl-Straub, S. (Sarah)

Abstract

Mutations in the granulin gene (GRN) cause familial frontotemporal dementia. Understanding the structural brain changes in presymptomatic GRN carriers would enforce the use of neuroimaging biomarkers for early diagnosis and monitoring. We studied 100 presymptomatic GRN mutation carriers and 94 noncarriers from the Genetic Frontotemporal dementia initiative (GENFI), with MRI structural images. We analyzed 3T MRI structural images using the FreeSurfer pipeline to calculate the whole brain cortical thickness (CTh) for each subject. We also perform a vertex-wise general linear model to assess differences between groups in the relationship between CTh and diverse covariables as gender, age, the estimated years to onset and education. We also explored differences according to TMEM106B genotype, a possible disease modifier. Whole brain CTh did not differ between carriers and noncarriers. Both groups showed age-related cortical thinning. The group-by-age interaction analysis showed that this age-related cortical thinning was significantly greater in GRN carriers in the left superior frontal cortex. TMEM106B did not significantly influence the age-related cortical thinning. Our results validate and expand previous findings suggesting an

Published
2021
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3. Apathy in presymptomatic genetic frontotemporal dementia predicts cognitive decline and is driven by structural brain changes

Author

Malpetti, M. (Maura), Jones, P.S. (P. Simon), Tsvetanov, K.A. (Kamen A.), Rittman, T. (Timothy), Swieten, J.C. (John) van, Borroni, B. (Barbara), Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Heller, C. (Carolin), Todd, E.G. (Emily G.), Bocchetta, M. (Martina), Cash, D.M. (David M.), Convery, R.S. (Rhian S.), Peakman, G. (Georgia), Moore, K.M. (Katrina M.), Rohrer, J.D. (Jonathan), Kievit, R.A. (Rogier A.), Rowe, J.B. (James), Malpetti, M. (Maura), Jones, P.S. (P. Simon), Tsvetanov, K.A. (Kamen A.), Rittman, T. (Timothy), Swieten, J.C. (John) van, Borroni, B. (Barbara), Sánchez-Valle, R. (Raquel), Moreno, F. (Fermin), Laforce, R. (Robert), Graff, C. (Caroline), Synofzik, M. (Matthis), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Finger, E. (Elizabeth), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C.R. (Chris R.), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Frisoni, G.B. (Giovanni B.), Ghidoni, R. (Roberta), Sorbi, S. (Sandro), Heller, C. (Carolin), Todd, E.G. (Emily G.), Bocchetta, M. (Martina), Cash, D.M. (David M.), Convery, R.S. (Rhian S.), Peakman, G. (Georgia), Moore, K.M. (Katrina M.), Rohrer, J.D. (Jonathan), Kievit, R.A. (Rogier A.), and Rowe, J.B. (James)

Abstract

Introduction: Apathy adversely affects prognosis and survival of patients with frontotemporal dementia (FTD). We test whether apathy develops in presymptomatic genetic FTD, and is associated with cognitive decline and brain atrophy. Methods: Presymptomatic carriers of MAPT, GRN or C9orf72 mutations (N = 304), and relatives without mutations (N = 296) underwent clinical assessments and MRI at baseline, and annually for 2 years. Longitudinal changes in apathy, cognition, gray matter volumes, and their relationships were analyzed with latent growth curve modeling. Results: Apathy severity increased over time in presymptomatic carriers, but not in non-carriers. In presymptomatic carriers, baseline apathy predicted cognitive decline over two years, but not vice versa. Apathy progression was associated with baseline low gray matter volume in frontal and cingulate regions. Discussion: Apathy is an early marker of FTD-related changes and predicts a subsequent subclinical deterioration of cognition before dementia onset. Apathy may be a modifiable factor in those at risk of FTD.

Published
2020
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4. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

