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230 results on '"Cantoni, Valentina"'

1. A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Author

Swift, Imogen J., Rademakers, Rosa, Finch, NiCole, Baker, Matt, Ghidoni, Roberta, Benussi, Luisa, Binetti, Giuliano, Rossi, Giacomina, Synofzik, Matthis, Wilke, Carlo, Mengel, David, Graff, Caroline, Takada, Leonel T., Sánchez-Valle, Raquel, Antonell, Anna, Galimberti, Daniela, Fenoglio, Chiara, Serpente, Maria, Arcaro, Marina, Schreiber, Stefanie, Vielhaber, Stefan, Arndt, Philipp, Santana, Isabel, Almeida, Maria Rosario, Moreno, Fermín, Barandiaran, Myriam, Gabilondo, Alazne, Stubert, Johannes, Gómez-Tortosa, Estrella, Agüero, Pablo, Sainz, M. José, Gohda, Tomohito, Murakoshi, Maki, Kamei, Nozomu, Kittel-Schneider, Sarah, Reif, Andreas, Weigl, Johannes, Jian, Jinlong, Liu, Chuanju, Serrero, Ginette, Greither, Thomas, Theil, Gerit, Lohmann, Ebba, Gazzina, Stefano, Bagnoli, Silvia, Coppola, Giovanni, Bruni, Amalia, Quante, Mirja, Kiess, Wieland, Hiemisch, Andreas, Jurkutat, Anne, Block, Matthew S., Carlson, Aaron M., Bråthen, Geir, Sando, Sigrid Botne, Grøntvedt, Gøril Rolfseng, Lauridsen, Camilla, Heslegrave, Amanda, Heller, Carolin, Abel, Emily, Gómez-Núñez, Alba, Puey, Roger, Arighi, Andrea, Rotondo, Enmanuela, Jiskoot, Lize C., Meeter, Lieke H. H., Durães, João, Lima, Marisa, Tábuas-Pereira, Miguel, Lemos, João, Boeve, Bradley, Petersen, Ronald C., Dickson, Dennis W., Graff-Radford, Neill R., LeBer, Isabelle, Sellami, Leila, Lamari, Foudil, Clot, Fabienne, Borroni, Barbara, Cantoni, Valentina, Rivolta, Jasmine, Lleó, Alberto, Fortea, Juan, Alcolea, Daniel, Illán-Gala, Ignacio, Andres-Cerezo, Lucie, Van Damme, Philip, Clarimon, Jordi, Steinacker, Petra, Feneberg, Emily, Otto, Markus, van der Ende, Emma L., van Swieten, John C., Seelaar, Harro, Zetterberg, Henrik, Sogorb-Esteve, Aitana, and Rohrer, Jonathan D.

Published
2024
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2. Diagnostic accuracy of research criteria for prodromal frontotemporal dementia

Author

Benussi, Alberto, Premi, Enrico, Grassi, Mario, Alberici, Antonella, Cantoni, Valentina, Gazzina, Stefano, Archetti, Silvana, Gasparotti, Roberto, Fumagalli, Giorgio G., Bouzigues, Arabella, Russell, Lucy L., Samra, Kiran, Cash, David M., Bocchetta, Martina, Todd, Emily G., Convery, Rhian S., Swift, Imogen, Sogorb-Esteve, Aitana, Heller, Carolin, van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert Jr., Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B., Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, Mendonça, Alexandre, Tiraboschi, Pietro, Butler, Chris R., Santana, Isabel, Gerhard, Alexander, Le Ber, Isabelle, Pasquier, Florence, Ducharme, Simon, Levin, Johannes, Sorbi, Sandro, Otto, Markus, Padovani, Alessandro, Rohrer, Jonathan D., and Borroni, Barbara

Published
2024
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4. Network structure and transcriptomic vulnerability shape atrophy in frontotemporal dementia

Author

Shafiei, Golia, Bazinet, Vincent, Dadar, Mahsa, Manera, Ana L, Collins, D Louis, Dagher, Alain, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B, Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Butler, Chris, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Jiskoot, Lize C, Seelaar, Harro, van Swieten, John C, Rohrer, Jonathan D, Misic, Bratislav, Ducharme, Simon, Initiative, Frontotemporal Lobar Degeneration Neuroimaging, Rosen, Howard, Dickerson, Bradford C, Domoto-Reilly, Kimoko, Knopman, David, Boeve, Bradley F, Boxer, Adam L, Kornak, John, Miller, Bruce L, Seeley, William W, Gorno-Tempini, Maria-Luisa, McGinnis, Scott, Mandelli, Maria Luisa, Initiative, GENetic Frontotemporal dementia, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Russell, Lucy L, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, 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, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, van der Ende, Emma, Poos, Jackie, Papma, Janne M, Giannini, Lucia, and van Minkelen, Rick

Subjects
Biomedical and Clinical Sciences, Health Sciences, Psychology, Acquired Cognitive Impairment, Dementia, Aging, Neurodegenerative, Frontotemporal Dementia (FTD), Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Alzheimer's Disease, Aetiology, 2.1 Biological and endogenous factors, Neurological, Humans, Frontotemporal Dementia, Transcriptome, Brain, Pick Disease of the Brain, Atrophy, Connectome, Magnetic Resonance Imaging, Neuropsychological Tests, Frontotemporal Lobar Degeneration Neuroimaging Initiative, GENetic Frontotemporal dementia Initiative, connectome, disease epicentre, frontotemporal dementia, gene expression, network spreading, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Biomedical and clinical sciences, Health sciences
Abstract

Connections among brain regions allow pathological perturbations to spread from a single source region to multiple regions. Patterns of neurodegeneration in multiple diseases, including behavioural variant of frontotemporal dementia (bvFTD), resemble the large-scale functional systems, but how bvFTD-related atrophy patterns relate to structural network organization remains unknown. Here we investigate whether neurodegeneration patterns in sporadic and genetic bvFTD are conditioned by connectome architecture. Regional atrophy patterns were estimated in both genetic bvFTD (75 patients, 247 controls) and sporadic bvFTD (70 patients, 123 controls). First, we identified distributed atrophy patterns in bvFTD, mainly targeting areas associated with the limbic intrinsic network and insular cytoarchitectonic class. Regional atrophy was significantly correlated with atrophy of structurally- and functionally-connected neighbours, demonstrating that network structure shapes atrophy patterns. The anterior insula was identified as the predominant group epicentre of brain atrophy using data-driven and simulation-based methods, with some secondary regions in frontal ventromedial and antero-medial temporal areas. We found that FTD-related genes, namely C9orf72 and TARDBP, confer local transcriptomic vulnerability to the disease, modulating the propagation of pathology through the connectome. Collectively, our results demonstrate that atrophy patterns in sporadic and genetic bvFTD are jointly shaped by global connectome architecture and local transcriptomic vulnerability, providing an explanation as to how heterogenous pathological entities can lead to the same clinical syndrome.

Published
2023

11. Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

Author

Nelson, Annabel, Thomas, David L., Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, 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, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Samra, Kiran, MacDougall, Amy M., Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Jiskoot, Lize, Seelaar, Harro, Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alex, Ducharme, Simon, Le Ber, Isabelle, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., and Russell, Lucy L.

Published
2023
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12. Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study

Author

Esteve, Aitana Sogorb, Heller, Carolin, Greaves, Caroline V., Zetterberg, Henrik, Swift, Imogen J., Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Premi, Enrico, Pengo, Marta, Mattioli, Irene, Cantoni, Valentina, Dukart, Juergen, Gasparotti, Roberto, Buratti, Emanuele, Padovani, Alessandro, Bocchetta, Martina, Todd, Emily G., Bouzigues, Arabella, Cash, David M., Convery, Rhian S., Russell, Lucy L., Foster, Phoebe, Thomas, David L., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Jr, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Tsvetanov, Kamen A., Vandenberghe, Rik, Finger, Elizabeth, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris R., Ducharme, Simon, Gerhard, Alexander, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Rohrer, Jonathan D., and Borroni, Barbara

Published
2023
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13. Structural brain splitting is a hallmark of Granulin-related frontotemporal dementia

Author

Afonso, Sónia, Almeida, Maria Rosario, Andersson, Christin, Antonell, Anna, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bouzigues, Arabella, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, Fede, Giuseppe Di, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gauthier, Serge, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Lombardi, Jolina, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Panman, Jessica, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Gazzina, Stefano, Grassi, Mario, Premi, Enrico, Alberici, Antonella, Benussi, Alberto, Archetti, Silvana, Gasparotti, Roberto, Bocchetta, Martina, Cash, David M., Todd, Emily G., Peakman, Georgia, Convery, Rhian S., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Jr, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Rowe, James B., Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Butler, Chris R., Santana, Isabel, Gerhard, Alexander, Ber, Isabelle Le, Pasquier, Florence, Ducharme, Simon, Levin, Johannes, Danek, Adrian, Sorbi, Sandro, Otto, Markus, Rohrer, Jonathan D., and Borroni, Barbara

Published
2022
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14. Examining empathy deficits across familial forms of frontotemporal dementia within the GENFI cohort

Author

Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L., Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Foster, Phoebe H., Russell, Lucy L., Peakman, Georgia, Convery, Rhian S., Bouzigues, Arabella, Greaves, Caroline V., Bocchetta, Martina, Cash, David M., van Swieten, John C., Jiskoot, Lize C., Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alex, Ducharme, Simon, Le Ber, Isabelle, Tagliavini, Fabrizio, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, and Rohrer, Jonathan D.

Published
2022
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15. Alpha tACS Improves Cognition and Modulates Neurotransmission in Dementia with Lewy Bodies.

