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203. APOEε4 associates with microglial activation independently of Aβ plaques and tau tangles

Author

Ferrari-Souza, João Pedro, Lussier, Firoza Z, Leffa, Douglas T, Therriault, Joseph, Tissot, Cécile, Bellaver, Bruna, Ferreira, Pâmela CL, Malpetti, Maura, Wang, Yi-Ting, Povala, Guilherme, Benedet, Andréa L, Ashton, Nicholas J, Chamoun, Mira, Servaes, Stijn, Bezgin, Gleb, Kang, Min Su, Stevenson, Jenna, Rahmouni, Nesrine, Pallen, Vanessa, Poltronetti, Nina Margherita, O'Brien, John T, Rowe, James B, Cohen, Ann D, Lopez, Oscar L, Tudorascu, Dana L, Karikari, Thomas K, Klunk, William E, Villemagne, Victor L, Soucy, Jean-Paul, Gauthier, Serge, Souza, Diogo O, Zetterberg, Henrik, Blennow, Kaj, Zimmer, Eduardo R, Rosa-Neto, Pedro, Pascoal, Tharick A, Ferrari-Souza, João Pedro [0000-0003-2183-1551], Lussier, Firoza Z [0000-0002-6877-4825], Leffa, Douglas T [0000-0002-4890-8451], Therriault, Joseph [0000-0002-7826-4781], Tissot, Cécile [0000-0003-2711-3833], Bellaver, Bruna [0000-0002-2212-3373], Ferreira, Pâmela CL [0000-0003-2134-9829], Malpetti, Maura [0000-0001-8923-9656], Povala, Guilherme [0000-0002-2023-6569], Benedet, Andréa L [0000-0001-8219-1741], Chamoun, Mira [0000-0001-7001-5652], Servaes, Stijn [0000-0002-4431-957X], Kang, Min Su [0000-0003-0745-6222], O'Brien, John T [0000-0002-0837-5080], Rowe, James B [0000-0001-7216-8679], Lopez, Oscar L [0000-0002-8546-8256], Karikari, Thomas K [0000-0003-1422-4358], Zetterberg, Henrik [0000-0003-3930-4354], Blennow, Kaj [0000-0002-1890-4193], Zimmer, Eduardo R [0000-0002-5349-0053], Rosa-Neto, Pedro [0000-0001-9116-1376], Pascoal, Tharick A [0000-0001-9057-8014], and Apollo - University of Cambridge Repository

Subjects
Amyloid beta-Peptides, Apolipoproteins E, Alzheimer Disease, Positron-Emission Tomography, Apolipoprotein E4, Animals, Brain, Plaque, Amyloid, tau Proteins, Microglia, Temporal Lobe
Abstract

Animal studies suggest that the apolipoprotein E ε4 (APOEε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [18F]AZD4694), tau ([18F]MK6240), and microglial activation ([11C]PBR28). We found that APOEε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOEε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOEε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOEε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

Published
2023

204. 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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205. iPSC-Astrocyte morphology reflects patient clinical markers

Author

Rowland, Helen A, primary, Miller, Georgina, additional, Liu, Qiang, additional, Sharp, Nicola R, additional, Ng, Bryan, additional, Wei, Tina, additional, Arunasalam, Kanisa, additional, Koychev, Ivan, additional, Hedegaard, Anne, additional, Ribe, Elena M, additional, Chan, Dennis, additional, Chessell, Tharani, additional, Kocagoncu, Ece, additional, Lawson, Jennifer, additional, Malhotra, Paresh A, additional, Ridha, Basil H, additional, Rowe, James B, additional, Thomas, Alan J, additional, Zamboni, Giovanna, additional, Zetterberg, Henrik, additional, Cader, Zameel, additional, Wade-Martins, Richard, additional, Lovestone, Simon, additional, Nevado Holgado, Alejo, additional, Kormilitzin, Andrey, additional, and Buckley, Noel J, additional

Published
2023
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206. Multisystem pathology in McLeod syndrome

Author

Schon, Katherine R., primary, O'Donovan, Dominic G., additional, Briggs, Mayen, additional, Rowe, James B., additional, Wijesekera, Lokesh, additional, Chinnery, Patrick F., additional, and van den Ameele, Jelle, additional

Published
2023
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209. Examining empathy deficits across familial forms of frontotemporal dementia within the GENFI cohort

Author

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

Subjects
Empathic concern, Cognitive Neuroscience, Medizin, Empathy, Frontotemporal dementia, Interpersonal Reactivity Index, Perspective taking, C9orf72 Protein, Humans, Mutation, Progranulins, tau Proteins, Frontotemporal Dementia, Pick Disease of the Brain, Experimental and Cognitive Psychology, genetics [Progranulins], diagnosis [Frontotemporal Dementia], mental disorders, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], genetics [tau Proteins], Neuropsychology and Physiological Psychology
Abstract

© 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/)., Background: Reduced empathy is a common symptom in frontotemporal dementia (FTD). Although empathy deficits have been extensively researched in sporadic cases, few studies have explored the differences in familial forms of FTD. Methods: Empathy was examined using a modified version of the Interpersonal Reactivity Index (mIRI) in 676 participants from the Genetic FTD Initiative: 216 mutation-negative controls, 192 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. Using global scores from the CDR® plus NACC FTLD, mutation carriers were divided into three groups, asymptomatic (0), very mildly symptomatic/prodromal (.5), or fully symptomatic (1 or more). The mIRI Total score, as well as the subscores of Empathic Concern (EC) and Perspective Taking (PT) were assessed. Linear regression models with bootstrapping were used to assess empathy ratings across genetic groups, as well as across phenotypes in the symptomatic carriers. Neural correlates of empathy deficits were examined using a voxel-based morphometry (VBM) analysis. Results: All fully symptomatic groups scored lower on the mIRI Total, EC, and PT when compared to controls and their asymptomatic or prodromal counterparts (all p < .001). Prodromal C9orf72 expansion carriers also scored significantly lower than controls on the mIRI Total score (p = .046). In the phenotype analysis, all groups (behavioural variant FTD, primary progressive aphasia and FTD with amyotrophic lateral sclerosis) scored significantly lower than controls (all p < .007). VBM revealed an overlapping neural correlate of the mIRI Total score across genetic groups in the orbitofrontal lobe but with additional involvement in the temporal lobe, insula and basal ganglia in both the GRN and MAPT groups, and uniquely more posterior regions such as the parietal lobe and thalamus in the GRN group, and medial temporal structures in the MAPT group. Conclusions: Significant empathy deficits present in genetic FTD, particularly in symptomatic individuals and those with a bvFTD phenotype, while prodromal deficits are only seen using the mIRI in C9orf72 expansion carriers., This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) 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. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. RC/CG are supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). MB is supported by a Fellowship award from the Alzheimer's Society, UK (AS-JF-19a-004-517). MB's work is 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. JCVS was supported by the Dioraphte Foundation grant 09-02-03-00, the Association for Frontotemporal Dementias Research Grant 2009, The Netherlands Organisation for Scientific Research grant HCMI 056-13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield project. FM received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease (CIBERNED). RS-V is supported by an Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2), and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). CG received funding from JPND-Prefrontals VR Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation and Stockholm County Council ALF. MM has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. JBR has received funding from the Wellcome Trust (103838) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). EF has received funding from a CIHR grant #327387. DG received support from the EU Joint Programme – Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. MO has received funding from BMBF (FTLDc).