Author

Russell, L.L. (Lucy L.), Greaves, C.V. (Caroline V.), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Convery, R.S. (Rhian S.), Moore, K. (Katrina), Cash, D.M. (David M.), Swieten, J.C. (John) van, Jiskoot, L.C. (Lize), Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Rotondo, E. (Emanuela), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Warren, J.D. (Jason), Rohrer, J.D. (Jonathan), Rossor, M. (Martin), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Heller, C. (Carolin), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Poos, J.M. (Jackie), Thornton, A.S. (Andrew), Pijnenburg, Y. (Yolanda), Barandiaran, M. (Myriam), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), Tainta, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Borrego-Ecija, S. (Sergi), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu MPsych, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S.E. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (Daid), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Karnarth, H.-O. (Hans-Otto), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Maruta MPsych, C. (Carolina), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giuseppe), Muscio, C. (Cristina), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro NPsych, D. (Diana), Almeida, M.R. (Maria R.), Castelo-Branco, M. (Miguel), Leitão, M.J. (Maria J.), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Thompson, P.M. (Paul), Langheinrich, T. (Tobias), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), Anderl-Straub, S. (Sarah), Russell, L.L. (Lucy L.), Greaves, C.V. (Caroline V.), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Convery, R.S. (Rhian S.), Moore, K. (Katrina), Cash, D.M. (David M.), Swieten, J.C. (John) van, Jiskoot, L.C. (Lize), Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Rotondo, E. (Emanuela), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Otto, M. (Markus), Warren, J.D. (Jason), Rohrer, J.D. (Jonathan), Rossor, M. (Martin), Fox, N.C. (Nick), Woollacott, I.O.C. (Ione O.C.), Shafei, R. (Rachelle), Heller, C. (Carolin), Guerreiro, R. (Rita), Bras, J. (Jose), Thomas, D.L. (David L), Mead, S. (Simon), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Papma, J.M. (Janne), Poos, J.M. (Jackie), Thornton, A.S. (Andrew), Pijnenburg, Y. (Yolanda), Barandiaran, M. (Myriam), Indakoetxea, B. (Begoña), Gabilondo, A. (Alazne), Tainta, M. (Mikel), de Arriba, M. (Maria), Gorostidi, A. (Ana), Zulaica, M. (Miren), Villanua, J. (Jorge), Diaz, Z. (Zigor), Borrego-Ecija, S. (Sergi), Olives, J. (Jaume), Lladó, A. (Albert), Balasa, M. (Mircea), Antonell, A. (Anna), Bargallo, N. (Nuria), Premi, E. (Enrico), Cosseddu MPsych, M. (Maura), Gazzina, S. (Stefano), Padovani, A. (Alessandro), Gasparotti, R. (Roberto), Archetti, S. (Silvana), Black, S.E. (Sandra), Mitchell, S. (Sara), Rogaeva, E. (Ekaterina), Freedman, M. (Morris), Keren, R. (Ron), Tang-Wai, D. (Daid), Öijerstedt, L. (Linn), Andersson, C. (Christin), Jelic, S. (Svetislav Svetislav), Thonberg, H. (Håkan), Arighi, A. (Andrea), Fenoglio, C. (Chiara), Scarpini, E. (Elio), Fumagalli, G. (Giorgio), Cope, T. (Thomas), Timberlake, C. (Carolyn), Rittman, T. (Timothy), Shoesmith, C. (Christen), Bartha, R. (Robart), Rademakers, S. (Suzanne), Wilke, C. (Carlo), Karnarth, H.-O. (Hans-Otto), Bender, B. (Benjamin), Bruffaerts, R. (Rose), Vandamme, P. (Philip), Vandenbulcke, M. (Mathieu), Ferreira, C.B. (Catarina B.), Miltenberger, G. (Gabriel), Maruta MPsych, C. (Carolina), Verdelho, A. (Ana), Afonso, S. (Sónia), Taipa, R. (Ricardo), Caroppo, P. (Paola), Di Fede, G. (Giuseppe), Giaccone, G. (Giuseppe), Muscio, C. (Cristina), Prioni, S. (Sara), Redaelli, V. (Veronica), Rossi, G. (Giacomina), Tiraboschi, P. (Pietro), Duro NPsych, D. (Diana), Almeida, M.R. (Maria R.), Castelo-Branco, M. (Miguel), Leitão, M.J. (Maria J.), Tabuas-Pereira, M. (Miguel), Santiago, B. (Beatriz), Gauthier, S. (Serge), Rosa-Neto, P. (Pedro), Veldsman, M. (Michele), Thompson, P.M. (Paul), Langheinrich, T. (Tobias), Prix, C. (Catharina), Hoegen, T. (Tobias), Wlasich, E. (Elisabeth), Loosli, S. (Sandra), Schonecker, S. (Sonja), Semler, E. (Elisa), and Anderl-Straub, S. (Sarah)

Abstract

A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the

Published
2020
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5. White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study