Author

Benussi, Alberto, Cantoni, Valentina, Rivolta, Jasmine, Zoppi, Nicola, Cotelli, Maria Sofia, Bianchi, Marta, Cotelli, Maria, and Borroni, Barbara

Abstract

Background: Dementia with Lewy bodies (DLB) is characterized by a marked shift of electroencephalographic (EEG) power and dominant rhythm, from the α toward the θ frequency range. Transcranial alternate current stimulation (tACS) is a non‐invasive brain stimulation technique that allows entrainment of cerebral oscillations at desired frequencies. Objectives: Our goal is to evaluate the effects of occipital α‐tACS on cognitive functions and neurophysiological measures in patients with DLB. Methods: We conducted a double‐blind, randomized, sham‐controlled, cross‐over clinical trial in 14 participants with DLB. Participants were randomized to receive either α‐tACS (60 minutes of 3 mA peak‐to‐peak stimulation at 12 Hz) or sham stimulation applied over the occipital cortex. Clinical evaluations were performed to assess visuospatial and executive functions, as well as verbal episodic memory. Neurophysiological assessments and EEG recordings were conducted at baseline and following both α‐tACS and sham stimulations. Results: Occipital α‐tACS was safe and well‐tolerated. We observed a significant enhancement in visuospatial abilities and executive functions, but no improvement in verbal episodic memory. We observed an increase in short latency afferent inhibition, a neurophysiological marker indirectly and partially dependent on cholinergic transmission, coinciding with an increase in α power and a decrease in Δ power following α‐tACS stimulation, effects not seen with sham stimulation. Conclusions: This study demonstrates that occipital α‐tACS is safe and enhances visuospatial and executive functions in patients with DLB. Improvements in indirect markers of cholinergic transmission and EEG changes indicate significant neurophysiological engagement. These findings justify further exploration of α‐tACS as a therapeutic option for DLB patients. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Published
2024
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16. Serum total TDP-43 levels are decreased in frontotemporal dementia patients with C9orf72 repeat expansion or concomitant motoneuron disease phenotype

Author

Katisko, Kasper, Huber, Nadine, Kokkola, Tarja, Hartikainen, Päivi, Krüger, Johanna, Heikkinen, Anna-Leena, Paananen, Veera, Leinonen, Ville, Korhonen, Ville E., Helisalmi, Seppo, Herukka, Sanna-Kaisa, Cantoni, Valentina, Gadola, Yasmine, Archetti, Silvana, Remes, Anne M., Haapasalo, Annakaisa, Borroni, Barbara, and Solje, Eino

Published
2022
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20. Differential early subcortical involvement in genetic FTD within the GENFI cohort

Author

Afonso, Sónia, Rosario Almeida, Maria, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, João Leitão, Maria, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Bocchetta, Martina, Todd, Emily G., Peakman, Georgia, Cash, David M., Convery, Rhian S., Russell, Lucy L., Thomas, David L., Eugenio Iglesias, Juan, van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Borroni, Barbara, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Carmela Tartaglia, Maria, Rowe, James B., Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris R., Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, and Rohrer, Jonathan D.

Published
2021
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24. Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia

Author

Samra, Kiran, Peakman, Georgia, MacDougall, Amy M., Bouzigues, Arabella, Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Jiskoot, Lize, Seelaar, Harro, Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alexander, Ducharme, Simon, Ber, Isabelle Le, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Russell, Lucy L., Bocchetta, Martina, Cash, David, Thomas, David L., 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, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Samra, Kiran, Peakman, Georgia, MacDougall, Amy M., Bouzigues, Arabella, Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Jiskoot, Lize, Seelaar, Harro, Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alexander, Ducharme, Simon, Ber, Isabelle Le, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Russell, Lucy L., Bocchetta, Martina, Cash, David, Thomas, David L., 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, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, and Afonso, Sónia

Abstract

INTRODUCTION: We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). METHODS: Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). RESULTS: The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. DISCUSSION: Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. Highlights: The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS). No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale. Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains. A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.

Published
2024

27. Impaired glymphatic system in genetic frontotemporal dementia: a GENFI study.

Author

Premi, Enrico, Diano, Matteo, Mattioli, Irene, Altomare, Daniele, Cantoni, Valentina, Bocchetta, Martina, Gasparotti, Roberto, Buratti, Emanuele, Pengo, Marta, Bouzigues, Arabella, Russell, Lucy L, Foster, Phoebe H, Ferry-Bolder, Eve, Heller, Carolin, Swieten, John C van, Jiskoot, Lize C, Seelaar, Harro, Moreno, Fermin, Sanchez-Valle, Raquel, and Galimberti, Daniela

Published
2024
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30. Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers: a GENFI study

Author

Pérez-Millan, Agnès, Borrego-Écija, Sergi, van Swieten, John C., Jiskoot, Lize, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Tiraboschi, Pietro, Seelaar, Harro, Langheinrich, Tobias, Rohrer, Jonathan D., Sala-Llonch, Roser, Sánchez-Valle, Raquel, GENFI The Genetic FTD Initiative, Ullgren, Abbe, Rollin, Adeline, Camuzat, Agnès, Esteve, Aitana Sogorb, Gabilondo, Alazne, Lladó, Albert, Benussi, Alberto, Brice, Alexis, Gorostidi, Ana, Verdelho, Ana, Arighi, Andrea, Antonell, Anna, Bertrand, Anne, Engel, Annerose, Vogels, Annick, Bouzigues, Arabella, Funkiewiez, Aurélie, Nacmias, Benedetta, Bender, Benjamin, Ferrari, Camilla, Wilke, Carlo, Heller, Carolin, Maruta, Carolina, Greaves, Caroline V., Timberlake, Carolyn, Ferreira, Catarina B., Prix, Catharina, Fenoglio, Chiara, Shoesmith, Christen, Polito, Cristina, Rinaldi, Daisy, Saracino, Dario, Cash, David, Thomas, David L., Tang-Wai, David, Duro, Diana, Rogaeva, Ekaterina, Scarpini, Elio, Wlasich, Elisabeth, Buratti, Emanuele, Todd, Emily, Premi, Enrico, do Couto, Frederico Simões, Miltenberger, Gabriel, Lombardi, Gemma, Rossi, Giacomina, Fumagalli, Giorgio, Giaccone, Giorgio, Di Fede, Giuseppe, Kuchcinski, Gregory, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J., Poos, Jackie, M. Papma, Janne, Nicholas, Jennifer, Durães, João, Lombardi, Jolina, Juncà-Parella, Jordi, Sarto, Jordi, Villanua, Jorge, Samra, Kiran, Poesen, Koen, Öijerstedt, Linn, Graf, Lisa, Giannini, Lucia, Russell, Lucy L., Leitão, Maria João, Almeida, Maria Rosario, Serpente, Maria, Lima, Marisa, Cañada, Marta, Bocchetta, Martina, Polyakova, Maryna, Vandenbulcke, Mathieu, Bertoux, Maxime, Veldsman, Michele, Castelo-Branco, Miguel, Tábuas-Pereira, Miguel, Tainta, Mikel, Balasa, Mircea, Zulaica, Miren, Freedman, Morris, Barandiaran, Myriam, Bargalló, Nuria, Wagemann, Olivia, Colliot, Olivier, Caroppo, Paola, Alves, Patricia, Thompson, Paul, Rosa-Neto, Pedro, Van Damme, Philip, Shafei, Rachelle, Convery, Rhian S., van Minkelen, Rick, Bartha, Robart, Gasparotti, Roberto, Keren, Ron, Rademakers, Rosa, Bruffaerts, Rose, Sayah, Sabrina, Black, Sandra, Loosli, Sandra, Mitchell, Sara, Prioni, Sara, Anderl-Straub, Sarah, Gauthier, Serge, Afonso, Sónia, Schönecker, Sonja, Gazzina, Stefano, Lebouvier, Thibaud, Cope, Thomas, Rittman, Timothy, Hoegen, Tobias, Bessi, Valentina, Cantoni, Valentina, Redaelli, Veronica, Jelic, Vesna, Deramecourt, Vincent, Borracci, Vittoria, The Genetic FTD Initiative, GENFI, Almeida, Maria Rosario, Serpente, Maria, Lima, Marisa, Cañada, Marta, Bocchetta, Martina, Polyakova, Maryna, Vandenbulcke, Mathieu, Bertoux, Maxime, Veldsman, Michele, Castelo-Branco, Miguel, Tábuas-Pereira, Miguel, Tainta, Mikel, Balasa, Mircea, Zulaica, Miren, Freedman, Morris, Barandiaran, Myriam, Bargalló, Nuria, Wagemann, Olivia, Colliot, Olivier, Caroppo, Paola, Alves, Patricia, Thompson, Paul, Rosa-Neto, Pedro, Van Damme, Philip, Tiraboschi, Pietro, Shafei, Rachelle, Convery, Rhian S, van Minkelen, Rick, Bartha, Robart, Gasparotti, Roberto, Keren, Ron, Rademakers, Rosa, Bruffaerts, Rose, Sayah, Sabrina, Black, Sandra, Loosli, Sandra, Mitchell, Sara, Prioni, Sara, Anderl-Straub, Sarah, Gauthier, Serge, Afonso, Sónia, Schönecker, Sonja, Gazzina, Stefano, Lebouvier, Thibaud, Cope, Thomas, Rittman, Timothy, Hoegen, Tobias, Bessi, Valentina, Cantoni, Valentina, Redaelli, Veronica, Jelic, Vesna, Deramecourt, Vincent, Borracci, Vittoria, Ullgren, Abbe, Rollin, Adeline, Camuzat, Agnès, Esteve, Aitana Sogorb, Gabilondo, Alazne, Lladó, Albert, Benussi, Alberto, Brice, Alexis, Gorostidi, Ana, Verdelho, Ana, Arighi, Andrea, Antonell, Anna, Bertrand, Anne, Engel, Annerose, Vogels, Annick, Bouzigues, Arabella, Funkiewiez, Aurélie, Nacmias, Benedetta, Bender, Benjamin, Ferrari, Camilla, Wilke, Carlo, Heller, Carolin, Maruta, Carolina, Greaves, Caroline V, Timberlake, Carolyn, Ferreira, Catarina B, Prix, Catharina, Fenoglio, Chiara, Shoesmith, Christen, Polito, Cristina, Rinaldi, Daisy, Saracino, Dario, Cash, David, Thomas, David L, Tang-Wai, David, Duro, Diana, Rogaeva, Ekaterina, Scarpini, Elio, Wlasich, Elisabeth, Buratti, Emanuele, Todd, Emily, Premi, Enrico, do Couto, Frederico Simões, Miltenberger, Gabriel, Lombardi, Gemma, Rossi, Giacomina, Fumagalli, Giorgio, Giaccone, Giorgio, Di Fede, Giuseppe, Kuchcinski, Gregory, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Poos, Jackie, M Papma, Janne, Nicholas, Jennifer, Durães, João, Lombardi, Jolina, Juncà-Parella, Jordi, Sarto, Jordi, Villanua, Jorge, Samra, Kiran, Poesen, Koen, Öijerstedt, Linn, Graf, Lisa, Giannini, Lucia, Russell, Lucy L, and Leitão, Maria João

Subjects
diagnostic imaging [Brain Stem], pathology [Motor Neurons], diagnostic imaging [Motor Neuron Disease], diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [White Matter], pathology [Brain Stem], Neurology, pathology [White Matter], pathology [Frontotemporal Dementia], Mutation, C9orf72, Humans, genetics [Motor Neuron Disease], ddc:610, Human medicine, Neurology (clinical), genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], Brainstem, GENFI, Frontotemporal dementia
Abstract

Background and objectives The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. Methods We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. Results A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. Discussion We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.