Published
2022

210. An Automated Toolbox to Predict Single Subject Atrophy in Presymptomatic Granulin Mutation Carriers

Author

Premi, Enrico, Costa, Tommaso, Moreno, Fermin, Panman, Jessica, Papma, Janne, Pievani, Michela, Pijnenburg, Yolande, Polito, Cristina, Prioni, Sara, Prix, Catharina, Rademakers As London Ontario Geneticist, Rosa, Redaelli, Veronica, Rittman, Tim, Santana, Isabel, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Scarpini, Elio, Schönecker, Sonja, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Laforce, Robert, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, L Thomas, David, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Van Damme, Philip, Ducharme, Simon, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Graff, Caroline, Galimberti, Daniela, Masellis, Mario, Tartaglia, Carmela, Rowe, James B, Finger, Elizabeth, Gazzina, Stefano, Tagliavini, Fabrizio, de Mendonça, Alexandre, Vandenberghe, Rik, Gerhard, Alexander, Butler, Chris R, Danek, Adrian, Synofzik, Matthis, Levin, Johannes, Otto, Markus, Ghidoni, Roberta, Benussi, Alberto, Frisoni, Giovanni B, Sorbi, Sandro, Peakman, Georgia, Todd, Emily, Bocchetta, Martina, Rohrer, Johnathan D, Borroni, Barbara, Members, GENFI Consortium, Afonso, Sónia, Rosario Almeida, Maria, Cauda, Franco, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Luisa, Gasparotti, Roberto, Bessi, Valentina, Binetti, Giuliano, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Bruffaerts, Rose, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Archetti, Silvana, Cope, Thomas, de Arriba, María, Di Fede, Giuseppe, Díaz, Zigor, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, B Ferreira, Catarina, Fox, Nick, Freedman, Morris, Alberici, Antonella, Fumagalli, Giorgio, Gabilondo, Alazne, Gauthier, Serge, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, van Swieten, John C, Jelic, Vesna, Jiskoot, Lize, Karnath, Hans Otto, Keren, Ron, Langheinrich, Tobias, João Leitão, Maria, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Sanchez-Valle, Raquel, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, GENFI Consortium Members, Neurology, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository

Subjects
genetics [Granulins], Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic, Atrophy, Brain, Granulins, Humans, Magnetic Resonance Imaging, Mutation, Progranulins, Frontotemporal Dementia, Medizin, genetics [Mutation], diagnostic imaging [Frontotemporal Dementia], frontotemporal dementia, genetics [Progranulins], methods [Magnetic Resonance Imaging], SDG 3 - Good Health and Well-being, pathology [Brain], Settore BIO/13 - Biologia Applicata, ddc:610, diagnostic imaging [Brain], genetics [Frontotemporal Dementia], pathology [Atrophy], Frontotemporal dementia, granulin, magnetic resonance imaging, mutation, preclinical, presymptomatic, General Neuroscience, General Medicine, Psychiatry and Mental health, Clinical Psychology, pathology [Frontotemporal Dementia], Geriatrics and Gerontology
Abstract

Background:Magnetic resonance imaging (MRI) measures may be used as outcome markers in frontotemporal dementia (FTD). Objectives:To predict MRI cortical thickness (CT) at follow-up at the single subject level, using brain MRI acquired at baseline in preclinical FTD. Methods:84 presymptomatic subjects carrying Granulin mutations underwent MRI scans at baseline and at follow-up (31.2±16.5 months). Multivariate nonlinear mixed-effects model was used for estimating individualized CT at follow-up based on baseline MRI data. The automated user-friendly preGRN-MRI script was coded. Results:Prediction accuracy was high for each considered brain region (i.e., prefrontal region, real CT at follow-up versus predicted CT at follow-up, mean error ≤1.87%). The sample size required to detect a reduction in decline in a 1-year clinical trial was equal to 52 subjects (power = 0.80, alpha = 0.05). Conclusion:The preGRN-MRI tool, using baseline MRI measures, was able to predict the expected MRI atrophy at follow-up in presymptomatic subjects carrying GRN mutations with good performances. This tool could be useful in clinical trials, where deviation of CT from the predicted model may be considered an effect of the intervention itself. 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 StratNeuro; Swedish Dementia foundation and Stockholm County Council ALF/Region Stockholm.