Author

Sudre, C.H. (Carole H.), Bocchetta, M. (Martina), Heller, C. (Carolin), Convery, R. (Rhian), Neason, M. (Mollie), Moore, K.M. (Katrina M.), Cash, D.M. (David M.), Thomas, D.L. (David L), Woollacott, I.O.C. (Ione O.C.), Foiani, M. (Martha), Heslegrave, A. (Amanda), Shafei, R. (Rachelle), Greaves, C. (Caroline), Swieten, J.C. (John) van, Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Otto, M. (Markus), Zetterberg, H. (Henrik), Ourselin, S. (Sebastien), Cardoso, M.J. (M. Jorge), Rohrer, J.D. (Jonathan), Sudre, C.H. (Carole H.), Bocchetta, M. (Martina), Heller, C. (Carolin), Convery, R. (Rhian), Neason, M. (Mollie), Moore, K.M. (Katrina M.), Cash, D.M. (David M.), Thomas, D.L. (David L), Woollacott, I.O.C. (Ione O.C.), Foiani, M. (Martha), Heslegrave, A. (Amanda), Shafei, R. (Rachelle), Greaves, C. (Caroline), Swieten, J.C. (John) van, Moreno, F. (Fermin), Sánchez-Valle, R. (Raquel), Borroni, B. (Barbara), Laforce, R. (Robert), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Graff, C. (Caroline), Galimberti, D. (Daniela), Rowe, J.B. (James), Finger, E. (Elizabeth), Synofzik, M. (Matthis), Vandenberghe, R. (Rik), De Mendonça, A. (Alexandre), Tagliavini, F. (Fabrizio), Santana, I. (Isabel), Ducharme, S. (Simon), Butler, C. (Chris), Gerhard, A. (Alex), Levin, J. (Johannes), Danek, A. (Adrian), Frisoni, G.B. (Giovanni B.), Sorbi, S. (Sandro), Otto, M. (Markus), Zetterberg, H. (Henrik), Ourselin, S. (Sebastien), Cardoso, M.J. (M. Jorge), and Rohrer, J.D. (Jonathan)

Abstract

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers – in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load – a di

Published
2019
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6. Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: Initial application to the GENFI cohort

Author

Cury, C. (Claire), Durrleman, S. (Stanley), Cash, D.M. (David M.), Lorenzi, M. (Marco), Nicholas, J.M. (Jennifer M.), Bocchetta, M. (Martina), Swieten, J.C. (John) van, Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Ourselin, S. (Sebastien), Rohrer, J.D. (Jonathan D.), Modat, M. (Marc), Andersson, C. (Christin), Archetti, S. (Silvana), Arighi, A. (Andrea), Benussi, L. (Luisa), Black, S. (Sandra), Cosseddu, M. (Maura), Fallstrm, M. (Marie), Ferreira, C. (Carlos), Fenoglio, C. (Chiara), Fox, N. (Nick), Freedman, M. (Morris), Fumagalli, G. (Giorgio), Gazzina, S. (Stefano), Ghidoni, R. (Roberta), Grisoli, M. (Marina), Jelic, V. (Vesna), Jiskoot, L.C. (Lize), Keren, R. (Ron), Lombardi, G. (Gemma), Maruta, C. (Carolina), Meeter, L.H.H. (Lieke), Thornton, A.S. (Andrew), Nacmias, B. (Benedetta), ijerstedt, L. (Linn), Padovani, A. (Alessandro), Panman, J. (Jessica), Pievani, M. (Michela), Polito, C. (Cristina), Premi, E. (Enrico), Prioni, S. (Sara), Rademakers, S. (Suzanne), Redaelli, V. (Veronica), Rogaeva, E. (Ekaterina), Rossi, G. (Giacomina), Rossor, M. (Martin), Scarpini, E. (Elio), Tang-Wai, D. (David), Tartaglia, C. (Carmela), Thonberg, H. (Håkan), Tiraboschi, P. (Pietro), Verdelho, A. (Ana), Warren, J. (Jason), Cury, C. (Claire), Durrleman, S. (Stanley), Cash, D.M. (David M.), Lorenzi, M. (Marco), Nicholas, J.M. (Jennifer M.), Bocchetta, M. (Martina), Swieten, J.C. (John) van, Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Ourselin, S. (Sebastien), Rohrer, J.D. (Jonathan D.), Modat, M. (Marc), Andersson, C. (Christin), Archetti, S. (Silvana), Arighi, A. (Andrea), Benussi, L. (Luisa), Black, S. (Sandra), Cosseddu, M. (Maura), Fallstrm, M. (Marie), Ferreira, C. (Carlos), Fenoglio, C. (Chiara), Fox, N. (Nick), Freedman, M. (Morris), Fumagalli, G. (Giorgio), Gazzina, S. (Stefano), Ghidoni, R. (Roberta), Grisoli, M. (Marina), Jelic, V. (Vesna), Jiskoot, L.C. (Lize), Keren, R. (Ron), Lombardi, G. (Gemma), Maruta, C. (Carolina), Meeter, L.H.H. (Lieke), Thornton, A.S. (Andrew), Nacmias, B. (Benedetta), ijerstedt, L. (Linn), Padovani, A. (Alessandro), Panman, J. (Jessica), Pievani, M. (Michela), Polito, C. (Cristina), Premi, E. (Enrico), Prioni, S. (Sara), Rademakers, S. (Suzanne), Redaelli, V. (Veronica), Rogaeva, E. (Ekaterina), Rossi, G. (Giacomina), Rossor, M. (Martin), Scarpini, E. (Elio), Tang-Wai, D. (David), Tartaglia, C. (Carmela), Thonberg, H. (Håkan), Tiraboschi, P. (Pietro), Verdelho, A. (Ana), and Warren, J. (Jason)

Abstract

Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer's disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure. In this paper we propose a spatiotemporal analysis pipeline based on Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects. We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease.