Published
2022
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32. Prodromal language impairment in genetic frontotemporal dementia within the GENFI cohort

Author

Samra, Kiran, primary, MacDougall, Amy M., additional, Bouzigues, Arabella, additional, Bocchetta, Martina, additional, Cash, David M., additional, Greaves, Caroline V., additional, Convery, Rhian S., additional, van Swieten, John C., additional, Jiskoot, Lize, additional, Seelaar, Harro, additional, Moreno, Fermin, additional, Sanchez-Valle, Raquel, additional, Laforce, Robert, additional, Graff, Caroline, additional, Masellis, Mario, additional, Tartaglia, Maria Carmela, additional, Rowe, James B., additional, Borroni, Barbara, additional, Finger, Elizabeth, additional, Synofzik, Matthis, additional, Galimberti, Daniela, additional, Vandenberghe, Rik, additional, de Mendonça, Alexandre, additional, Butler, Chris R., additional, Gerhard, Alex, additional, Ducharme, Simon, additional, Le Ber, Isabelle, additional, Tiraboschi, Pietro, additional, Santana, Isabel, additional, Pasquier, Florence, additional, Levin, Johannes, additional, Otto, Markus, additional, Sorbi, Sandro, additional, Rohrer, Jonathan D., additional, Russell, Lucy L., additional, Nelson, Annabel, additional, Thomas, David L., additional, Todd, Emily, additional, Benotmane, Hanya, additional, Nicholas, Jennifer, additional, Shafei, Rachelle, additional, Timberlake, Carolyn, additional, Cope, Thomas, additional, Rittman, Timothy, additional, Benussi, Alberto, additional, Premi, Enrico, additional, Gasparotti, Roberto, additional, Archetti, Silvana, additional, Gazzina, Stefano, additional, Cantoni, Valentina, additional, Arighi, Andrea, additional, Fenoglio, Chiara, additional, Scarpini, Elio, additional, Fumagalli, Giorgio, additional, Borracci, Vittoria, additional, Rossi, Giacomina, additional, Giaccone, Giorgio, additional, Di Fede, Giuseppe, additional, Caroppo, Paola, additional, Prioni, Sara, additional, Redaelli, Veronica, additional, Tang-Wai, David, additional, Rogaeva, Ekaterina, additional, Castelo-Branco, Miguel, additional, Freedman, Morris, additional, Keren, Ron, additional, Black, Sandra, additional, Mitchell, Sara, additional, Shoesmith, Christen, additional, Bartha, Robart, additional, Rademakers, Rosa, additional, Poos, Jackie, additional, Papma, Janne M., additional, Giannini, Lucia, additional, van Minkelen, Rick, additional, Pijnenburg, Yolande, additional, Nacmias, Benedetta, additional, Ferrari, Camilla, additional, Polito, Cristina, additional, Lombardi, Gemma, additional, Bessi, Valentina, additional, Veldsman, Michele, additional, Andersson, Christin, additional, Thonberg, Hakan, additional, Öijerstedt, Linn, additional, Jelic, Vesna, additional, Thompson, Paul, additional, Langheinrich, Tobias, additional, Lladó, Albert, additional, Antonell, Anna, additional, Olives, Jaume, additional, Balasa, Mircea, additional, Bargalló, Nuria, additional, Borrego-Ecija, Sergi, additional, Verdelho, Ana, additional, Maruta, Carolina, additional, Ferreira, Catarina B., additional, Miltenberger, Gabriel, additional, do Couto, Frederico Simões, additional, Gabilondo, Alazne, additional, Gorostidi, Ana, additional, Villanua, Jorge, additional, Cañada, Marta, additional, Tainta, Mikel, additional, Zulaica, Miren, additional, Barandiaran, Myriam, additional, Alves, Patricia, additional, Bender, Benjamin, additional, Wilke, Carlo, additional, Graf, Lisa, additional, Vogels, Annick, additional, Vandenbulcke, Mathieu, additional, Van Damme, Philip, additional, Bruffaerts, Rose, additional, Poesen, Koen, additional, Rosa-Neto, Pedro, additional, Gauthier, Serge, additional, Camuzat, Agnès, additional, Brice, Alexis, additional, Bertrand, Anne, additional, Funkiewiez, Aurélie, additional, Rinaldi, Daisy, additional, Saracino, Dario, additional, Colliot, Olivier, additional, Sayah, Sabrina, additional, Prix, Catharina, additional, Wlasich, Elisabeth, additional, Wagemann, Olivia, additional, Loosli, Sandra, additional, Schönecker, Sonja, additional, Hoegen, Tobias, additional, Lombardi, Jolina, additional, Anderl-Straub, Sarah, additional, Rollin, Adeline, additional, Kuchcinski, Gregory, additional, Bertoux, Maxime, additional, Lebouvier, Thibaud, additional, Deramecourt, Vincent, additional, Santiago, Beatriz, additional, Duro, Diana, additional, Leitão, Maria João, additional, Almeida, Maria Rosario, additional, Tábuas-Pereira, Miguel, additional, and Afonso, Sónia, additional

Published
2023
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33. Language impairment in the genetic forms of behavioural variant frontotemporal dementia

Author

Samra, Kiran, MacDougall, Amy M., Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Seelaar, Harro, Jiskoot, Lize, Moreno, Fermin, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Sanchez-Valle, Raquel, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Laforce, Robert, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Graff, Caroline, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Masellis, Mario, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, De Mendonça, Alexandre, Butler, Christopher R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Russell, Lucy L., Nelson, Annabel, Thomas, David L., Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, 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, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger-Miltenyi, Gabriel, Simões Do Couto, Frederico, Neurology, Amsterdam Neuroscience - Neurodegeneration, Repositório da Universidade de Lisboa, Genetic FTD Initiative (GENFI), Erasmus MC other, Radiology & Nuclear Medicine, Clinical Genetics, Samra, Kiran [0000-0002-3105-7099], Apollo - University of Cambridge Repository, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Nelson, Annabel, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, 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, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, and Miltenberger, Gabriel

Subjects
Progranulin, Medizin, genetics [Mutation], tau Proteins, diagnostic imaging [Frontotemporal Dementia], frontotemporal dementia, Settore BIO/13 - Biologia Applicata, C9orf72, progranulin, Genetics, Humans, genetics, Language Development Disorders, ddc:610, tau, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], Frontotemporal dementia, Language, Tau, language, C9orf72 Protein, Magnetic Resonance Imaging, genetics [tau Proteins], Neurology, FOS: Biological sciences, Frontotemporal Dementia, Mutation, Human medicine, Neurology (clinical), Atrophy
Abstract

Funder: CIBERNED, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative Schorling Foundation, Funder: Swedish Alzheimer Foundation, Funder: Karolinska Institutet; doi: http://dx.doi.org/10.13039/501100004047, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Miriam Marks Brain Research UK, BACKGROUND: Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. METHODS: Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. RESULTS: 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. CONCLUSIONS: Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.

Published
2023
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35. Temporal order of clinical and biomarker changes in familial frontotemporal dementia

Author

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

Subjects
Clinical Trials as Topic, C9orf72 Protein, biomarkers, genetics [Mutation], tau Proteins, General Medicine, Article, General Biochemistry, Genetics and Molecular Biology, genetics [tau Proteins], Chemistry, Frontotemporal Dementia, Mutation, Disease Progression, Humans, ddc:610, Human medicine, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Biology, Biomarkers, dementia
Abstract

Data availability: The datasets analyzed for the current study reflect collaborative efforts of two research consortia: ALLFTD and GENFI. Each consortium provides clinical data access based on established policies for data use: processes for request are available for review at allftd.org/data for ALLFTD data and by emailing genfi@ucl.ac.uk. Certain data elements from both consortia (for example raw MRI images) may be restricted due to the potential for identifiability in the context of the sensitive nature of the genetic data. The deidentified combined dataset will be available for request through the FTD Prevention Initiative in 2023 (https://www.thefpi.org/). Code availability: Custom R code is available at https://doi.org/10.5281/zenodo.6687486. Copyright © The Author(s). Unlike 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, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects. Data collection and dissemination of the data presented in this paper were supported by the ALLFTD Consortium (U19: AG063911, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke) and the former ARTFL and LEFFTDS Consortia (ARTFL: U54 NS092089, funded by the National Institute of Neurological Diseases and Stroke and National Center for Advancing Translational Sciences; LEFFTDS: U01 AG045390, funded by the National Institute on Aging and the National Institute of Neurological Diseases and Stroke). The manuscript was reviewed by the ALLFTD Executive Committee for scientific content. The authors acknowledge the invaluable contributions of the study participants and families as well as the assistance of the support staffs at each of the participating sites. This work is also supported by the Association for Frontotemporal Degeneration (including the FTD Biomarkers Initiative), the Bluefield Project to Cure FTD, Larry L. Hillblom Foundation (2018-A-025-FEL (A.M.S.)), the National Institutes of Health (AG038791 (A.L.B.), AG032306 (H.J.R.), AG016976 (W.K.), AG062677 (Ron C. Peterson), AG019724 (B.L.M.), AG058233 (Suzee E. Lee), AG072122 (Walter Kukull), P30 AG062422 (B.L.M.), K12 HD001459 (N.G.), K23AG061253 (A.M.S.), AG062422 (RCP), K24AG045333 (H.J.R.)) and the Rainwater Charitable Foundation. Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias (NCRAD), which receives government support under a cooperative agreement grant (U24 AG021886 (T.F.)) awarded by the National Institute on Aging (NIA), were used in this study. This work was also supported by Medical Research Council UK GENFI grant MR/M023664/1 (J.D.R.), the Bluefield Project, the National Institute for Health Research including awards to Cambridge and UCL Biomedical Research Centres and a JPND GENFI-PROX grant (2019–02248). Several authors of this publication are members of the European Reference Network for Rare Neurologic Diseases, project 739510. J.D.R. and L.L.R. are also supported by the National Institute for Health and Care Research (NIHR) UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.D.R. is also supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a-004-517). RC and C.G. are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). J.B.R. is supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014; the views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care), the Wellcome Trust (220258), the Cambridge Centre for Parkinson-plus and the Medical Research Council (SUAG/092 G116768); I.L.B. is supported by ANR-PRTS PREV-DemAls, PHRC PREDICT-PGRN, and several authors of this publication are members of the European Reference Network for Rare Neurological Diseases (project 739510). J.L. is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). R.S.-V. was funded at the Hospital Clinic de Barcelona by Instituto de Salud Carlos III, Spain (grant code PI20/00448 to RSV) and Fundació Marató TV3, Spain (grant code 20143810 to R.S.-V.). M.M. was, in part, funded by the UK Medical Research Council, the Italian Ministry of Health and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, by Canadian Institutes of Health Research operating grants (MOP- 371851 and PJT-175242) and by funding from the Weston Brain Institute. R.L. is supported by the Canadian Institutes of Health Research and the Chaire de Recherche sur les Aphasies Primaires Progressives Fondation Famille Lemaire. C.G. is supported by the Swedish Frontotemporal Dementia Initiative Schörling Foundation, Swedish Research Council, JPND Prefrontals, 2015–02926,2018–02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Karolinska Institutet Doctoral Funding, KI Strat-Neuro, Swedish Dementia Foundation, and Stockholm County Council ALF/Region Stockholm. J.L. is supported by Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (German Research Foundation, EXC 2145 Synergy 390857198). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK.