Published
2022

215. 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

220. Functional imaging of response selection

Author

Rowe, James Benedict

Subjects
612.8233
Abstract

The functions of the prefrontal cortex remain controversial. Electrophysio- logical and lesion studies in monkeys have emphasised a role in working memory. In contrast, human functional neuroimaging studies and neuropsychology have emphasised a role in executive processes and volition. An alternative interpretation of the role of the prefrontal cortex is proposed in this thesis: that the prefrontal cortex mediates the attentional selection of sensory, mnemonic and motor representations in non-prefrontal cortex. This hypothesis is tested in a series of functional imaging experiments. In the first two experiments (chapters 4 and 5), event-related functional magnetic resonance imaging (fMRI) was used to re-examine the role of the prefrontal cortex in spatial and spatio-temporal working memory. Maintenance of information in memory was associated with activation of posterior prefrontal cortex (area 8). In contrast, the selection of an item from several remembered items was associated with activation of the middle and anterior parts of the prefrontal cortex (including area 46). To test the generalisation of 'selection' as a function of prefrontal cortex, experiment three (chapter 6) required subjects to select either a finger to move, or a colour from a multicolour display. Free selection was associated with activation of the prefrontal cortex (area 46) bilaterally, regardless of sensory or motor modality. The selection of voluntary actions has been proposed to depend on top-down modulation of motor regions by prefrontal cortex. The fourth and fifth experiments used structural equation modelling of fMRI time -series to measure the effective connectivity among prefrontal, premotor and parietal cortex. In young (chapter 7) and old (chapter 8) normal subjects, attention to action specifically enhanced coupling between prefrontal and premotor regions. This effect was not seen in patients with Parkinson's disease (chapter 8). Lastly, positron emission tomography was used to study planning in the Tower of London task, a common clinical measure of prefrontal function. Several variants of the task were developed, to distinguish the neural basis of the task's multiple cognitive components (chapter 9). The prefrontal cortex was activated in association with generation, selection or memory for moves, rather than planning towards a specified goal. The results support a generalised role in attentional selection of neuronal representations, whether stimuli, actions, or remembered items. The hypothesised attentional selection of responses is consistent with the activation of prefrontal cortex in working memory tasks and during attention to voluntary action. This role is compatible with the neurophysiological properties of individual neurons in the prefrontal cortex and the results of neuroimaging and lesion studies.

Published
2002

224. Network connectivity and structural correlates of survival in progressive supranuclear palsy and corticobasal syndrome

Author

Whiteside, David J, Street, Duncan, Murley, Alexander G, Jones, P Simon, Malpetti, Maura, Ghosh, Boyd CP, Coyle-Gilchrist, Ian, Gerhard, Alexander, Hu, Michele T, Klein, Johannes C, Leigh, P Nigel, Church, Alistair, Burn, David J, Morris, Huw R, Rowe, James B, Rittman, Timothy, Whiteside, David J [0000-0002-5890-9220], Klein, Johannes C [0000-0002-8553-2801], Apollo - University of Cambridge Repository, Whiteside, David J. [0000-0002-5890-9220], and Klein, Johannes C. [0000-0002-8553-2801]

Subjects
Corticobasal Degeneration, connectivity, tauopathies, fMRI, Medizin, Humans, Neurodegenerative Diseases, corticobasal syndrome, prediction, progressive supranuclear palsy, Supranuclear Palsy, Progressive, Prognosis, survival
Abstract

in press; CA extern There is a pressing need to understand the factors that predict prognosis in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), with high heterogeneity over the poor average survival. We test the hypothesis that the magnitude and distribution of connectivity changes in PSP and CBS predict the rate of progression and survival time, using datasets from the Cambridge Centre for Parkinson-plus and the UK National PSP Research Network (PROSPECT-MR). Resting-state functional MRI images were available from 146 participants with PSP, 82 participants with CBS, and 90 healthy controls. Large-scale networks were identified through independent component analyses, with correlations taken between component time series. Independent component analysis was also used to select between-network connectivity components to compare with baseline clinical severity, longitudinal rate of change in severity, and survival. Transdiagnostic survival predictors were identified using partial least squares regression for Cox models, with connectivity compared to patients' demographics, structural imaging, and clinical scores using five-fold cross-validation. In PSP and CBS, between-network connectivity components were identified that differed from controls, were associated with disease severity, and were related to survival and rate of change in clinical severity. A transdiagnostic component predicted survival beyond demographic and motion metrics but with lower accuracy than an optimal model that included the clinical and structural imaging measures. Cortical atrophy enhanced the connectivity changes that were most predictive of survival. Between-network connectivity is associated with variability in prognosis in PSP and CBS but does not improve predictive accuracy beyond clinical and structural imaging metrics.

Published
2023

225. Multisystem pathology in McLeod syndrome

Author

Schon, Katherine R, O'Donovan, Dominic G, Briggs, Mayen, Rowe, James B, Wijesekera, Lokesh, Chinnery, Patrick F, Van Den Ameele, Jelle, Schon, Katherine R [0000-0001-8054-8954], van den Ameele, Jelle [0000-0002-2744-0810], and Apollo - University of Cambridge Repository

Subjects
raised CK, autopsy, McLeod syndrome, XK gene
Abstract

We present a comprehensive characterization of clinical, neuropathological, and multisystem features of a man with genetically confirmed McLeod neuroacanthocytosis syndrome, including video and autopsy findings. A 61-year-old man presented with a movement disorder and behavioral change. Examination showed dystonic choreiform movements in all four limbs, reduced deep-tendon reflexes, and wide-based gait. He had oromandibular dyskinesia causing severe dysphagia. Elevated serum creatinine kinase (CK) was first noted in his thirties, but investigations, including muscle biopsy at that time, were inconclusive. Brain magnetic resonance imaging showed white matter volume loss, atrophic basal ganglia, and chronic small vessel ischemia. Despite raised CK, electromyography did not show myopathic changes. Exome gene panel testing was negative, but targeted genetic analysis revealed a hemizygous pathogenic variant in the XK gene c.895C > T p.(Gln299Ter), consistent with a diagnosis of McLeod syndrome. The patient died of sepsis, and autopsy showed astrocytic gliosis and atrophy of the basal ganglia, diffuse iron deposition in the putamen, and mild Alzheimer's pathology. Muscle pathology was indicative of mild chronic neurogenic atrophy without overt myopathic features. He had non-specific cardiomyopathy and splenomegaly. McLeod syndrome is an ultra-rare neurodegenerative disorder caused by X-linked recessive mutations in the XK gene. Diagnosis has management implications since patients are at risk of severe transfusion reactions and cardiac complications. When a clinical diagnosis is suspected, candidate genes should be interrogated rather than solely relying on exome panels.

Published
2023

226. Syndromes associated with frontotemporal lobar degeneration change response patterns on visual analogue scales

Author

Williams, Rebecca S, Adams, Natalie E, Hughes, Laura E, Rouse, Matthew A, Murley, Alexander G, Naessens, Michelle, Street, Duncan, Holland, Negin, Rowe, James B, and Apollo - University of Cambridge Repository

Subjects
Visual Analog Scale, Frontotemporal Dementia, Humans, Bayes Theorem, Syndrome, Frontotemporal Lobar Degeneration
Abstract

Self-report scales are widely used in cognitive neuroscience and psychology. However, they rest on the central assumption that respondents engage meaningfully. We hypothesise that this assumption does not hold for many patients, especially those with syndromes associated with frontotemporal lobar degeneration. In this study we investigated differences in response patterns on a visual analogue scale between people with frontotemporal degeneration and controls. We found that people with syndromes associated with frontotemporal lobar degeneration respond with more invariance and less internal consistency than controls, with Bayes Factors = 15.2 and 14.5 respectively indicating strong evidence for a group difference. There was also evidence that patient responses feature lower entropy. These results have important implications for the interpretation of self-report data in clinical populations. Meta-response markers related to response patterns, rather than the values reported on individual items, may be an informative addition to future research and clinical practise.