Published
2019
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7. Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort

Author

Jiskoot, L.C. (Lize), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Cash, D.M. (David M.), Thomas, D.L. (David L), Modat, M. (Marc), Ourselin, S. (Sebastien), Rombouts, S.A.R.B. (Serge), Dopper, E.G.P. (Elise), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Minkelen, R. (Rick) van, Ende, E.L. (Emma) van der, Donker Kaat, L. (Laura), Pijnenburg, Y.A.L. (Yolande), Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), de Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Papma, J.M. (Janne), Swieten, J.C. (John) van, Rohrer, J.D. (Jonathan), Jiskoot, L.C. (Lize), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Cash, D.M. (David M.), Thomas, D.L. (David L), Modat, M. (Marc), Ourselin, S. (Sebastien), Rombouts, S.A.R.B. (Serge), Dopper, E.G.P. (Elise), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Minkelen, R. (Rick) van, Ende, E.L. (Emma) van der, Donker Kaat, L. (Laura), Pijnenburg, Y.A.L. (Yolande), Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), de Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Papma, J.M. (Janne), Swieten, J.C. (John) van, and Rohrer, J.D. (Jonathan)

Abstract

Objective: We aimed to investigate mutation-specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72, MAPT, and GRN mutations by use of diffusion-weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study. Methods: One hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72, MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left–right asymmetry analyses on G

Published
2018
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8. Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort

Author

Jiskoot, L.C. (Lize), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Cash, D.M. (David M.), Thomas, D.L. (David L), Modat, M. (Marc), Ourselin, S. (Sebastien), Rombouts, S.A.R.B. (Serge), Dopper, E.G.P. (Elise), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Minkelen, R. (Rick) van, Ende, E.L. (Emma) van der, Donker Kaat, L. (Laura), Pijnenburg, Y.A.L. (Yolande), Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), de Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Papma, J.M. (Janne), Swieten, J.C. (John) van, Rohrer, J.D. (Jonathan), Jiskoot, L.C. (Lize), Bocchetta, M. (Martina), Nicholas, J.M. (Jennifer), Cash, D.M. (David M.), Thomas, D.L. (David L), Modat, M. (Marc), Ourselin, S. (Sebastien), Rombouts, S.A.R.B. (Serge), Dopper, E.G.P. (Elise), Meeter, L.H.H. (Lieke), Panman, J.L. (Jessica), Minkelen, R. (Rick) van, Ende, E.L. (Emma) van der, Donker Kaat, L. (Laura), Pijnenburg, Y.A.L. (Yolande), Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), de Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Papma, J.M. (Janne), Swieten, J.C. (John) van, and Rohrer, J.D. (Jonathan)

Abstract

Objective: We aimed to investigate mutation-specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72, MAPT, and GRN mutations by use of diffusion-weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study. Methods: One hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72, MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left–right asymmetry analyses on G

Published
2018
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9. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

Author

Young, A.L. (Alexandra L.), Marinescu, R.V. (Razvan V.), Oxtoby, N.P. (Neil P.), Bocchetta, M. (Martina), Yong, K. (Keir), Firth, N.C. (Nicholas C.), Cash, D.M. (David M.), Thomas, D.L. (David L), Dick, K.M. (Katrina M.), Cardoso, J. (Jorge), Swieten, J.C. (John) van, Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Warren, J.D. (Jason), Crutch, S. (Sebastian), Fox, N.C. (Nick), Ourselin, S. (Sebastien), Schott, J.M. (Jonathan M.), Rohrer, J.D. (Jonathan), Alexander, D.C. (Daniel C.), Young, A.L. (Alexandra L.), Marinescu, R.V. (Razvan V.), Oxtoby, N.P. (Neil P.), Bocchetta, M. (Martina), Yong, K. (Keir), Firth, N.C. (Nicholas C.), Cash, D.M. (David M.), Thomas, D.L. (David L), Dick, K.M. (Katrina M.), Cardoso, J. (Jorge), Swieten, J.C. (John) van, Borroni, B. (Barbara), Galimberti, D. (Daniela), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Warren, J.D. (Jason), Crutch, S. (Sebastian), Fox, N.C. (Nick), Ourselin, S. (Sebastien), Schott, J.M. (Jonathan M.), Rohrer, J.D. (Jonathan), and Alexander, D.C. (Daniel C.)

Abstract

The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10-4) or temporal stage (p = 3.96 × 10-5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.