Published
2022
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37. Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative cohort

Author

Bocchetta, Martina, Todd, Emily G, Bouzigues, Arabella, Cash, David M, Nicholas, Jennifer M, Convery, Rhian S, Russell, Lucy L, Thomas, David L, Malone, Ian B, Iglesias, Juan Eugenio, Van Swieten, John C, Jiskoot, Lize C, Seelaar, Harro, Borroni, Barbara, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, De Mendonca, Alexandre, Santana, Isabel, Butler, Chris R, Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Rohrer, Jonathan D, Esteve, Aitana Sogorb, Nelson, Annabel, Heller, Carolin, Greaves, Caroline V, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, 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, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Bocchetta, Martina [0000-0003-1814-5024], Todd, Emily G [0000-0003-1551-5691], Cash, David M [0000-0001-7833-616X], Malone, Ian B [0000-0001-7512-7856], Jiskoot, Lize C [0000-0002-1120-1858], Seelaar, Harro [0000-0003-1989-7527], Borroni, Barbara [0000-0001-9340-9814], Sanchez-Valle, Raquel [0000-0001-7750-896X], Synofzik, Matthis [0000-0002-2280-7273], Graff, Caroline [0000-0002-9949-2951], Vandenberghe, Rik [0000-0001-6237-2502], Ducharme, Simon [0000-0002-7309-1113], Gerhard, Alexander [0000-0002-8071-6062], Danek, Adrian [0000-0001-8857-5383], Pasquier, Florence [0000-0001-9880-9788], Apollo - University of Cambridge Repository, Genetic Frontotemporal dementia Initiative (GENFI), Neurology, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Esteve, Aitana Sogorb, Nelson, Annabel, Heller, Carolin, Greaves, Caroline V, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, 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, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, and Balasa, Mircea

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, Neurology, SDG 3 - Good Health and Well-being, brain volumetry, diffusion imaging, genetic frontotemporal dementia, MRI imaging, Medizin, presymptomatic stage, ddc:610, Biological Psychiatry
Abstract

Funder: Deutsche Forschungsgemeinschaft, Funder: Dementia Research Institute, Funder: Leonard Wolfson Experimental Neurology Centre, Funder: Canadian Institutes of Health Research, Funder: Medical Research Council, Funder: Miriam Marks Brain Research UK Senior Fellowship, Funder: Wolfson Foundation, Funder: Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie, Funder: NVIDIA, Funder: Alzheimer's Research UK, Funder: Alzheimer's Society and Alzheimer's Research, Funder: Brain Research UK, Funder: University College London, Biomarkers that can predict disease progression in individuals with genetic frontotemporal dementia are urgently needed. We aimed to identify whether baseline MRI-based grey and white matter abnormalities are associated with different clinical progression profiles in presymptomatic mutation carriers in the GENetic Frontotemporal dementia Initiative. Three hundred eighty-seven mutation carriers were included (160 GRN, 160 C9orf72, 67 MAPT), together with 240 non-carrier cognitively normal controls. Cortical and subcortical grey matter volumes were generated using automated parcellation methods on volumetric 3T T1-weighted MRI scans, while white matter characteristics were estimated using diffusion tensor imaging. Mutation carriers were divided into two disease stages based on their global CDR®+NACC-FTLD score: presymptomatic (0 or 0.5) and fully symptomatic (1 or greater). The w-scores in each grey matter volumes and white matter diffusion measures were computed to quantify the degree of abnormality compared to controls for each presymptomatic carrier, adjusting for their age, sex, total intracranial volume, and scanner type. Presymptomatic carriers were classified as 'normal' or 'abnormal' based on whether their grey matter volume and white matter diffusion measure w-scores were above or below the cut point corresponding to the 10th percentile of the controls. We then compared the change in disease severity between baseline and one year later in both the 'normal' and 'abnormal' groups within each genetic subtype, as measured by the CDR®+NACC-FTLD sum-of-boxes score and revised Cambridge Behavioural Inventory total score. Overall, presymptomatic carriers with normal regional w-scores at baseline did not progress clinically as much as those with abnormal regional w-scores. Having abnormal grey or white matter measures at baseline was associated with a statistically significant increase in the CDR®+NACC-FTLD of up to 4 points in C9orf72 expansion carriers, and 5 points in the GRN group as well as a statistically significant increase in the revised Cambridge Behavioural Inventory of up to 11 points in MAPT, 10 points in GRN, and 8 points in C9orf72 mutation carriers. Baseline regional brain abnormalities on MRI in presymptomatic mutation carriers are associated with different profiles of clinical progression over time. These results may be helpful to inform stratification of participants in future trials.

Published
2023
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38. Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort

Author

Samra, Kiran, MacDougall, Amy M, Bouzigues, Arabella, Bocchetta, Martina, Cash, David M, Greaves, Caroline V, Convery, Rhian S, Hardy, Chris, van Swieten, John C, Seelaar, Harro, Jiskoot, Lize C, Moreno, Fermin, Sanchez-Valle, Raquel, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R, Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Warren, Jason D, Rohrer, Jonathan D, Russell, Lucy L, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, Arriba, María de, Fede, Giuseppe Di, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Cerveau, Institut du, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, João Leitão, Maria, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, Minkelen, Rick van, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Damme, Philip Van, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, GENetic Frontotemporal dementia Initiative (GENFI), Bruffaerts, Rose, Bocchetta, Martina [0000-0003-1814-5024], Cash, David M [0000-0001-7833-616X], Seelaar, Harro [0000-0003-1989-7527], Jiskoot, Lize C [0000-0002-1120-1858], Sanchez-Valle, Raquel [0000-0001-7750-896X], Graff, Caroline [0000-0002-9949-2951], Borroni, Barbara [0000-0001-9340-9814], Synofzik, Matthis [0000-0002-2280-7273], Vandenberghe, Rik [0000-0001-6237-2502], Gerhard, Alexander [0000-0002-8071-6062], Ducharme, Simon [0000-0002-7309-1113], Pasquier, Florence [0000-0001-9880-9788], Apollo - University of Cambridge Repository, Neurology, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, du Cerveau, Institut, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Damme, Philip Van, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Fede, Giuseppe Di, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, João Leitão, Maria, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, and Mead, Simon

Subjects
Cellular and Molecular Neuroscience, Psychiatry and Mental health, Neurology, SDG 3 - Good Health and Well-being, Medizin, MAPT, primary progressive aphasia, ddc:610, c9orf72, GRN, Biological Psychiatry
Abstract

Funder: Alzheimer's Research UK, Funder: Bluefield Project, Funder: Royal National Institute, Funder: Weston Brain Institute and Ontario Brain Institute, Funder: Alzheimer Nederland and the Bluefield, Funder: Alzheimer's Society, Funder: Dementia Research Centre, Funder: Medical Research Council, Funder: National Institute for Health Research University College London/Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre Clinical Research Facility, Funder: Alzheimer Foundation, Funder: Alzheimer's Society and Alzheimer's Research UK, Funder: Association for Frontotemporal Dementias Research Grant 2009, Funder: Brain Research UK, Funder: Dementia Research Institute Ltd, Funder: The Wolfson Foundation, Funder: UK Dementia Research Institute, Funder: UK Dementia Research Institute Ltd, Funder: Deaf People Dunhill Medical Trust Pauline Ashley Fellowship, Funder: Frontotemporal Dementia Research Studentships, Funder: Germany’s Federal Ministry of Education and Research, Funder: Miriam Marks Brain Research UK Senior Fellowship, Funder: Tau Consortium and the Center for Networked Biomedical Research, Funder: Mady Browaeys Fund for Research into Frontotemporal Dementia, Funder: Brain Foundation and Stockholm County Council ALF, Funder: Deutsche Forschungsgemeinschaft German Research Foundation under Germany’s Excellence Strategy, Funder: Alzheimer’s Research UK, Funder: Memory of David Blechner, Funder: Swedish FTD Inititative-Schörling Foundation, Primary progressive aphasia is most commonly a sporadic disorder, but in some cases, it can be genetic. This study aimed to understand the clinical, cognitive and imaging phenotype of the genetic forms of primary progressive aphasia in comparison to the canonical nonfluent, semantic and logopenic subtypes seen in sporadic disease. Participants with genetic primary progressive aphasia were recruited from the international multicentre GENetic Frontotemporal dementia Initiative study and compared with healthy controls as well as a cohort of people with sporadic primary progressive aphasia. Symptoms were assessed using the GENetic Frontotemporal dementia Initiative language, behavioural, neuropsychiatric and motor scales. Participants also underwent a cognitive assessment and 3 T volumetric T1-weighted MRI. One C9orf72 (2%), 1 MAPT (6%) and 17 GRN (44%) symptomatic mutation carriers had a diagnosis of primary progressive aphasia. In the GRN cohort, 47% had a diagnosis of nonfluent variant primary progressive aphasia, and 53% had a primary progressive aphasia syndrome that did not fit diagnostic criteria for any of the three subtypes, called primary progressive aphasia-not otherwise specified here. The phenotype of the genetic nonfluent variant primary progressive aphasia group largely overlapped with that of sporadic nonfluent variant primary progressive aphasia, although the presence of an associated atypical parkinsonian syndrome was characteristic of sporadic and not genetic disease. The primary progressive aphasia -not otherwise specified group however was distinct from the sporadic subtypes with impaired grammar/syntax in the presence of relatively intact articulation, alongside other linguistic deficits. The pattern of atrophy seen on MRI in the genetic nonfluent variant primary progressive aphasia group overlapped with that of the sporadic nonfluent variant primary progressive aphasia cohort, although with more posterior cortical involvement, whilst the primary progressive aphasia-not otherwise specified group was strikingly asymmetrical with involvement particularly of the insula and dorsolateral prefrontal cortex but also atrophy of the orbitofrontal cortex and the medial temporal lobes. Whilst there are overlapping symptoms between genetic and sporadic primary progressive aphasia syndromes, there are also distinct features. Future iterations of the primary progressive aphasia consensus criteria should encompass such information with further research needed to understand the earliest features of these disorders, particularly during the prodromal period of genetic disease.