Published
2023

227. Corporate Social Responsibility as Business Strategy

Author

Rowe, James

Subjects
Globalization and Regulation
Abstract

I argue that Corporate Social Responsibility (CSR), particularly the corporate code of conduct, has been one of global business’ preferred strategies for quelling popular discontent with corporate power. By “business strategy” I mean organized responses, through organizations like the International Chamber of Commerce (ICC), to the threat public regulation poses to business’s collective self-interest. Attention to CSR’s historical development reveals it has flourished as discourse and practice at times when corporations became subject to intense public scrutiny. In this essay I outline two periods of corporate crisis, and account for the role codes have played in quieting public concern over increasing corporate power: 1) When developing countries along with Western unions and social activists were calling for a ‘New International Economic Order’ that would more tightly regulate the activity of Transnational Corporations (1960-1976); and 2) When mass anti-globalization demonstrations and high profile corporate scandals are increasing the demand for regulation (1998-Present).

Published
2005

228. Neuropsychiatric symptoms in genetic frontotemporal dementia: developing a new module for Clinical Rating Scales

Author

Samra, Kiran, Macdougall, Amy, Peakman, Georgia, Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Moreno, Fermin, Sánchez-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 Mendonca, 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., Rademakers, Rosa, Bruffaerts, Rose, Genetic FTD Initiative (GENFI), Neurology, Genetic FTD Initiative (GENFI), Samra, Kiran [0000-0002-3105-7099], Peakman, Georgia [0000-0002-3319-138X], Bocchetta, Martina [0000-0003-1814-5024], Convery, Rhian S [0000-0002-9477-1812], van Swieten, John C [0000-0001-6278-6844], Jiskoot, Lize C [0000-0002-1120-1858], Seelaar, Harro [0000-0003-1989-7527], Rowe, James B [0000-0001-7216-8679], Borroni, Barbara [0000-0001-9340-9814], Finger, Elizabeth [0000-0003-4461-7427], Synofzik, Matthis [0000-0002-2280-7273], Galimberti, Daniela [0000-0002-9284-5953], Gerhard, Alexander [0000-0002-8071-6062], Ducharme, Simon [0000-0002-7309-1113], Le Ber, Isabelle [0000-0002-2508-5181], Tiraboschi, Pietro [0000-0002-2171-1720], Sorbi, Sandro [0000-0002-0380-6670], Rohrer, Jonathan D [0000-0002-6155-8417], Apollo - University of Cambridge Repository, Miltenberger, Gabriel, Couto, Frederico Simões do, 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, Damme, Philip Van, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, 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, 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, Minkelen, Rick van, 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 Repositório da Universidade de Lisboa

Subjects
genetics [Hallucinations], GENETICS, Hallucinations, Clinical Neurology, Medizin, C9ORF72, PROGRESSION, Anxiety, DIAGNOSIS, PHENOTYPE, AMYOTROPHIC-LATERAL-SCLEROSIS, diagnosis [Frontotemporal Dementia], SDG 3 - Good Health and Well-being, CRITERIA, Humans, ddc:610, MUTATION, genetics [Frontotemporal Dementia], Psychiatry, NEUROPSYCHIATRY, Science & Technology, PSYCHIATRIC-SYMPTOMS, FRONTOTEMPORAL DEMENTIA, Mental Status and Dementia Tests, HEXANUCLEOTIDE REPEAT EXPANSION, PREVALENCE, Psychiatry and Mental health, Psychotic Disorders, Frontotemporal Dementia, Surgery, Neurosciences & Neurology, Human medicine, Neurology (clinical), Life Sciences & Biomedicine
Abstract

Peer reviewed: True, Acknowledgements: We thank the research participants and their families for their contribution to the study. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510., Funder: Bluefield Project, Funder: National Institute for Health Research Cambridge Biomedical Research Centre, BACKGROUND: Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage. METHODS: 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale. RESULTS: Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single 'psychosis' neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal. CONCLUSIONS: Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC FTLD. Inclusion of these features brings us closer to optimising the rating scale for use in trials.

Published
2023

232. Longitudinal Synaptic Loss in Primary Tauopathies: An In Vivo [11 C] UCB‐J Positron Emission Tomography Study

Author

Holland, Negin, primary, Jones, P. Simon, additional, Savulich, George, additional, Naessens, Michelle, additional, Malpetti, Maura, additional, Whiteside, David J., additional, Street, Duncan, additional, Swann, Peter, additional, Hong, Young T., additional, Fryer, Tim D., additional, Rittman, Timothy, additional, Mulroy, Eoin, additional, Aigbirhio, Franklin I., additional, Bhatia, Kailash P., additional, O'Brien, John T., additional, and Rowe, James B., additional

Published
2023
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234. Prioritization of Drug Targets for Neurodegenerative Diseases by Integrating Genetic and Proteomic Data From Brain and Blood