Published
2018
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10. Distinct neuroanatomical correlates of neuropsychiatric symptoms in the three main forms of genetic frontotemporal dementia in the GENFI Cohort

Author

Sellami, L. (Leila), Bocchetta, M. (Martina), Masellis, M. (Mario), Cash, D.M. (David M.), Dick, K.M. (Katrina M.), Swieten, J.C. (John) van, Borroni, B. (Barbara), Galimberti, D. (Daniela), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G. (Giovanni), Finger, E. (Elizabeth), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Warren, J.D. (Jason), Rohrer, J.D. (Jonathan), Laforce, R. (Robert), Sellami, L. (Leila), Bocchetta, M. (Martina), Masellis, M. (Mario), Cash, D.M. (David M.), Dick, K.M. (Katrina M.), Swieten, J.C. (John) van, Borroni, B. (Barbara), Galimberti, D. (Daniela), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G. (Giovanni), Finger, E. (Elizabeth), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Warren, J.D. (Jason), Rohrer, J.D. (Jonathan), and Laforce, R. (Robert)

Abstract

Background: The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations

Published
2018
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11. Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: A GENFI study

Author

Schneider, R. (Raphael), McKeever, P. (Paul), Kim, T. (Taehyung), Graff, C. (Caroline), Swieten, J.C. (John) van, Karydas, A. (Anna), Boxer, A.L. (Adam), Rosen, H. (Howie), Miller, B.L. (Bruce Lars), Laforce, R. (Robert), Galimberti, D. (Daniela), Masellis, M. (Mario), Borroni, B. (Barbara), Zhang, Z. (Zhaolei), Zinman, L. (Lorne), Rohrer, J.D. (Jonathan), Tartaglia, M.C. (Maria Carmela), Robertson, J. (Janice), Schneider, R. (Raphael), McKeever, P. (Paul), Kim, T. (Taehyung), Graff, C. (Caroline), Swieten, J.C. (John) van, Karydas, A. (Anna), Boxer, A.L. (Adam), Rosen, H. (Howie), Miller, B.L. (Bruce Lars), Laforce, R. (Robert), Galimberti, D. (Daniela), Masellis, M. (Mario), Borroni, B. (Barbara), Zhang, Z. (Zhaolei), Zinman, L. (Lorne), Rohrer, J.D. (Jonathan), Tartaglia, M.C. (Maria Carmela), and Robertson, J. (Janice)

Abstract

Objective: To determine whether exosomal microRNAs (miRNAs) in cerebrospinal fluid (CSF) of patients with frontotemporal dementia (FTD) can serve as diagnostic biomarkers, we assessed miRNA expression in the Genetic Frontotemporal Dementia Initiative (GENFI) cohort and in sporadic FTD. Methods: GENFI participants were either carriers of a pathogenic mutation in progranulin, chromosome 9 open reading frame 72 or microtubule-associated protein tau or were at risk of carrying a mutation because a first-degree relative was a known symptomatic mutation carrier. Exosomes were isolated from CSF of 23 presymptomatic and 15 symptomatic mutation carriers and 11 healthy non-mutation carriers. Expression of 752 miRNAs was measured using quantitative PCR (qPCR) arrays and validated by qPCR using individual primers. MiRNAs found differentially expressed in symptomatic compared with presymptomatic mutation carriers were further evaluated in a cohort of 17 patients with sporadic FTD, 13 patients with sporadic Alzheimer's disease (AD) and 10 healthy controls (HCs) of similar age. Results: In the GENFI cohort, miR-204-5p and miR-632 were significantly decreased in symptomatic compared with presymptomatic mutation carriers. Decrease of miR-204-5p and miR-632 revealed receiver operator characteristics with an area of 0.89 (90% CI 0.79 to 0.98) and 0.81 (90% CI 0.68 to 0.93), respectively, and when combined an area of 0.93 (90% CI 0.87 to 0.99). In sporadic FTD, only miR-632 was significantly decreased compared with AD and HCs. Decrease of miR-632 revealed an area of 0.90 (90% CI 0.81 to 0.98). Conclusions: Exosomal miR-204-5p and miR-632 have potential as diagnostic biomarkers for genetic FTD and miR-632 also for sporadic FTD.