Published
2023
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39. Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers

Author

Finger, Elizabeth, Malik, Rubina, Bocchetta, Martina, Coleman, Kristy, Graff, Caroline, Borroni, Barbara, Masellis, Mario, Laforce, Robert, Greaves, Caroline V., Russell, Lucy L., Convery, Rhian S., Bouzigues, Arabella, Cash, David M., Otto, Markus, Synofzik, Matthis, Rowe, James B., Galimberti, Daniela, Tiraboschi, Pietro, Bartha, Robert, Shoesmith, Christen, Tartaglia, Maria Carmela, van Swieten, John C., Seelaar, Harro, Jiskoot, Lize C., Sorbi, Sandro, Butler, Chris R., Gerhard, Alexander, Sanchez-Valle, Raquel, De Mendonça, Alexandre, Moreno, Fermin, Vandenberghe, Rik, Le Ber, Isabelle, Levin, Johannes, Pasquier, Florence, Santana, Isabel, Rohrer, Jonathan D., Ducharme, Simon, Esteve, Aitana Sogorb, Heller, Carolin, Thomas, David L., Todd, Emily G., Nicholas, Jennifer, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J., 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, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger-Miltenyi, Gabriel, Simões Do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Genetic FTD Initiative, GENFI, the Genetic FTD Initiative (GENFI), Repositório da Universidade de Lisboa, Bocchetta, Martina [0000-0003-1814-5024], Graff, Caroline [0000-0002-9949-2951], Borroni, Barbara [0000-0001-9340-9814], Cash, David M [0000-0001-7833-616X], Synofzik, Matthis [0000-0002-2280-7273], Seelaar, Harro [0000-0003-1989-7527], Jiskoot, Lize C [0000-0002-8120-7366], Gerhard, Alexander [0000-0002-8071-6062], Sanchez-Valle, Raquel [0000-0001-7750-896X], Vandenberghe, Rik [0000-0001-6237-2502], Pasquier, Florence [0000-0001-9880-9788], Ducharme, Simon [0000-0002-7309-1113], Apollo - University of Cambridge Repository, Neurology, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, 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, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Esteve, Aitana Sogorb, Heller, Carolin, Thomas, David L, Todd, Emily G, Nicholas, Jennifer, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, 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, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, and Borrego-Ecija, Sergi

Subjects
Adult, C9orf72 Protein, neurodevelopment, Nocturnal pulsed oximetry, Medizin, Brain, Neurodegenerative Diseases, tau Proteins, Amyotrophic lateral sclerosis, frontotemporal dementia, Phrenic nerve, Young Adult, Progranulins, Pick Disease of the Brain, Respiratory tests, Mutation, C9orf72, MAPT, Humans, ddc:610, Neurology (clinical), Human medicine, GRN, Respiratory function
Abstract

© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved., While frontotemporal dementia has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with ageing. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between 19 and 30 years of age. Structural brain differences and improved performance on some cognitive tests were found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26 years. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia-causing genetic mutations. These results have implications for the design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes that occur during the neurodevelopmental period., This project was supported by Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and by Canadian Institutes of Health Research operating grants (327387; 452843; 70797). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC), and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), the Alzheimer’s Society grant (AS-PG-16-007), the Bluefield Project and the EU Joint Programme – Neurodegenerative Disease Research (GENFI-PROX grant 2019-02248). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a- 004-517). M.B.’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). J.B.R. is funded by the Wellcome Trust (103838) and the National Institute for Health Research Cambridge Biomedical Research Centre. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). It is also funded by the Ministry of Health, Italy (S.S.). R.V.’s work is supported by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie. R.S.-V.’s work is supported by Instituto de Salud Carlos III (grant number 20/00448), cofunded by the EU. ANR-PRTS PrevdemALS study funding (I.L.B.). Several authors of this publication (J.C.vS., M.S., A.D., M.O., R.V., I.L.B., J.D.R.) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) - Project ID No 739510.

Published
2023
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40. Temporal dynamics predict symptom onset and cognitive decline in familial frontotemporal dementia

Author

Whiteside, David J, Malpetti, Maura, Jones, P Simon, Ghosh, Boyd CP, Coyle‐Gilchrist, Ian, van Swieten, John C, Seelaar, Harro, Jiskoot, Lize, Borroni, Barbara, Sanchez‐Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Butler, Chris R, Santana, Isabel, Ber, Isabelle Le, Gerhard, Alexander, Ducharme, Simon, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Pasquier, Florence, Bouzigues, Arabella, Russell, Lucy L, Rohrer, Jonathan D, Rowe, James B, Rittman, Timothy, Esteve, Aitana Sogorb, Nelson, Annabel, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, Timberlake, Carolyn, Cope, Thomas, 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, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang‐Wai, David, Rogaeva, Ekaterina, Castelo‐Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego‐Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa‐Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl‐Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas‐Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Whiteside, David [0000-0002-5890-9220], Apollo - University of Cambridge Repository, GENFI Consortium, Repositório da Universidade de Lisboa, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Simões do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Heller, Carolin, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Russell, Lucy L, Bocchetta, Martina, Shafei, Rachelle, Convery, Rhian S, 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, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, and Neurology

Subjects
Epidemiology, FEATURED ARTICLE, Medizin, Clinical Neurology, NETWORK CONNECTIVITY, frontotemporal dementia, disease progression, functional magnetic resonance imaging (fMRI), network dynamics, presymptomatic, DISEASE, Cellular and Molecular Neuroscience, Developmental Neuroscience, SDG 3 - Good Health and Well-being, Humans, Cognitive Dysfunction, ddc:610, BRAIN, BATTERY, Science & Technology, Health Policy, Brain, FUNCTIONAL CONNECTIVITY, Magnetic Resonance Imaging, STATE, TIME, Psychiatry and Mental health, COMPENSATION, Frontotemporal Dementia, Mutation, FEATURED ARTICLES, Neurology (clinical), Human medicine, Neurosciences & Neurology, Geriatrics and Gerontology, Life Sciences & Biomedicine
Abstract

© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Introduction: We tested whether changes in functional networks predict cognitive decline and conversion from the presymptomatic prodrome to symptomatic disease in familial frontotemporal dementia (FTD). Methods: For hypothesis generation, 36 participants with behavioral variant FTD (bvFTD) and 34 controls were recruited from one site. For hypothesis testing, we studied 198 symptomatic FTD mutation carriers, 341 presymptomatic mutation carriers, and 329 family members without mutations. We compared functional network dynamics between groups, with clinical severity and with longitudinal clinical progression. Results: We identified a characteristic pattern of dynamic network changes in FTD, which correlated with neuropsychological impairment. Among presymptomatic mutation carriers, this pattern of network dynamics was found to a greater extent in those who subsequently converted to the symptomatic phase. Baseline network dynamic changes predicted future cognitive decline in symptomatic participants and older presymptomatic participants. Discussion: Dynamic network abnormalities in FTD predict cognitive decline and symptomatic conversion. Highlights: We investigated brain network predictors of dementia symptom onset Frontotemporal dementia results in characteristic dynamic network patterns Alterations in network dynamics are associated with neuropsychological impairment Network dynamic changes predict symptomatic conversion in presymptomatic carriers Network dynamic changes are associated with longitudinal cognitive decline., GENFI was funded by the Medical Research Council UK (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (by DLR/BMBF 2019-02248) and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). The study was co-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge (BRC-1215-20014), the Cambridge Centre for Parkinson-plus (RG95450); the Wellcome Trust (220258); the Evelyn Trust (17/09) and Medical Research Council (SUAG/092 116768).

Published
2022
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42. Early neurotransmitters changes in prodromal frontotemporal dementia:A GENFI study

Author

Premi, Enrico, Pengo, Marta, Mattioli, Irene, Cantoni, Valentina, Dukart, Juergen, Gasparotti, Roberto, Buratti, Emanuele, Padovani, Alessandro, Bocchetta, Martina, Todd, Emily G., Bouzigues, Arabella, Cash, David M., Convery, Rhian S., Russell, Lucy L., Thomas, David L., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Tsvetanov, Kamen A., Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris R., Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Rohrer, Jonathan D., Borroni, Barbara, Premi, Enrico, Pengo, Marta, Mattioli, Irene, Cantoni, Valentina, Dukart, Juergen, Gasparotti, Roberto, Buratti, Emanuele, Padovani, Alessandro, Bocchetta, Martina, Todd, Emily G., Bouzigues, Arabella, Cash, David M., Convery, Rhian S., Russell, Lucy L., Thomas, David L., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Galimberti, Daniela, Sanchez-Valle, Raquel, Laforce, Robert, Moreno, Fermin, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Tsvetanov, Kamen A., Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris R., Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Rohrer, Jonathan D., and Borroni, Barbara

Abstract

Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches. Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD. Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p < 0.05, Family Wise Error corrected). In symptomatic FTD, a widespread involvement of dopamine, serotonin, glutamate and acetylcholine pathways across all genetic subtypes was found. Social cognition scores, loss of empathy and poor response to emotional cues were found to correlate with the strength of GMV colocalization of dopamine and serotonin pathways (all p < 0.01). Conclusions: This study, indirectly assessing neurotransmitter deficits in monogenic FTD, provides novel insight into disease mechanisms and might suggest potential therapeutic targets to counteract disease-related symptoms.