Author

Ge, Yi-Jun, primary, Ou, Ya-Nan, additional, Deng, Yue-Ting, additional, Wu, Bang-Sheng, additional, Yang, Liu, additional, Zhang, Ya-Ru, additional, Chen, Shi-Dong, additional, Huang, Yu-Yuan, additional, Dong, Qiang, additional, Tan, Lan, additional, Yu, Jin-Tai, additional, Ferrari, Raffaele, additional, Hernandez, Dena G., additional, Nalls, Michael A., additional, Rohrer, Jonathan D., additional, Ramasamy, Adaikalavan, additional, Kwok, John B.J., additional, Dobson-Stone, Carol, additional, Brooks, William S., additional, Schofield, Peter R., additional, Halliday, Glenda M., additional, Hodges, John R., additional, Piguet, Olivier, additional, Bartley, Lauren, additional, Thompson, Elizabeth, additional, Haan, Eric, additional, Hernández, Isabel, additional, Ruiz, Agustín, additional, Boada, Mercè, additional, Borroni, Barbara, additional, Padovani, Alessandro, additional, Cruchaga, Carlos, additional, Cairns, Nigel J., additional, Benussi, Luisa, additional, Binetti, Giuliano, additional, Ghidoni, Roberta, additional, Forloni, Gianluigi, additional, Galimberti, Daniela, additional, Fenoglio, Chiara, additional, Serpente, Maria, additional, Scarpini, Elio, additional, Clarimón, Jordi, additional, Lleó, Alberto, additional, Blesa, Rafael, additional, Waldö, Maria Landqvist, additional, Nilsson, Karin, additional, Nilsson, Christer, additional, Mackenzie, Ian R.A., additional, Hsiung, Ging-Yuek R., additional, Mann, David M.A., additional, Grafman, Jordan, additional, Morris, Christopher M., additional, Attems, Johannes, additional, Griffiths, Timothy D., additional, McKeith, Ian G., additional, Thomas, Alan J., additional, Pietrini, P., additional, Huey, Edward D., additional, Wassermann, Eric M., additional, Baborie, Atik, additional, Jaros, Evelyn, additional, Tierney, Michael C., additional, Pastor, Pau, additional, Razquin, Cristina, additional, Ortega-Cubero, Sara, additional, Alonso, Elena, additional, Perneczky, Robert, additional, Diehl-Schmid, Janine, additional, Alexopoulos, Panagiotis, additional, Kurz, Alexander, additional, Rainero, Innocenzo, additional, Rubino, Elisa, additional, Pinessi, Lorenzo, additional, Rogaeva, Ekaterina, additional, St. George-Hyslop, Peter, additional, Rossi, Giacomina, additional, Tagliavini, Fabrizio, additional, Giaccone, Giorgio, additional, Rowe, James B., additional, Schlachetzki, Johannes C.M., additional, Uphill, James, additional, Collinge, John, additional, Mead, Simon, additional, Danek, Adrian, additional, Van Deerlin, Vivianna M., additional, Grossman, Murray, additional, Trojanowski, John Q., additional, van der Zee, Julie, additional, Deschamps, William, additional, Van Langenhove, Tim, additional, Cruts, Marc, additional, Van Broeckhoven, Christine, additional, Cappa, Stefano F., additional, Le Ber, Isabelle, additional, Hannequin, Didier, additional, Golfier, Véronique, additional, Vercelletto, Martine, additional, Brice, Alexis, additional, Nacmias, Benedetta, additional, Sorbi, Sandro, additional, Bagnoli, Silvia, additional, Piaceri, Irene, additional, Nielsen, Jørgen E., additional, Hjermind, Lena E., additional, Riemenschneider, Matthias, additional, Mayhaus, Manuel, additional, Ibach, Bernd, additional, Gasparoni, Gilles, additional, Pichler, Sabrina, additional, Gu, Wei, additional, Rossor, Martin N., additional, Fox, Nick C., additional, Warren, Jason D., additional, Spillantini, Maria Grazia, additional, Morris, Huw R., additional, Rizzu, Patrizia, additional, Heutink, Peter, additional, Snowden, Julie S., additional, Rollinson, Sara, additional, Richardson, Anna, additional, Gerhard, Alexander, additional, Bruni, Amalia C., additional, Maletta, Raffaele, additional, Frangipane, Francesca, additional, Cupidi, Chiara, additional, Bernardi, Livia, additional, Anfossi, Maria, additional, Gallo, Maura, additional, Conidi, Maria Elena, additional, Smirne, Nicoletta, additional, Rademakers, Rosa, additional, Baker, Matt, additional, Dickson, Dennis W., additional, Graff-Radford, Neill R., additional, Petersen, Ronald C., additional, Knopman, David, additional, Josephs, Keith A., additional, Boeve, Bradley F., additional, Parisi, Joseph E., additional, Seeley, William W., additional, Miller, Bruce L., additional, Karydas, Anna M., additional, Rosen, Howard, additional, van Swieten, John C., additional, Dopper, Elise G.P., additional, Seelaar, Harro, additional, Pijnenburg, Yolande A.L., additional, Scheltens, Philip, additional, Logroscino, Giancarlo, additional, Capozzo, Rosa, additional, Novelli, Valeria, additional, Puca, Annibale A., additional, Franceschi, Massimo, additional, Postiglione, Alfredo, additional, Milan, Graziella, additional, Sorrentino, Paolo, additional, Kristiansen, Mark, additional, Chiang, Huei-Hsin, additional, Graff, Caroline, additional, Pasquier, Florence, additional, Rollin, Adeline, additional, Deramecourt, Vincent, additional, Lebert, Florence, additional, Kapogiannis, Dimitrios, additional, Ferrucci, Luigi, additional, Pickering-Brown, Stuart, additional, Singleton, Andrew B., additional, Hardy, John, additional, and Momeni, Parastoo, additional

Published
2023
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235. Incidence of syndromes associated with Frontotemporal Lobar Degeneration (S19.004)

Author

Logroscino, Giancarlo, primary, Piccininni, Marco, additional, Graff, Caroline, additional, Hardiman, Orla, additional, Ludolph, Albert, additional, Moreno, Fermin, additional, Otto, Markus, additional, Remes, Anne, additional, Rowe, James, additional, Seelaar, Harro, additional, Solje, Eino, additional, Stefanova, Elka, additional, Traykov, Latchezar, additional, Jelic, Vesna, additional, Rydell, Melissa Thaeri, additional, Pender, Niall, additional, Anderl-Straub, Sarah, additional, Barandiaran, Myriam, additional, Gabilondo, Alazne, additional, Kruger, Johanna, additional, Murley, Alexander, additional, Rittman, Timothy, additional, van der Ende, Emma L., additional, Van Swieten, John, additional, Hartikainen, Paivi, additional, Stojmenovic, Gorana Mandic, additional, Meherabian, Shima, additional, Benussi, Luisa, additional, Alberici, Antonella, additional, Dell’Abate, Maria Teresa, additional, Zecca, Chiara, additional, and Borroni, Barbara, additional

Published
2023
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236. Creating the Pick’s disease International Consortium: Association study ofMAPTH2 haplotype with risk of Pick’s disease