Published
2018
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12. Distinct patterns of brain atrophy in Genetic Frontotemporal Dementia Initiative (GENFI) cohort revealed by visual rating scales

Author

Fumagalli, G.G. (Giorgio G.), Basilico, P. (Paola), Arighi, A. (Andrea), Bocchetta, M. (Martina), Dick, K.M. (Katrina M.), Cash, D.M. (David M.), Harding, S. (Sophie), Mercurio, M. (Matteo), Fenoglio, C. (Chiara), Pietroboni, A.M. (Anna M.), Ghezzi, L. (Laura), Swieten, J.C. (John) van, Borroni, B. (Barbara), De Mendonça, A. (Alexandre), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), Sorbi, S. (Sandro), Scarpini, E. (Elio), Rohrer, J.D. (Jonathan), Galimberti, D. (Daniela), Fumagalli, G.G. (Giorgio G.), Basilico, P. (Paola), Arighi, A. (Andrea), Bocchetta, M. (Martina), Dick, K.M. (Katrina M.), Cash, D.M. (David M.), Harding, S. (Sophie), Mercurio, M. (Matteo), Fenoglio, C. (Chiara), Pietroboni, A.M. (Anna M.), Ghezzi, L. (Laura), Swieten, J.C. (John) van, Borroni, B. (Barbara), De Mendonça, A. (Alexandre), Masellis, M. (Mario), Tartaglia, M.C. (Maria Carmela), Rowe, J.B. (James), Graff, C. (Caroline), Tagliavini, F. (Fabrizio), Frisoni, G.B. (Giovanni B.), Laforce, R. (Robert), Finger, E. (Elizabeth), Sorbi, S. (Sandro), Scarpini, E. (Elio), Rohrer, J.D. (Jonathan), and Galimberti, D. (Daniela)

Abstract

Background: In patients with frontotemporal dementia, it has been shown that brain atrophy occurs earliest in the anterior cingulate, insula and frontal lobes. We used visual rating scales to investigate whether identifying atrophy in these areas may be helpful in distinguishing symptomatic patients carrying different causal mutations in the microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame (C9ORF72) genes. We also analysed asymptomatic carriers to see whether it was possible to visually identify brain atrophy before the appearance of symptoms. Methods: Magnetic resonance imaging of 343 subjects (63 symptomatic mutation carriers, 132 presymptomatic mutation carriers and 148 control subjects) from the Genetic Frontotemporal Dementia Initiative study were analysed by two trained raters using a protocol of six visual rating scales that identified atrophy in key regions of the brain (orbitofrontal, anterior cingulate, frontoinsula, anterior and medial temporal lobes and posterior cortical areas). Results: Intra- and interrater agreement were greater than 0.73 for all the scales. Voxel-based morphometric analysis demonstrated a strong correlation between the visual rating scale scores and grey matter atrophy in the same region for each of the scales. Typical patterns of atrophy were identified: symmetric anterior and medial temporal lobe involvement for MAPT, asymmetric frontal and parietal loss for GRN, and a more widespread pattern for C9ORF72. Presymptomatic MAPT carriers showed greater atrophy in the medial temporal region than control subjects, but the visual rating scales could not identify presymptomatic atrophy in GRN or C9ORF72 carriers. Conclusions: These simple-to-use and reproducible scales may be useful tools in the clinical setting for the discrimination of different mutations of frontotemporal dementia, and they may even help to identify atrophy prior to onset in those with MAPT mutations.

Published
2018
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13. Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers

Author

Meeter, L.H.H. (Lieke), Gendron, T.F. (Tania F.), Sias, A.C. (Ana C.), Jiskoot, L.C. (Lize), Russo, S.P. (Silvia P.), Donker Kaat, L. (Laura), Papma, J.M. (Janne), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Dopper, E.G.P. (Elise), Franzen, S. (Sanne), Graff, C. (Caroline), Boxer, A.L. (Adam), Rosen, H.J. (Howard J.), Sánchez-Valle, R. (Raquel), Galimberti, D. (Daniela), Pijnenburg, Y.A.L. (Yolande), Benussi, L. (Luisa), Ghidoni, R. (Roberta), Borroni, B. (Barbara), Laforce, R. (Robert), del Campo, M. (Marta), Teunissen, C.E. (Charlotte), Thornton, A.S. (Andrew), Rojas, J.C. (Julio C.), Coppola, D. (Domenico), Geschwind, H., Rademakers, S. (Suzanne), Karydas, A.M. (Anna M.), Öijerstedt, L. (Linn), Scarpini, E. (Elio), Binetti, G. (Giuliano), Padovani, A. (Alessandro), Cash, D.M. (David M.), Dick, K.M. (Katrina M.), Bocchetta, M. (Martina), Miller, B.L. (Bruce Lars), Rohrer, J.D. (Jonathan), Petrucelli, L. (Leonard), Swieten, J.C. (John) van, Lee, S.E. (Suzee E.), Meeter, L.H.H. (Lieke), Gendron, T.F. (Tania F.), Sias, A.C. (Ana C.), Jiskoot, L.C. (Lize), Russo, S.P. (Silvia P.), Donker Kaat, L. (Laura), Papma, J.M. (Janne), Panman, J.L. (Jessica), Ende, E.L. (Emma) van der, Dopper, E.G.P. (Elise), Franzen, S. (Sanne), Graff, C. (Caroline), Boxer, A.L. (Adam), Rosen, H.J. (Howard J.), Sánchez-Valle, R. (Raquel), Galimberti, D. (Daniela), Pijnenburg, Y.A.L. (Yolande), Benussi, L. (Luisa), Ghidoni, R. (Roberta), Borroni, B. (Barbara), Laforce, R. (Robert), del Campo, M. (Marta), Teunissen, C.E. (Charlotte), Thornton, A.S. (Andrew), Rojas, J.C. (Julio C.), Coppola, D. (Domenico), Geschwind, H., Rademakers, S. (Suzanne), Karydas, A.M. (Anna M.), Öijerstedt, L. (Linn), Scarpini, E. (Elio), Binetti, G. (Giuliano), Padovani, A. (Alessandro), Cash, D.M. (David M.), Dick, K.M. (Katrina M.), Bocchetta, M. (Martina), Miller, B.L. (Bruce Lars), Rohrer, J.D. (Jonathan), Petrucelli, L. (Leonard), Swieten, J.C. (John) van, and Lee, S.E. (Suzee E.)