Published
2023

43. Anomia is present pre-symptomatically in frontotemporal dementia due to MAPT mutations

Author

Bouzigues, Arabella, Russell, Lucy L, Tiraboschi, Pietro, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Masellis, Mario, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Tartaglia, Maria Carmela, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Finger, Elizabeth, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, van Swieten, John C, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Seelaar, Harro, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Jiskoot, Lize, Sorbi, Sandro, Butler, Chris R, Graff, Caroline, Peakman, Georgia, Gerhard, Alexander, Langheinrich, Tobias, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Le Ber, Isabelle, Bocchetta, Martina, Levin, Johannes, Danek, Adrian, Otto, Markus, Pasquier, Florence, Santana, Isabel, Rohrer, Jonathan D, Genetic FTD Initiative, GENFI, Esteve, Aitana Sogorb, Nelson, Annabel, Greaves, Caroline V, Heller, Carolin, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Convery, Rhian S, 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, Rowe, James B, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Keren, Ron, Black, Sandra, Mitchell, Sara, Borroni, Barbara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Galimberti, Daniela, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Bouzigues, Arabella [0000-0002-0267-8590], Russell, Lucy L [0000-0001-5023-5893], Peakman, Georgia [0000-0002-3319-138X], Bocchetta, Martina [0000-0003-1814-5024], Greaves, Caroline V [0000-0002-6446-1960], Convery, Rhian S [0000-0002-9477-1812], Rowe, James B [0000-0001-7216-8679], Finger, Elizabeth [0000-0003-4461-7427], van Swieten, John C [0000-0001-6278-6844], Levin, Johannes [0000-0001-5092-4306], Otto, Markus [0000-0002-6647-5944], Apollo - University of Cambridge Repository, Esteve, Aitana Sogorb (Beitragende*r), Nelson, Annabel (Beitragende*r), Heller, Carolin (Beitragende*r), Cash, David (Beitragende*r), Thomas, David L (Beitragende*r), Benotmane, Hanya (Beitragende*r), Zetterberg, Henrik (Beitragende*r), Swift, Imogen J (Beitragende*r), Nicholas, Jennifer (Beitragende*r), Samra, Kiran (Beitragende*r), Shafei, Rachelle (Beitragende*r), Timberlake, Carolyn (Beitragende*r), Cope, Thomas (Beitragende*r), Rittman, Timothy (Beitragende*r), Benussi, Alberto (Beitragende*r), Premi, Enrico (Beitragende*r), Gasparotti, Roberto (Beitragende*r), Archetti, Silvana (Beitragende*r), Gazzina, Stefano (Beitragende*r), Cantoni, Valentina (Beitragende*r), Arighi, Andrea (Beitragende*r), Fenoglio, Chiara (Beitragende*r), Scarpini, Elio (Beitragende*r), Fumagalli, Giorgio (Beitragende*r), Borracci, Vittoria (Beitragende*r), Rossi, Giacomina (Beitragende*r), Giaccone, Giorgio (Beitragende*r), Caroppo, Paola (Beitragende*r), Prioni, Sara (Beitragende*r), Redaelli, Veronica (Beitragende*r), Tang-Wai, David (Beitragende*r), Rogaeva, Ekaterina (Beitragende*r), Castelo-Branco, Miguel (Beitragende*r), Keren, Ron (Beitragende*r), Black, Sandra (Beitragende*r), Mitchell, Sara (Beitragende*r), Shoesmith, Christen (Beitragende*r), Bartha, Robart (Beitragende*r), Rademakers, Rosa (Beitragende*r), Poos, Jackie (Beitragende*r), Papma, Janne M (Beitragende*r), Giannini, Lucia (Beitragende*r), Minkelen, Rick (Beitragende*r), Pijnenburg, Yolande (Beitragende*r), Nacmias, Benedetta (Beitragende*r), Ferrari, Camilla (Beitragende*r), Polito, Cristina (Beitragende*r), Lombardi, Gemma (Beitragende*r), Bessi, Valentina (Beitragende*r), Veldsman, Michele (Beitragende*r), Andersson, Christin (Beitragende*r), Thonberg, Hakan (Beitragende*r), Öijerstedt, Linn (Beitragende*r), Jelic, Vesna (Beitragende*r), Thompson, Paul (Beitragende*r), Lladó, Albert (Beitragende*r), Antonell, Anna (Beitragende*r), Olives, Jaume (Beitragende*r), Balasa, Mircea (Beitragende*r), Bargalló, Nuria (Beitragende*r), Borrego-Ecija, Sergi (Beitragende*r), Verdelho, Ana (Beitragende*r), Maruta, Carolina (Beitragende*r), Ferreira, Catarina B (Beitragende*r), Miltenberger, Gabriel (Beitragende*r), do Couto, Frederico Simões (Beitragende*r), Gabilondo, Alazne (Beitragende*r), Gorostidi, Ana (Beitragende*r), Villanua, Jorge (Beitragende*r), Cañada, Marta (Beitragende*r), Tainta, Mikel (Beitragende*r), Zulaica, Miren (Beitragende*r), Barandiaran, Myriam (Beitragende*r), Alves, Patricia (Beitragende*r), Bender, Benjamin (Beitragende*r), Wilke, Carlo (Beitragende*r), Graf, Lisa (Beitragende*r), Vogels, Annick (Beitragende*r), Vandenbulcke, Mathieu (Beitragende*r), Van Damme, Philip (Beitragende*r), Bruffaerts, Rose (Beitragende*r), Poesen, Koen (Beitragende*r), Rosa-Neto, Pedro (Beitragende*r), Gauthier, Serge (Beitragende*r), Camuzat, Agnès (Beitragende*r), Brice, Alexis (Beitragende*r), Bertrand, Anne (Beitragende*r), Funkiewiez, Aurélie (Beitragende*r), Rinaldi, Daisy (Beitragende*r), Saracino, Dario (Beitragende*r), Colliot, Olivier (Beitragende*r), Sayah, Sabrina (Beitragende*r), Prix, Catharina (Beitragende*r), Wlasich, Elisabeth (Beitragende*r), Wagemann, Olivia (Beitragende*r), Loosli, Sandra (Beitragende*r), Schönecker, Sonja (Beitragende*r), Hoegen, Tobias (Beitragende*r), Lombardi, Jolina (Beitragende*r), Anderl-Straub, Sarah (Beitragende*r), Rollin, Adeline (Beitragende*r), Kuchcinski, Gregory (Beitragende*r), Bertoux, Maxime (Beitragende*r), Lebouvier, Thibaud (Beitragende*r), Deramecourt, Vincent (Beitragende*r), Santiago, Beatriz (Beitragende*r), Duro, Diana (Beitragende*r), Leitão, Maria João (Beitragende*r), Almeida, Maria Rosario (Beitragende*r), Tábuas-Pereira, Miguel (Beitragende*r), Afonso, Sónia (Beitragende*r), Engel, Annerose (Beitragende*r), Polyakova, Maryna (Beitragende*r), Repositório da Universidade de Lisboa, Genetic FTD Initiative, GENFI, and Neurology

Subjects
Progranulin, Clinical Neurology, Medizin, Anomia, tau Proteins, Naming, IMPAIRMENTS, VARIANTS, diagnostic imaging [Frontotemporal Dementia], genetics [Progranulins], Cognition, Progranulins, Settore BIO/13 - Biologia Applicata, complications [Frontotemporal Dementia], mental disorders, C9orf72, Humans, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Biology, Science & Technology, C9orf72 Protein, MORPHOMETRIC ANALYSES, ANATOMY, ALZHEIMERS-DISEASE, genetics [tau Proteins], Neurology, Frontotemporal Dementia, Mutation, PATTERNS, Frontotemporal dementia, Tau, Human medicine, Neurosciences & Neurology, Neurology (clinical), complications [Anomia], Life Sciences & Biomedicine, MRI
Abstract

Funder: Alzheimer’s Research UK; doi: http://dx.doi.org/10.13039/501100002283, Funder: UCLH Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100012317, Funder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265, Funder: Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, Funder: Bluefield Project, INTRODUCTION: A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail. METHODS: We investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis. RESULTS: All symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions. CONCLUSION: This study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.

Published
2022
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44. Early neurotransmitters changes in prodromal frontotemporal dementia: A GENFI study