Author

Valentino, Rebecca R, primary, Scotton, William J, additional, Roemer, Shanu F, additional, Lashley, Tammaryn, additional, Heckman, Michael G, additional, Shoai, Maryam, additional, Martinez-Carrasco, Alejandro, additional, Tamvaka, Nicole, additional, Walton, Ronald L, additional, Baker, Matthew C, additional, Macpherson, Hannah L, additional, Real, Raquel, additional, Soto-Beasley, Alexandra I, additional, Mok, Kin, additional, Revesz, Tamas, additional, Warner, Thomas T, additional, Jaunmuktane, Zane, additional, Boeve, Bradley F, additional, Christopher, Elizabeth A, additional, DeTure, Michael, additional, Duara, Ranjan, additional, Graff-Radford, Neill R, additional, Josephs, Keith A, additional, Knopman, David S, additional, Koga, Shunsuke, additional, Murray, Melissa E, additional, Lyons, Kelly E, additional, Pahwa, Rajesh, additional, Parisi, Joseph E, additional, Petersen, Ronald C, additional, Whitwell, Jennifer, additional, Grinberg, Lea T, additional, Miller, Bruce, additional, Schlereth, Athena, additional, Seeley, William W, additional, Spina, Salvatore, additional, Grossman, Murray, additional, Irwin, David J, additional, Lee, Edward B, additional, Suh, EunRan, additional, Trojanowski, John Q, additional, Van Deerlin, Vivianna M, additional, Wolk, David A, additional, Connors, Theresa R, additional, Dooley, Patrick M, additional, Frosch, Matthew P, additional, Oakley, Derek H, additional, Aldecoa, Iban, additional, Balasa, Mircea, additional, Gelpi, Ellen, additional, Borrego-Écija, Sergi, additional, de Eugenio Huélamo, Rosa Maria, additional, Gascon-Bayarri, Jordi, additional, Sánchez-Valle, Raquel, additional, Sanz-Cartagena, Pilar, additional, Piñol-Ripoll, Gerard, additional, Molina-Porcel, Laura, additional, Bigio, Eileen H, additional, Flanagan, Margaret E, additional, Gefen, Tamar, additional, Rogalski, Emily J, additional, Weintraub, Sandra, additional, Redding-Ochoa, Javier, additional, Chang, Koping, additional, Troncoso, Juan C, additional, Prokop, Stefan, additional, Newell, Kathy L, additional, Ghetti, Bernardino, additional, Jones, Matthew, additional, Richardson, Anna, additional, Robinson, Andrew C, additional, Roncaroli, Federico, additional, Snowden, Julie, additional, Allinson, Kieren, additional, Green, Oliver, additional, Rowe, James B, additional, Singh, Poonam, additional, Beach, Thomas G, additional, Serrano, Geidy E, additional, Flowers, Xena E, additional, Goldman, James E, additional, Heaps, Allison C, additional, Leskinen, Sandra P, additional, Teich, Andrew F, additional, Black, Sandra E, additional, Keith, Julia L, additional, Masellis, Mario, additional, Bodi, Istvan, additional, King, Andrew, additional, Sarraj, Safa-Al, additional, Troakes, Claire, additional, Halliday, Glenda M, additional, Hodges, John R, additional, Kril, Jillian J, additional, Kwok, John B, additional, Piguet, Olivier, additional, Gearing, Marla, additional, Arzberger, Thomas, additional, Roeber, Sigrun, additional, Attems, Johannes, additional, Morris, Christopher M, additional, Thomas, Alan J, additional, Evers, Bret M., additional, White, Charles L, additional, Mechawar, Naguib, additional, Sieben, Anne A, additional, Cras, Patrick P, additional, De Vil, Bart B, additional, De Deyn, Peter Paul P.P., additional, Duyckaerts, Charles, additional, Ber, Isabelle Le, additional, Seihean, Danielle, additional, Turbant-Leclere, Sabrina, additional, MacKenzie, Ian R, additional, McLean, Catriona, additional, Cykowski, Matthew D, additional, Ervin, John F, additional, Wang, Shih-Hsiu J, additional, Graff, Caroline, additional, Nennesmo, Inger, additional, Nagra, Rashed M, additional, Riehl, James, additional, Kovacs, Gabor G, additional, Giaccone, Giorgio, additional, Nacmias, Benedetta, additional, Neumann, Manuela, additional, Ang, Lee-Cyn, additional, Finger, Elizabeth C, additional, Blauwendraat, Cornelis, additional, Nalls, Mike A, additional, Singleton, Andrew B, additional, Vitale, Dan, additional, Cunha, Cristina, additional, Carvalho, Agostinho, additional, Wszolek, Zbigniew K, additional, Morris, Huw R, additional, Rademakers, Rosa, additional, Hardy, John A, additional, Dickson, Dennis W, additional, Rohrer, Jonathan D, additional, and Ross, Owen A, additional

Published
2023
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237. APOE ε4 associates with microglial activation independently of Aβ plaques and tau tangles

Author

Ferrari-Souza, João Pedro, primary, Lussier, Firoza Z., additional, Leffa, Douglas T., additional, Therriault, Joseph, additional, Tissot, Cécile, additional, Bellaver, Bruna, additional, Ferreira, Pâmela C. L., additional, Malpetti, Maura, additional, Wang, Yi-Ting, additional, Povala, Guilherme, additional, Benedet, Andréa L., additional, Ashton, Nicholas J., additional, Chamoun, Mira, additional, Servaes, Stijn, additional, Bezgin, Gleb, additional, Kang, Min Su, additional, Stevenson, Jenna, additional, Rahmouni, Nesrine, additional, Pallen, Vanessa, additional, Poltronetti, Nina Margherita, additional, O’Brien, John T., additional, Rowe, James B., additional, Cohen, Ann D., additional, Lopez, Oscar L., additional, Tudorascu, Dana L., additional, Karikari, Thomas K., additional, Klunk, William E., additional, Villemagne, Victor L., additional, Soucy, Jean-Paul, additional, Gauthier, Serge, additional, Souza, Diogo O., additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Zimmer, Eduardo R., additional, Rosa-Neto, Pedro, additional, and Pascoal, Tharick A., additional

Published
2023
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238. 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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239. Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease

Author

Mok, Tze How, primary, Nihat, Akin, additional, Majbour, Nour, additional, Sequeira, Danielle, additional, Holm-Mercer, Leah, additional, Coysh, Thomas, additional, Darwent, Lee, additional, Batchelor, Mark, additional, Groveman, Bradley R, additional, Orr, Christina D, additional, Hughson, Andrew G, additional, Heslegrave, Amanda, additional, Laban, Rhiannon, additional, Veleva, Elena, additional, Paterson, Ross W, additional, Keshavan, Ashvini, additional, Schott, Jonathan M, additional, Swift, Imogen J, additional, Heller, Carolin, additional, Rohrer, Jonathan D, additional, Gerhard, Alexander, additional, Butler, Christopher, additional, Rowe, James B, additional, Masellis, Mario, additional, Chapman, Miles, additional, Lunn, Michael P, additional, Bieschke, Jan, additional, Jackson, Graham S, additional, Zetterberg, Henrik, additional, Caughey, Byron, additional, Rudge, Peter, additional, Collinge, John, additional, and Mead, Simon, additional