Abstract

Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses. Results: Poly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus. Interpretation: This study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

Published
2018
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14. Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: A GENFI study

Author

Premi, E. (Enrico), Grassi, M. (Mario), Swieten, J.C. (John) van, Galimberti, D. (Daniela), Graff, C. (Caroline), Masellis, M. (Mario), Tartaglia, C. (Carmela), Tagliavini, F. (Fabrizio), Rowe, J.B. (James), Laforce, R. (Robert), Finger, E. (Elizabeth), Frisoni, G.B. (Giovanni B.), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Gazzina, S. (Stefano), Cosseddu, M. (Maura), Archetti, S. (Silvana), Gasparotti, R. (Roberto), Manes, M. (Marta), Alberici, P. (Paola), Cardoso, M.J. (Manuel Jorge), Bocchetta, M. (Martina), Cash, D.M. (David M.), Ourselin, S. (Sebastien), Padovani, A. (Alessandro), Rohrer, J.D. (Jonathan), Borroni, B. (Barbara), Premi, E. (Enrico), Grassi, M. (Mario), Swieten, J.C. (John) van, Galimberti, D. (Daniela), Graff, C. (Caroline), Masellis, M. (Mario), Tartaglia, C. (Carmela), Tagliavini, F. (Fabrizio), Rowe, J.B. (James), Laforce, R. (Robert), Finger, E. (Elizabeth), Frisoni, G.B. (Giovanni B.), De Mendonça, A. (Alexandre), Sorbi, S. (Sandro), Gazzina, S. (Stefano), Cosseddu, M. (Maura), Archetti, S. (Silvana), Gasparotti, R. (Roberto), Manes, M. (Marta), Alberici, P. (Paola), Cardoso, M.J. (Manuel Jorge), Bocchetta, M. (Martina), Cash, D.M. (David M.), Ourselin, S. (Sebastien), Padovani, A. (Alessandro), Rohrer, J.D. (Jonathan), and Borroni, B. (Barbara)

Abstract

Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the sl

Published
2017
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15. Comparison of arterial spin labeling registration strategies in the multi-center GENetic frontotemporal dementia initiative (GENFI)

Author

Mutsaerts, H.-J. (Henk-Jan), Petr, J. (Jan), Thomas, D.L. (David L), Vita, E.d. (Enrico de), Cash, D.M. (David M), Osch, M.J.v. (Matthias J.P. van), Golay, A. (Alain), Groot, P.F. (Paul F.C.), Ourselin, S. (Sebastien), Swieten, J.v. (John van), Laforce, R. (Robert), Tagliavini, F. (Fabrizio), Borroni, B. (Barbara), Galimberti, D. (Daniela), Rowe, J.B. (James), Graff, M.J. (Maud J.L.), Pizzini, F.B. (Francesca B.), Finger, E. (Elizabeth), Sorbi, S. (Sandro), Castelo Branco, M. (Miguel), Rohrer, J.D. (Jonathan D), Masellis, M. (Mario), MacIntosh, B.J. (Bradley J), Mutsaerts, H.-J. (Henk-Jan), Petr, J. (Jan), Thomas, D.L. (David L), Vita, E.d. (Enrico de), Cash, D.M. (David M), Osch, M.J.v. (Matthias J.P. van), Golay, A. (Alain), Groot, P.F. (Paul F.C.), Ourselin, S. (Sebastien), Swieten, J.v. (John van), Laforce, R. (Robert), Tagliavini, F. (Fabrizio), Borroni, B. (Barbara), Galimberti, D. (Daniela), Rowe, J.B. (James), Graff, M.J. (Maud J.L.), Pizzini, F.B. (Francesca B.), Finger, E. (Elizabeth), Sorbi, S. (Sandro), Castelo Branco, M. (Miguel), Rohrer, J.D. (Jonathan D), Masellis, M. (Mario), and MacIntosh, B.J. (Bradley J)