Author

Premi, Enrico, primary, Pengo, Marta, additional, Mattioli, Irene, additional, Cantoni, Valentina, additional, Dukart, Juergen, additional, Gasparotti, Roberto, additional, Buratti, Emanuele, additional, Padovani, Alessandro, additional, Bocchetta, Martina, additional, Todd, Emily G., additional, Bouzigues, Arabella, additional, Cash, David M., additional, Convery, Rhian S., additional, Russell, Lucy L., additional, Foster, Phoebe, additional, Thomas, David L., additional, van Swieten, John C., additional, Jiskoot, Lize C., additional, Seelaar, Harro, additional, Galimberti, Daniela, additional, Sanchez-Valle, Raquel, additional, Laforce, Robert, additional, Moreno, Fermin, additional, Synofzik, Matthis, additional, Graff, Caroline, additional, Masellis, Mario, additional, Tartaglia, Maria Carmela, additional, Rowe, James B., additional, Tsvetanov, Kamen A., additional, Vandenberghe, Rik, additional, Finger, Elizabeth, additional, Tiraboschi, Pietro, additional, de Mendonça, Alexandre, additional, Santana, Isabel, additional, Butler, Chris R., additional, Ducharme, Simon, additional, Gerhard, Alexander, additional, Levin, Johannes, additional, Otto, Markus, additional, Sorbi, Sandro, additional, Le Ber, Isabelle, additional, Pasquier, Florence, additional, Rohrer, Jonathan D., additional, Borroni, Barbara, additional, Esteve, Aitana Sogorb, additional, Heller, Carolin, additional, Greaves, Caroline V., additional, Zetterberg, Henrik, additional, Swift, Imogen J., additional, Samra, Kiran, additional, Shafei, Rachelle, additional, Timberlake, Carolyn, additional, Cope, Thomas, additional, Rittman, Timothy, additional, Arighi, Andrea, additional, Fenoglio, Chiara, additional, Scarpini, Elio, additional, Fumagalli, Giorgio, additional, Borracci, Vittoria, additional, Rossi, Giacomina, additional, Giaccone, Giorgio, additional, Di Fede, Giuseppe, additional, Caroppo, Paola, additional, Prioni, Sara, additional, Redaelli, Veronica, additional, Tang-Wai, David, additional, Rogaeva, Ekaterina, additional, Castelo-Branco, Miguel, additional, Freedman, Morris, additional, Keren, Ron, additional, Black, Sandra, additional, Mitchell, Sara, additional, Shoesmith, Christen, additional, Bartha, Robart, additional, Rademakers, Rosa, additional, Poos, Jackie, additional, Papma, Janne M., additional, Giannini, Lucia, additional, van Minkelen, Rick, additional, Pijnenburg, Yolande, additional, Nacmias, Benedetta, additional, Ferrari, Camilla, additional, Polito, Cristina, additional, Lombardi, Gemma, additional, Bessi, Valentina, additional, Veldsman, Michele, additional, Andersson, Christin, additional, Thonberg, Hakan, additional, Öijerstedt, Linn, additional, Jelic, Vesna, additional, Thompson, Paul, additional, Langheinrich, Tobias, additional, Lladó, Albert, additional, Antonell, Anna, additional, Olives, Jaume, additional, Balasa, Mircea, additional, Bargalló, Nuria, additional, Borrego-Ecija, Sergi, additional, Verdelho, Ana, additional, Maruta, Carolina, additional, Ferreira, Catarina B., additional, Miltenberger, Gabriel, additional, do Couto, Frederico Simões, additional, Gabilondo, Alazne, additional, Gorostidi, Ana, additional, Villanua, Jorge, additional, Cañada, Marta, additional, Tainta, Mikel, additional, Zulaica, Miren, additional, Barandiaran, Myriam, additional, Alves, Patricia, additional, Bender, Benjamin, additional, Wilke, Carlo, additional, Graf, Lisa, additional, Vogels, Annick, additional, Vandenbulcke, Mathieu, additional, Van Damme, Philip, additional, Bruffaerts, Rose, additional, Poesen, Koen, additional, Rosa-Neto, Pedro, additional, Gauthier, Serge, additional, Camuzat, Agnès, additional, Brice, Alexis, additional, Bertrand, Anne, additional, Funkiewiez, Aurélie, additional, Rinaldi, Daisy, additional, Saracino, Dario, additional, Colliot, Olivier, additional, Sayah, Sabrina, additional, Prix, Catharina, additional, Wlasich, Elisabeth, additional, Wagemann, Olivia, additional, Loosli, Sandra, additional, Schönecker, Sonja, additional, Hoegen, Tobias, additional, Lombardi, Jolina, additional, Anderl-Straub, Sarah, additional, Rollin, Adeline, additional, Kuchcinski, Gregory, additional, Bertoux, Maxime, additional, Lebouvier, Thibaud, additional, Deramecourt, Vincent, additional, Santiago, Beatriz, additional, Duro, Diana, additional, Leitão, Maria João, additional, Almeida, Maria Rosario, additional, Tábuas-Pereira, Miguel, additional, and Afonso, Sónia, additional

Published
2023
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45. Data‐driven staging of genetic frontotemporal dementia using multi‐modal <scp>MRI</scp>

Author

McCarthy, Jillian, Borroni, Barbara, Tartaglia, Maria Carmela, Neason, Mollie, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne, Peakman, Georgia, Piaceri, Irene, Finger, Elizabeth, Pievani, Michela, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rittman, Tim, Rogaeva, Ekaterina, Vandenberghe, Rik, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Tábuas-Pereira, Miguel, de Mendonça, Alexandre, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Vandamme, Philip, Tagliavini, Fabrizio, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Santana, Isabel, Butler, Chris, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Sanchez-Valle, Raquel, Otto, Markus, Frisoni, Giovanni B, Ghidoni, Roberta, Sorbi, Sandro, Jiskoot, Lize C, Seelaar, Harro, van Swieten, John C, Rohrer, Jonathan D, Iturria-Medina, Yasser, Ducharme, Simon, Moreno, Fermin, Initiative, GENetic Frontotemporal Dementia, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Laforce, Robert, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Benussi, Luisa, Bessi, Valentina, Binetti, Giuliano, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Graff, Caroline, Bras, Jose, Bruffaerts, Rose, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, Cosseddu, Maura, Synofzik, Matthis, de Arriba, María, Di Fede, Giuseppe, Díaz, Zigor, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Carlos, Ferreira, Catarina B, Flanagan, Toby, Galimberti, Daniela, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Rowe, James B, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans Otto, Keren, Ron, Langheinrich, Tobias, Leitão, Maria João, Lladó, Albert, Masellis, Mario, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina M, Nacmias, Benedetta, Repositório da Universidade de Lisboa, Neurology, Amsterdam Neuroscience - Neurodegeneration, McCarthy, Jillian [0000-0002-9285-0023], Borroni, Barbara [0000-0001-9340-9814], Apollo - University of Cambridge Repository, GENetic Frontotemporal Dementia Initiative (GENFI), Clinical Genetics, and Clinical Psychology

Subjects
disease progression, frontotemporal dementia, magnetic resonance imaging, unsupervised machine learning, BIOMARKER, Heterozygote, Medizin, Neuroimaging, diagnostic imaging [Frontotemporal Dementia], Magnetic resonance imaging, SDG 3 - Good Health and Well-being, HARMONIZATION, Settore BIO/13 - Biologia Applicata, NEUROFILAMENT LIGHT-CHAIN, BEHAVIORAL VARIANT, CRITERIA, Humans, Radiology, Nuclear Medicine and imaging, ddc:610, Cross-Sectional Studies, Language, Magnetic Resonance Imaging, Frontotemporal Dementia, genetics [Frontotemporal Dementia], Unsupervised machine learning, Disease progression, Science & Technology, Radiological and Ultrasound Technology, Radiology, Nuclear Medicine & Medical Imaging, Neurosciences, DEGENERATION, DIFFUSION, psychology [Frontotemporal Dementia], Neurology, GRAY-MATTER ATROPHY, Neurosciences & Neurology, Neurology (clinical), Anatomy, Life Sciences & Biomedicine, GENFI, CLINICAL-TRIALS, Frontotemporal dementia
Abstract

Funder: Fondation Brain Canada; Id: http://dx.doi.org/10.13039/100009408, Funder: Fonds de Recherche du Québec ‐ Santé; Id: http://dx.doi.org/10.13039/501100000156, Funder: Health Canada; Id: http://dx.doi.org/10.13039/501100000008, Funder: Brain Canada Foundation; Id: http://dx.doi.org/10.13039/100009408, Frontotemporal dementia in genetic forms is highly heterogeneous and begins many years to prior symptom onset, complicating disease understanding and treatment development. Unifying methods to stage the disease during both the presymptomatic and symptomatic phases are needed for the development of clinical trials outcomes. Here we used the contrastive trajectory inference (cTI), an unsupervised machine learning algorithm that analyzes temporal patterns in high-dimensional large-scale population datasets to obtain individual scores of disease stage. We used cross-sectional MRI data (gray matter density, T1/T2 ratio as a proxy for myelin content, resting-state functional amplitude, gray matter fractional anisotropy, and mean diffusivity) from 383 gene carriers (269 presymptomatic and 115 symptomatic) and a control group of 253 noncarriers in the Genetic Frontotemporal Dementia Initiative. We compared the cTI-obtained disease scores to the estimated years to onset (age-mean age of onset in relatives), clinical, and neuropsychological test scores. The cTI based disease scores were correlated with all clinical and neuropsychological tests (measuring behavioral symptoms, attention, memory, language, and executive functions), with the highest contribution coming from mean diffusivity. Mean cTI scores were higher in the presymptomatic carriers than controls, indicating that the method may capture subtle pre-dementia cerebral changes, although this change was not replicated in a subset of subjects with complete data. This study provides a proof of concept that cTI can identify data-driven disease stages in a heterogeneous sample combining different mutations and disease stages of genetic FTD using only MRI metrics.

Published
2022
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46. Cognitive composites for genetic frontotemporal dementia: GENFI-Cog