Published
2023
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240. Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials

Author

Street, Duncan, primary, Jabbari, Edwin, additional, Costantini, Alyssa, additional, Jones, P Simon, additional, Holland, Negin, additional, Rittman, Timothy, additional, Jensen, Marte T, additional, Chelban, Viorica, additional, Goh, Yen Y, additional, Guo, Tong, additional, Heslegrave, Amanda J, additional, Roncaroli, Federico, additional, Klein, Johannes C, additional, Ansorge, Olaf, additional, Allinson, Kieren S J, additional, Jaunmuktane, Zane, additional, Revesz, Tamas, additional, Warner, Thomas T, additional, Lees, Andrew J, additional, Zetterberg, Henrik, additional, Russell, Lucy L, additional, Bocchetta, Martina, additional, Rohrer, Jonathan D, additional, Burn, David J, additional, Pavese, Nicola, additional, Gerhard, Alexander, additional, Kobylecki, Christopher, additional, Leigh, P Nigel, additional, Church, Alistair, additional, Hu, Michele T M, additional, Houlden, Henry, additional, Morris, Huw, additional, and Rowe, James B, additional

Published
2023
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241. Microglial activation in the frontal cortex predicts cognitive decline in frontotemporal dementia

Author

Malpetti, Maura, primary, Cope, Thomas E, additional, Street, Duncan, additional, Jones, P Simon, additional, Hezemans, Frank H, additional, Mak, Elijah, additional, Tsvetanov, Kamen A, additional, Rittman, Timothy, additional, Bevan-Jones, W Richard, additional, Patterson, Karalyn, additional, Passamonti, Luca, additional, Fryer, Tim D, additional, Hong, Young T, additional, Aigbirhio, Franklin I, additional, O’Brien, John T, additional, and Rowe, James B, additional

Published
2023
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242. 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, 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., and Ducharme, Simon

Abstract

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.

Published
2023

243. 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, 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, and Sánchez-Valle, Raquel

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
2023

244. Motor symptoms in genetic frontotemporal dementia:developing a new module for clinical rating scales

Author

MacDougall, Amy M., Samra, Kiran, Peakman, Georgia, Bouzigues, Arabella, Bocchetta, Martina, Cash, David, 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, 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, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Russell, Lucy L., Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, MacDougall, Amy M., Samra, Kiran, Peakman, Georgia, Bouzigues, Arabella, Bocchetta, Martina, Cash, David, 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, 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, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Russell, Lucy L., Poos, Jackie, Papma, Janne M., Giannini, Lucia, and van Minkelen, Rick

Abstract

Objective: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). Methods: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). Results: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). Conclusions: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

Published
2023

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

Author

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., Russell, Lucy L., 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.

Abstract

Objective: To identify whether language impairment exists presymptomatically in genetic frontotemporal dementia (FTD), and if so, the key differences between the main genetic mutation groups. Methods: 682 participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 290 asymptomatic and 82 prodromal mutation carriers (with C9orf72, GRN, and MAPT mutations) as well as 310 mutation-negative controls. Language was assessed using items from the Progressive Aphasia Severity Scale, as well as the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency task. Participants also underwent a 3 T volumetric T1-weighted MRI from which regional brain volumes within the language network were derived and compared between the groups. Results: 3% of asymptomatic (4% C9orf72, 4% GRN, 2% MAPT) and 48% of prodromal (46% C9orf72, 42% GRN, 64% MAPT) mutation carriers had impairment in at least one language symptom compared with 13% of controls. In prodromal mutation carriers significantly impaired word retrieval was seen in all three genetic groups whilst significantly impaired grammar/syntax and decreased fluency was seen only in C9orf72 and GRN mutation carriers, and impaired articulation only in the C9orf72 group. Prodromal MAPT mutation carriers had significant impairment on the category fluency task and the BNT whilst prodromal C9orf72 mutation carriers were impaired on the category fluency task only. Atrophy in the dominant perisylvian language regions differed between groups, with earlier, more widespread volume loss in C9orf72, and later focal atrophy in the temporal lobe in MAPT mutation carriers. Conclusions: Language deficits exist in the prodromal but not asymptomatic stages of genetic FTD across all three genetic groups. Improved understanding of the language phenotype prior to phenoconversion to fully symptomatic FTD will help develop outcome measures for future presymptomatic trials.

Published
2023

246. Case study of vibration in a mobile milling machine

Author

Rowe, James, Langrand, Christopher, Debuchy, Roger, Rowe, James, Langrand, Christopher, and Debuchy, Roger

Abstract

Many industries rely on heavy-duty machinery such as cranes, pipelines, motors, which are subject to wear and tear. Milling of such parts using conventional machine tools presents many drawbacks and is impossible in some cases. In such situations, mobile machine tools can be used to machine directly on site. However, mobile machines are flexible, and are prone to detrimental vibrations during cutting operations. Vibrational stability in the surfacing process has been extensively studied in conventional milling. However, the focus of this article is an original study on a mobile milling machine used for on-site surfacing operations. An experimental investigation into the vibrational behavior of the machine is carried out and a sensorless method is used to detect the onset of chatter. Machine flexibility is discussed using a tool-point frequency response function and references from the literature. Milling operations are carried out over a range machining parameter to determine an experimental stability limit. Internal sensors for spindle motor consumption and spindle motor encoder are monitored during the machining process. A threshold is established for determining the appearance of chatter using only the machine’s internal sensors.

Published
2023

247. 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., 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, and Rohrer, Jonathan D.

Abstract

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 poi

Published
2023

248. Genetic forms of primary progressive aphasia within the GENetic Frontotemporal dementia Initiative (GENFI) cohort:Comparison with sporadic primary progressive aphasia

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., 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., and Russell, Lucy L.