Abstract

Purpose: To compare registration strategies to align arterial spin labeling (ASL) with 3D T1-weighted (T1w) images, with the goal of reducing the between-subject variability of cerebral blood flow (CBF) images. Materials and Methods: Multi-center 3T ASL data were collected at eight sites with four different sequences in the multi-center GENetic Frontotemporal dementia Initiative (GENFI) study. In a total of 48 healthy controls, we compared the following image registration options: (I) which images to use for registration (perfusion-weighted images [PWI] to the segmented gray matter (GM) probability map (pGM) (CBF-pGM) or M0 to T1w (M0-T1w); (II) which transformation to use (rigid-body or non-rigid); and (III) whether to mask or not (no masking, M0-based FMRIB software library Brain Extraction Tool [BET] masking). In addition to visual comparison, we quantified image similarity using the Pearson correlation coefficient (CC), and used the Mann-Whitney U rank sum test. Results: CBF-pGM outperformed M0-T1w (CC improvement 47.2% ± 22.0%; P < 0.001), and the non-rigid transformation outperformed rigid-body (20.6% ± 5.3%; P < 0.001). Masking only improved the M0-T1w rigid-body registration (14.5% ± 15.5%; P = 0.007). Conclusion: The choice of image registration strategy impacts ASL group analyses. The non-rigid transformation is promising but requires validation. CBF-pGM rigid-body registration without masking can be used as a default strategy. In patients with expansive perfusion deficits, M0-T1w may outperform CBF-pGM in sequences with high effective spatial resolution. BET-masking only improves M0-T1w registration when the M0 image has sufficient contrast.

Published
2017
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16. Neurofilament light chain: a biomarker for genetic frontotemporal dementia

Author

Meeter, L.H.H. (Lieke), Dopper, E.G.P. (Elise), Jiskoot, L.C. (Lize), Sánchez-Valle, R. (Raquel), Graff, C. (Caroline), Benussi, L. (Luisa), Ghidoni, R. (Roberta), Pijnenburg, Y.A.L. (Yolande), Borroni, B. (Barbara), Galimberti, D. (Daniela), Laforce, R. (Robert), Masellis, M. (Mario), Vandenberghe, R. (Rik), Ber, I.L. (Isabelle Le), Otto, M. (Markus), Thornton, A.S. (Andrew), Papma, J.M. (Janne), Rombouts, S.A.R.B. (Serge), Balasa, M. (Mircea), Öijerstedt, L. (Linn), Jelic, V. (Vesna), Dick, K.M. (Katrina M.), Cash, D.M. (David M.), Harding, S.R. (Sophie R.), Jorge Cardoso, M. (M.), Ourselin, S. (Sebastien), Rossor, M. (Martin), Padovani, A. (Alessandro), Scarpini, E. (Elio), Fenoglio, C. (Chiara), Tartaglia, M.C. (Maria Carmela), Lamari, F. (Foudil), Barro, C. (Christian), Kuhle, J. (Jens), Rohrer, J.D. (Jonathan), Teunissen, C.E. (Charlotte), Swieten, J.C. (John) van, Meeter, L.H.H. (Lieke), Dopper, E.G.P. (Elise), Jiskoot, L.C. (Lize), Sánchez-Valle, R. (Raquel), Graff, C. (Caroline), Benussi, L. (Luisa), Ghidoni, R. (Roberta), Pijnenburg, Y.A.L. (Yolande), Borroni, B. (Barbara), Galimberti, D. (Daniela), Laforce, R. (Robert), Masellis, M. (Mario), Vandenberghe, R. (Rik), Ber, I.L. (Isabelle Le), Otto, M. (Markus), Thornton, A.S. (Andrew), Papma, J.M. (Janne), Rombouts, S.A.R.B. (Serge), Balasa, M. (Mircea), Öijerstedt, L. (Linn), Jelic, V. (Vesna), Dick, K.M. (Katrina M.), Cash, D.M. (David M.), Harding, S.R. (Sophie R.), Jorge Cardoso, M. (M.), Ourselin, S. (Sebastien), Rossor, M. (Martin), Padovani, A. (Alessandro), Scarpini, E. (Elio), Fenoglio, C. (Chiara), Tartaglia, M.C. (Maria Carmela), Lamari, F. (Foudil), Barro, C. (Christian), Kuhle, J. (Jens), Rohrer, J.D. (Jonathan), Teunissen, C.E. (Charlotte), and Swieten, J.C. (John) van

Abstract

Objective: To evaluate cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels in genetic frontotemporal dementia (FTD) as a potential biomarker in the presymptomatic stage and during the conversion into the symptoma

Published
2016
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