Author

Poos, Jackie M, Moore, Katrina M, Seelaar, Harro, Vandamme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B, Miltenberger, Gabriel, Maruta, Carolina, Verdelho, Ana, Afonso, Sónia, Taipa, Ricardo, Caroppo, Paola, Di Fede, Giuseppe, Pijnenburg, Yolande A L, Giaccone, Giorgio, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Duro, Diana, Almeida, Maria Rosario, Castelo-Branco, Miguel, Leitão, Maria João, Tabuas-Pereira, Miguel, Santiago, Beatriz, Moreno, Fermin, Gauthier, Serge, Rosa-Neto, Pedro, Veldsman, Michele, Thompson, Paul, Langheinrich, Tobias, Prix, Catharina, Hoegen, Tobias, Wlasich, Elisabeth, Loosli, Sandra, Schonecker, Sonja, Sanchez-Valle, Raquel, Anderl-Straub, Sarah, Lombardi, Jolina, Bargalló, Nuria, Benussi, Alberto, Cantoni, Valentina, Bertoux, Maxime, Bertrand, Anne, Brice, Alexis, Camuzat, Agnès, Colliot, Olivier, Borroni, Barbara, Sayah, Sabrina, Funkiewiez, Aurélie, Rinaldi, Daisy, Lombardi, Gemma, Nacmias, Benedetta, Saracino, Dario, Bessi, Valentina, Ferrari, Camilla, Cañada, Marta, Deramecourt, Vincent, Laforce, Robert, Kuchcinski, Gregory, Lebouvier, Thibaud, Ourselin, Sebastien, Polito, Cristina, Rollin, Adeline, Masellis, Mario, Tartaglia, Carmela, Graff, Caroline, Galimberti, Daniela, Nicholas, Jennifer, Rowe, James B, Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonça, Alexandre, Tiraboschi, Pietro, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alexander, Russell, Lucy L, Levin, Johannes, Danek, Adrian, Otto, Markus, Le Ber, Isabel, Pasquier, Florence, van Swieten, John C, Rohrer, Jonathan D, Initiative, Genetic FTD, Bouzigues, Arabella, Rossor, Martin N, Peakman, Georgia, Fox, Nick C, Warren, Jason D, Bocchetta, Martina, Swift, Imogen J, Shafei, Rachelle, Heller, Carolin, Todd, Emily, Cash, David, Woollacott, Ione, Zetterberg, Henrik, Convery, Rhian S, Nelson, Annabel, Guerreiro, Rita, Bras, Jose, Thomas, David L, Mead, Simon, Meeter, Lieke, Panman, Jessica, van Minkelen, Rick, Barandiaran, Myriam, Indakoetxea, Begoña, Jiskoot, Lize C, Gabilondo, Alazne, Tainta, Mikel, Gorostidi, Ana, Zulaica, Miren, Díez, Alina, Villanua, Jorge, Borrego-Ecija, Sergi, Olives, Jaume, Lladó, Albert, Balasa, Mircea, van der Ende, Emma, Antonell, Anna, Bargallo, Nuria, Premi, Enrico, Gazzina, Stefano, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Rogaeva, Ekaterina, Freedman, Morris, van den Berg, Esther, Keren, Ron, Tang-Wai, David, Thonberg, Hakan, Öijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Papma, Janne M, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Karnarth, Hans-Otto, Bender, Benjamin, Bruffaerts, Rose, Neurology, Amsterdam Neuroscience - Neurodegeneration, Medical Research Council, Clinical Genetics, Rowe, James [0000-0001-7216-8679], Rohrer, Jonathan D [0000-0002-6155-8417], and Apollo - University of Cambridge Repository

Subjects
PROGRESSION, Neuropsychological Tests, Composite score, Genetic FTD Initiative (GENFI), diagnosis [Frontotemporal Dementia], Cognition, CRITERIA, Attention, genetics [Frontotemporal Dementia], 11 Medical and Health Sciences, Language, Executive function, Frontotemporal dementia, Memory, Neuropsychology, Social cognition, Humans, Mutation, Prodromal Symptoms, Sample Size, tau Proteins, Frontotemporal Dementia, CARRIERS, Neurology, Psychology, Life Sciences & Biomedicine, CLINICAL-TRIALS, RC321-571, medicine.medical_specialty, Cognitive Neuroscience, Clinical Neurology, genetics [Mutation], Neurosciences. Biological psychiatry. Neuropsychiatry, Physical medicine and rehabilitation, Cog, mental disorders, medicine, ddc:610, RC346-429, Science & Technology, Research, Neurosciences, medicine.disease, genetics [tau Proteins], Neurosciences & Neurology, Neurology (clinical), Neurology. Diseases of the nervous system
Abstract

Funder: Alzheimer's Research UK, Funder: Alzheimer's Society, Funder: Brain Research UK, Funder: the Wolfson Foundation, Funder: NIHR UCL/H Biomedical Research Centre, Funder: Leonard Wolfson Experimental Neurology Centre Clinical Research Facility, Funder: UK Dementia Research Institute, Funder: UK Medical Research Council, Funder: Bluefield project, Funder: the Association for Frontotemporal Dementias Research Grant 2009, BACKGROUND: Clinical endpoints for upcoming therapeutic trials in frontotemporal dementia (FTD) are increasingly urgent. Cognitive composite scores are often used as endpoints but are lacking in genetic FTD. We aimed to create cognitive composite scores for genetic frontotemporal dementia (FTD) as well as recommendations for recruitment and duration in clinical trial design. METHODS: A standardized neuropsychological test battery covering six cognitive domains was completed by 69 C9orf72, 41 GRN, and 28 MAPT mutation carriers with CDR�� plus NACC-FTLD ��� 0.5 and 275 controls. Logistic regression was used to identify the combination of tests that distinguished best between each mutation carrier group and controls. The composite scores were calculated from the weighted averages of test scores in the models based on the regression coefficients. Sample size estimates were calculated for individual cognitive tests and composites in a theoretical trial aimed at preventing progression from a prodromal stage (CDR�� plus NACC-FTLD 0.5) to a fully symptomatic stage (CDR�� plus NACC-FTLD ��� 1). Time-to-event analysis was performed to determine how quickly mutation carriers progressed from CDR�� plus NACC-FTLD = 0.5 to ��� 1 (and therefore how long a trial would need to be). RESULTS: The results from the logistic regression analyses resulted in different composite scores for each mutation carrier group (i.e. C9orf72, GRN, and MAPT). The estimated sample size to detect a treatment effect was lower for composite scores than for most individual tests. A Kaplan-Meier curve showed that after 3 years, ~ 50% of individuals had converted from CDR�� plus NACC-FTLD 0.5 to ��� 1, which means that the estimated effect size needs to be halved in sample size calculations as only half of the mutation carriers would be expected to progress from CDR�� plus NACC FTLD 0.5 to ��� 1 without treatment over that time period. DISCUSSION: We created gene-specific cognitive composite scores for C9orf72, GRN, and MAPT mutation carriers, which resulted in substantially lower estimated sample sizes to detect a treatment effect than the individual cognitive tests. The GENFI-Cog composites have potential as cognitive endpoints for upcoming clinical trials. The results from this study provide recommendations for estimating sample size and trial duration.

Published
2022
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48. Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia

Author

Sogorb-Esteve, Aitana, Nilsson, Johanna, Borroni, Barbara, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, de Mendonça, Alexandre, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Galimberti, Daniela, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Sanchez-Valle, Raquel, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Laforce, Robert, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Moreno, Fermin, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Synofzik, Matthis, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Swift, Imogen J, Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, Santana, Isabel, Butler, Chris R, Ducharme, Simon, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Heller, Carolin, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Gobom, Johan, Brinkmalm, Ann, Blennow, Kaj, Zetterberg, Henrik, Rohrer, Jonathan D, Initiative, GENetic FTD, Nelson, Annabel, Bocchetta, Martina, Bouzigues, Arabella, Greaves, Caroline V, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Russell, Lucy L, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Peakman, Georgia, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Convery, Rhian S, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, van Swieten, John C, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Seelaar, Harro, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Neurology, Amsterdam Neuroscience - Neurodegeneration, Clinical Genetics, GENetic FTD Initiative, Poesen, Koen, Van Damme, Philip, Bruffaerts, rose, Vandenbulcke, Mathieu, Vogels, ann, Bocchetta, Martina [0000-0003-1814-5024], and Apollo - University of Cambridge Repository

Subjects
Synaptic dysfunction, Cognitive Neuroscience, cerebrospinal fluid [gamma-Synuclein], Medizin, cerebrospinal fluid [Syntaxin 1], Syntaxin 1, genetics [Mutation], tau Proteins, cerebrospinal fluid [Frontotemporal Dementia], frontotemporal dementia, beta-Synuclein, gamma-Synuclein, Settore BIO/13 - Biologia Applicata, Humans, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Biology, genetics [beta-Synuclein], genetics [Syntaxin 1], C9orf72 Protein, synaptic dysfunction, cerebrospinal fluid [C9orf72 Protein], Research, Biomarkers, Frontotemporal dementia, Mutation, Neurogranin, Frontotemporal Dementia, biomarkers, genetics [Neurogranin], genetics [tau Proteins], Neurology, cerebrospinal fluid [Biomarkers], genetics [gamma-Synuclein], Neurology (clinical), Human medicine, cerebrospinal fluid [Neurogranin]
Abstract

Background Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for most of the inheritance: C9orf72, GRN, and MAPT. Impaired synaptic health is a common mechanism in all three genetic variants, so developing fluid biomarkers of this process could be useful as a readout of cellular dysfunction within therapeutic trials. Methods A total of 193 cerebrospinal fluid (CSF) samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72, 23 GRN, 23 MAPT) and 55 symptomatic (26 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 61 mutation-negative controls were measured using a microflow LC PRM-MS set-up targeting 15 synaptic proteins: AP-2 complex subunit beta, complexin-2, beta-synuclein, gamma-synuclein, 14–3-3 proteins (eta, epsilon, zeta/delta), neurogranin, Rab GDP dissociation inhibitor alpha (Rab GDI alpha), syntaxin-1B, syntaxin-7, phosphatidylethanolamine-binding protein 1 (PEBP-1), neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), and neuronal pentraxin 2 (NPTX2). Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex. Results CSF levels of eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: beta-synuclein, gamma-synuclein, 14–3-3-eta, neurogranin, Rab GDI alpha, syntaxin-1B, syntaxin-7, and PEBP-1, with three other proteins increased in MAPT mutation carriers compared with the other genetic groups (AP-2 complex subunit beta, complexin-2, and 14–3-3 zeta/delta). In contrast, CSF NPTX1 and NPTX2 levels were affected in all three genetic groups (decreased compared with controls), with NPTXR concentrations being affected in C9orf72 and GRN mutation carriers only (decreased compared with controls). No changes were seen in the CSF levels of these proteins in presymptomatic mutation carriers. Concentrations of the neuronal pentraxins were correlated with brain volumes in the presymptomatic period for the C9orf72 and GRN groups, suggesting that they become abnormal in proximity to symptom onset. Conclusions Differential synaptic impairment is seen in the genetic forms of FTD, with abnormalities in multiple measures in those with MAPT mutations, but only changes in neuronal pentraxins within the GRN and C9orf72 mutation groups. Such markers may be useful in future trials as measures of synaptic dysfunction, but further work is needed to understand how these markers change throughout the course of the disease.

Published
2022
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49. Brain-derived tau: a novel blood-based biomarker for Alzheimer’s disease-type neurodegeneration

Author

Gonzalez-Ortiz, Fernando, primary, Turton, Michael, additional, Kac, Przemysław R, additional, Smirnov, Denis, additional, Premi, Enrico, additional, Ghidoni, Roberta, additional, Benussi, Luisa, additional, Cantoni, Valentina, additional, Saraceno, Claudia, additional, Rivolta, Jasmine, additional, Ashton, Nicholas J, additional, Borroni, Barbara, additional, Galasko, Douglas, additional, Harrison, Peter, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, and Karikari, Thomas K, additional

Published
2022
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