Abstract

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 3T 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

Published
2023

249. Neuropsychiatric symptoms in genetic frontotemporal dementia:developing a new module for Clinical Rating Scales

Author

Samra, Kiran, Macdougall, Amy, Peakman, Georgia, Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Moreno, Fermin, Sánchez-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 Mendonca, 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., Samra, Kiran, Macdougall, Amy, Peakman, Georgia, Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Jiskoot, Lize C., Seelaar, Harro, Moreno, Fermin, Sánchez-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 Mendonca, 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., and Russell, Lucy L.

Abstract

BACKGROUND: Current clinical rating scales in frontotemporal dementia (FTD) often do not incorporate neuropsychiatric features and may therefore inadequately measure disease stage. METHODS: 832 participants from the Genetic FTD Initiative (GENFI) were recruited: 522 mutation carriers and 310 mutation-negative controls. The standardised GENFI clinical questionnaire assessed the frequency and severity of 14 neuropsychiatric symptoms: visual, auditory, and tactile hallucinations, delusions, depression, anxiety, irritability/lability, agitation/aggression, euphoria/elation, aberrant motor behaviour, hypersexuality, hyperreligiosity, impaired sleep, and altered sense of humour. A principal component analysis (PCA) was performed to identify key groupings of neuropsychiatric and behavioural items in order to create a new neuropsychiatric module that could be used as an addition to the Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center Behaviour and Language Domains (NACC FTLD) rating scale. RESULTS: Overall, 46.4% of mutation carriers had neuropsychiatric symptoms (51.6% C9orf72, 40.8% GRN, 46.6% MAPT) compared with 24.5% of controls. Anxiety and depression were the most common in all genetic groups but fluctuated longitudinally and loaded separately in the PCA. Hallucinations and delusions loaded together, with the remaining neuropsychiatric symptoms loading with the core behavioural features of FTD. These results suggest using a single 'psychosis' neuropsychiatric module consisting of hallucinations and delusions. Adding this to the CDR plus NACC FTLD, called the CDR plus NACC FTLD-N, leads to a number of participants being scored more severely, including those who were previously considered asymptomatic now being scored as prodromal. CONCLUSIONS: Neuropsychiatric symptoms occur in mutation carriers at all disease stages across all three genetic groups. However, only psychosis features provided additional staging benefit to the CDR plus NACC

Published
2023

250. Cerebellar and subcortical atrophy contribute to psychiatric symptoms in frontotemporal dementia

Author

Bussy, Aurélie, Levy, Jake P., Best, Tristin, Patel, Raihaan, Cupo, Lani, Van Langenhove, Tim, Nielsen, Jørgen E., Pijnenburg, Yolande, Waldö, Maria Landqvist, Remes, Anne M., Schroeter, Matthias L., Santana, Isabel, Pasquier, Florence, Otto, Markus, Danek, Adrian, Levin, Johannes, Le Ber, Isabelle, Vandenberghe, Rik, Synofzik, Matthis, Moreno, Fermin, de Mendonça, Alexandre, Sanchez-Valle, Raquel, Laforce, Robert, Langheinrich, Tobias, Gerhard, Alexander, Graff, Caroline, Butler, Chris R., Sorbi, Sandro, Jiskoot, Lize, Seelaar, Harro, van Swieten, John C., Finger, Elizabeth, Tartaglia, Maria Carmela, Masellis, Mario, Tiraboschi, Pietro, Galimberti, Daniela, Borroni, Barbara, Rowe, James B., Bocchetta, Martina, Rohrer, Jonathan D., Devenyi, Gabriel A., Chakravarty, M. Mallar, Ducharme, Simon, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Bussy, Aurélie, Levy, Jake P., Best, Tristin, Patel, Raihaan, Cupo, Lani, Van Langenhove, Tim, Nielsen, Jørgen E., Pijnenburg, Yolande, Waldö, Maria Landqvist, Remes, Anne M., Schroeter, Matthias L., Santana, Isabel, Pasquier, Florence, Otto, Markus, Danek, Adrian, Levin, Johannes, Le Ber, Isabelle, Vandenberghe, Rik, Synofzik, Matthis, Moreno, Fermin, de Mendonça, Alexandre, Sanchez-Valle, Raquel, Laforce, Robert, Langheinrich, Tobias, Gerhard, Alexander, Graff, Caroline, Butler, Chris R., Sorbi, Sandro, Jiskoot, Lize, Seelaar, Harro, van Swieten, John C., Finger, Elizabeth, Tartaglia, Maria Carmela, Masellis, Mario, Tiraboschi, Pietro, Galimberti, Daniela, Borroni, Barbara, Rowe, James B., Bocchetta, Martina, Rohrer, Jonathan D., Devenyi, Gabriel A., Chakravarty, M. Mallar, Ducharme, Simon, Esteve, Aitana Sogorb, Nelson, Annabel, Bouzigues, Arabella, Poos, Jackie, Papma, Janne M., Giannini, Lucia, and van Minkelen, Rick

Abstract

Recent studies have reported early cerebellar and subcortical impact in the disease progression of genetic frontotemporal dementia (FTD) due to microtubule-associated protein tau (MAPT), progranulin (GRN) and chromosome 9 open reading frame 72 (C9orf72). However, the cerebello-subcortical circuitry in FTD has been understudied despite its essential role in cognition and behaviors related to FTD symptomatology. The present study aims to investigate the association between cerebellar and subcortical atrophy, and neuropsychiatric symptoms across genetic mutations. Our study included 983 participants from the Genetic Frontotemporal dementia Initiative including mutation carriers and noncarrier first-degree relatives of known symptomatic carriers. Voxel-wise analysis of the thalamus, striatum, globus pallidus, amygdala, and the cerebellum was performed, and partial least squares analyses (PLS) were used to link morphometry and behavior. In presymptomatic C9orf72 expansion carriers, thalamic atrophy was found compared to noncarriers, suggesting the importance of this structure in FTD prodromes. PLS analyses demonstrated that the cerebello-subcortical circuitry is related to neuropsychiatric symptoms, with significant overlap in brain/behavior patterns, but also specificity for each genetic mutation group. The largest differences were in the cerebellar atrophy (larger extent in C9orf72 expansion group) and more prominent amygdalar volume reduction in the MAPT group. Brain scores in the C9orf72 expansion carriers and MAPT carriers demonstrated covariation patterns concordant with atrophy patterns detectable up to 20 years before expected symptom onset. Overall, these results demonstrated the important role of the subcortical structures in genetic FTD symptom expression, particularly the cerebellum in C9orf72 and the amygdala in MAPT carriers.

Published
2023

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