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1. 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
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2. Language impairment in the genetic forms of behavioural variant frontotemporal dementia

Author: On Behalf of the Genetic FTD Initiative (GENFI), Samra, Kiran, MacDougall, Amy M., Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Seelaar, Harro, Jiskoot, Lize, Moreno, Fermin, 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, Christopher R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Russell, Lucy L., Nelson, Annabel, Thomas, David L., Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Maruta, Carolina, do Couto, Frederico Simões, and Veritati - Repositório Institucional da Universidade Católica Portuguesa
Subjects: Progranulin, C9orf72, Genetics, Tau, Frontotemporal dementia, Language
Abstract: Background: Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. Methods: Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. Results: 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. Conclusions: Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.
Published: 2023

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

Author: Bouzigues, Arabella, Russell, Lucy L, Tiraboschi, Pietro, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, Masellis, Mario, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Tartaglia, Maria Carmela, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Finger, Elizabeth, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, van Swieten, John C, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Seelaar, Harro, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Engel, Annerose, Polyakova, Maryna, Jiskoot, Lize, Sorbi, Sandro, Butler, Chris R, Graff, Caroline, Peakman, Georgia, Gerhard, Alexander, Langheinrich, Tobias, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Le Ber, Isabelle, Bocchetta, Martina, Levin, Johannes, Danek, Adrian, Otto, Markus, Pasquier, Florence, Santana, Isabel, Rohrer, Jonathan D, Genetic FTD Initiative, GENFI, Esteve, Aitana Sogorb, Nelson, Annabel, Greaves, Caroline V, Heller, Carolin, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Nicholas, Jennifer, Samra, Kiran, Convery, Rhian S, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Rowe, James B, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Keren, Ron, Black, Sandra, Mitchell, Sara, Borroni, Barbara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Galimberti, Daniela, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Bouzigues, Arabella [0000-0002-0267-8590], Russell, Lucy L [0000-0001-5023-5893], Peakman, Georgia [0000-0002-3319-138X], Bocchetta, Martina [0000-0003-1814-5024], Greaves, Caroline V [0000-0002-6446-1960], Convery, Rhian S [0000-0002-9477-1812], Rowe, James B [0000-0001-7216-8679], Finger, Elizabeth [0000-0003-4461-7427], van Swieten, John C [0000-0001-6278-6844], Levin, Johannes [0000-0001-5092-4306], Otto, Markus [0000-0002-6647-5944], Apollo - University of Cambridge Repository, Esteve, Aitana Sogorb (Beitragende*r), Nelson, Annabel (Beitragende*r), Heller, Carolin (Beitragende*r), Cash, David (Beitragende*r), Thomas, David L (Beitragende*r), Benotmane, Hanya (Beitragende*r), Zetterberg, Henrik (Beitragende*r), Swift, Imogen J (Beitragende*r), Nicholas, Jennifer (Beitragende*r), Samra, Kiran (Beitragende*r), Shafei, Rachelle (Beitragende*r), Timberlake, Carolyn (Beitragende*r), Cope, Thomas (Beitragende*r), Rittman, Timothy (Beitragende*r), Benussi, Alberto (Beitragende*r), Premi, Enrico (Beitragende*r), Gasparotti, Roberto (Beitragende*r), Archetti, Silvana (Beitragende*r), Gazzina, Stefano (Beitragende*r), Cantoni, Valentina (Beitragende*r), Arighi, Andrea (Beitragende*r), Fenoglio, Chiara (Beitragende*r), Scarpini, Elio (Beitragende*r), Fumagalli, Giorgio (Beitragende*r), Borracci, Vittoria (Beitragende*r), Rossi, Giacomina (Beitragende*r), Giaccone, Giorgio (Beitragende*r), Caroppo, Paola (Beitragende*r), Prioni, Sara (Beitragende*r), Redaelli, Veronica (Beitragende*r), Tang-Wai, David (Beitragende*r), Rogaeva, Ekaterina (Beitragende*r), Castelo-Branco, Miguel (Beitragende*r), Keren, Ron (Beitragende*r), Black, Sandra (Beitragende*r), Mitchell, Sara (Beitragende*r), Shoesmith, Christen (Beitragende*r), Bartha, Robart (Beitragende*r), Rademakers, Rosa (Beitragende*r), Poos, Jackie (Beitragende*r), Papma, Janne M (Beitragende*r), Giannini, Lucia (Beitragende*r), Minkelen, Rick (Beitragende*r), Pijnenburg, Yolande (Beitragende*r), Nacmias, Benedetta (Beitragende*r), Ferrari, Camilla (Beitragende*r), Polito, Cristina (Beitragende*r), Lombardi, Gemma (Beitragende*r), Bessi, Valentina (Beitragende*r), Veldsman, Michele (Beitragende*r), Andersson, Christin (Beitragende*r), Thonberg, Hakan (Beitragende*r), Öijerstedt, Linn (Beitragende*r), Jelic, Vesna (Beitragende*r), Thompson, Paul (Beitragende*r), Lladó, Albert (Beitragende*r), Antonell, Anna (Beitragende*r), Olives, Jaume (Beitragende*r), Balasa, Mircea (Beitragende*r), Bargalló, Nuria (Beitragende*r), Borrego-Ecija, Sergi (Beitragende*r), Verdelho, Ana (Beitragende*r), Maruta, Carolina (Beitragende*r), Ferreira, Catarina B (Beitragende*r), Miltenberger, Gabriel (Beitragende*r), do Couto, Frederico Simões (Beitragende*r), Gabilondo, Alazne (Beitragende*r), Gorostidi, Ana (Beitragende*r), Villanua, Jorge (Beitragende*r), Cañada, Marta (Beitragende*r), Tainta, Mikel (Beitragende*r), Zulaica, Miren (Beitragende*r), Barandiaran, Myriam (Beitragende*r), Alves, Patricia (Beitragende*r), Bender, Benjamin (Beitragende*r), Wilke, Carlo (Beitragende*r), Graf, Lisa (Beitragende*r), Vogels, Annick (Beitragende*r), Vandenbulcke, Mathieu (Beitragende*r), Van Damme, Philip (Beitragende*r), Bruffaerts, Rose (Beitragende*r), Poesen, Koen (Beitragende*r), Rosa-Neto, Pedro (Beitragende*r), Gauthier, Serge (Beitragende*r), Camuzat, Agnès (Beitragende*r), Brice, Alexis (Beitragende*r), Bertrand, Anne (Beitragende*r), Funkiewiez, Aurélie (Beitragende*r), Rinaldi, Daisy (Beitragende*r), Saracino, Dario (Beitragende*r), Colliot, Olivier (Beitragende*r), Sayah, Sabrina (Beitragende*r), Prix, Catharina (Beitragende*r), Wlasich, Elisabeth (Beitragende*r), Wagemann, Olivia (Beitragende*r), Loosli, Sandra (Beitragende*r), Schönecker, Sonja (Beitragende*r), Hoegen, Tobias (Beitragende*r), Lombardi, Jolina (Beitragende*r), Anderl-Straub, Sarah (Beitragende*r), Rollin, Adeline (Beitragende*r), Kuchcinski, Gregory (Beitragende*r), Bertoux, Maxime (Beitragende*r), Lebouvier, Thibaud (Beitragende*r), Deramecourt, Vincent (Beitragende*r), Santiago, Beatriz (Beitragende*r), Duro, Diana (Beitragende*r), Leitão, Maria João (Beitragende*r), Almeida, Maria Rosario (Beitragende*r), Tábuas-Pereira, Miguel (Beitragende*r), Afonso, Sónia (Beitragende*r), Engel, Annerose (Beitragende*r), Polyakova, Maryna (Beitragende*r), Repositório da Universidade de Lisboa, Genetic FTD Initiative, GENFI, and Neurology
Subjects: Progranulin, Clinical Neurology, Medizin, Anomia, tau Proteins, Naming, IMPAIRMENTS, VARIANTS, diagnostic imaging [Frontotemporal Dementia], genetics [Progranulins], Cognition, Progranulins, Settore BIO/13 - Biologia Applicata, complications [Frontotemporal Dementia], mental disorders, C9orf72, Humans, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Biology, Science & Technology, C9orf72 Protein, MORPHOMETRIC ANALYSES, ANATOMY, ALZHEIMERS-DISEASE, genetics [tau Proteins], Neurology, Frontotemporal Dementia, Mutation, PATTERNS, Frontotemporal dementia, Tau, Human medicine, Neurosciences & Neurology, Neurology (clinical), complications [Anomia], Life Sciences & Biomedicine, MRI
Abstract: Funder: Alzheimer’s Research UK; doi: http://dx.doi.org/10.13039/501100002283, Funder: UCLH Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100012317, Funder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265, Funder: Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, Funder: Bluefield Project, INTRODUCTION: A third of frontotemporal dementia (FTD) is caused by an autosomal-dominant genetic mutation in one of three genes: microtubule-associated protein tau (MAPT), chromosome 9 open reading frame 72 (C9orf72) and progranulin (GRN). Prior studies of prodromal FTD have identified impaired executive function and social cognition early in the disease but few have studied naming in detail. METHODS: We investigated performance on the Boston Naming Test (BNT) in the GENetic Frontotemporal dementia Initiative cohort of 499 mutation carriers and 248 mutation-negative controls divided across three genetic groups: C9orf72, MAPT and GRN. Mutation carriers were further divided into 3 groups according to their global CDR plus NACC FTLD score: 0 (asymptomatic), 0.5 (prodromal) and 1 + (fully symptomatic). Groups were compared using a bootstrapped linear regression model, adjusting for age, sex, language and education. Finally, we identified neural correlates of anomia within carriers of each genetic group using a voxel-based morphometry analysis. RESULTS: All symptomatic groups performed worse on the BNT than controls with the MAPT symptomatic group scoring the worst. Furthermore, MAPT asymptomatic and prodromal groups performed significantly worse than controls. Correlates of anomia in MAPT mutation carriers included bilateral anterior temporal lobe regions and the anterior insula. Similar bilateral anterior temporal lobe involvement was seen in C9orf72 mutation carriers as well as more widespread left frontal atrophy. In GRN mutation carriers, neural correlates were limited to the left hemisphere, and involved frontal, temporal, insula and striatal regions. CONCLUSION: This study suggests the development of early anomia in MAPT mutation carriers, likely to be associated with impaired semantic knowledge. Clinical trials focused on the prodromal period within individuals with MAPT mutations should use language tasks, such as the BNT for patient stratification and as outcome measures.
Published: 2022
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4. CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia

Author: the Genetic FTD Initiative, GENFI, Woollacott, Ione O.C., Swift, Imogen J., Sogorb-Esteve, Aitana, Heller, Carolin, Knowles, Kathryn, Bouzigues, Arabella, Russell, Lucy L., Peakman, Georgia, Greaves, Caroline V., Convery, Rhian, Heslegrave, Amanda, Rowe, James B., Borroni, Barbara, Galimberti, Daniela, Tiraboschi, Pietro, Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, van Swieten, John C., Seelaar, Harro, Jiskoot, Lize, Sorbi, Sandro, Butler, Chris R., Graff, Caroline, Gerhard, Alexander, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Synofzik, Matthis, Vandenberghe, Rik, Ducharme, Simon, Ber, Isabelle Le, Levin, Johannes, Otto, Markus, Pasquier, Florence, Santana, Isabel, Zetterberg, Henrik, Rohrer, Jonathan D., Nelson, Annabel, Bocchetta, Martina, Cash, David, Thomas, David L., Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Samra, Kiran, Maruta, Carolina, do Couto, Frederico Simões, Almeida, Maria Rosário, and Veritati - Repositório Institucional da Universidade Católica Portuguesa
Abstract: Background: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. Methods: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. Results: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. Conclusions: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.
Published: 2022

5. CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia

Author: Woollacott, Ione O C, Swift, Imogen J, Heslegrave, Amanda, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Rowe, James B, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Borroni, Barbara, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Galimberti, Daniela, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Tiraboschi, Pietro, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Masellis, Mario, Tábuas-Pereira, Miguel, Afonso, Sónia, Tartaglia, Maria Carmela, Finger, Elizabeth, van Swieten, John C, Seelaar, Harro, Sogorb-Esteve, Aitana, Jiskoot, Lize, Sorbi, Sandro, Butler, Chris R, Graff, Caroline, Gerhard, Alexander, Laforce, Robert, Sanchez-Valle, Raquel, de Mendonça, Alexandre, Moreno, Fermin, Synofzik, Matthis, Heller, Carolin, Vandenberghe, Rik, Ducharme, Simon, Ber, Isabelle Le, Levin, Johannes, Otto, Markus, Pasquier, Florence, Santana, Isabel, Zetterberg, Henrik, Rohrer, Jonathan D, Genetic FTD Initiative, GENFI, Knowles, Kathryn, Nelson, Annabel, Bocchetta, Martina, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Bouzigues, Arabella, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Russell, Lucy L, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Peakman, Georgia, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Greaves, Caroline V, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Convery, Rhian, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Genetic FTD Initiative, GENFI, Russell, Lucy L [0000-0001-5023-5893], Borroni, Barbara [0000-0001-9340-9814], Galimberti, Daniela [0000-0002-9284-5953], Tiraboschi, Pietro [0000-0002-2171-1720], Tartaglia, Maria Carmela [0000-0002-5944-8497], Finger, Elizabeth [0000-0003-4461-7427], Laforce, Robert [0000-0002-2031-490X], Sanchez-Valle, Raquel [0000-0001-7750-896X], Synofzik, Matthis [0000-0002-2280-7273], Ducharme, Simon [0000-0002-7309-1113], Otto, Markus [0000-0003-4273-4267], Rohrer, Jonathan D [0000-0002-6155-8417], Apollo - University of Cambridge Repository, Repositório da Universidade de Lisboa, Neurology, Clinical Genetics, and Amsterdam Neuroscience - Neurodegeneration
Subjects: C9orf72 Protein, General Neuroscience, Medizin, diagnosis [Frontotemporal Dementia], cerebrospinal fluid [Biomarkers], Pick Disease of the Brain, Settore BIO/13 - Biologia Applicata, Frontotemporal Dementia, genetics [Chitinase-3-Like Protein 1], Humans, ddc:610, Chitinase-3-Like Protein 1, Human medicine, Neurology (clinical), genetics [C9orf72 Protein], Neuroglia, Biomarkers
Abstract: Funder: Alzheimer's Research UK, Funder: Brain Research UK; Id: http://dx.doi.org/10.13039/100013790, Funder: The Wolfson Foundation; Id: http://dx.doi.org/10.13039/501100001320, Funder: Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, Funder: UK Dementia Research Institute; Id: http://dx.doi.org/10.13039/501100017510, Funder: UK DRI Ltd; Id: http://dx.doi.org/10.13039/501100017510, Funder: MRC UK GENFI, Funder: Bluefield Project, Funder: Dioraphte Foundation; Id: http://dx.doi.org/10.13039/501100010573, Funder: Weston Brain Institute; Id: http://dx.doi.org/10.13039/100012479, Funder: Ontario Brain Institute; Id: http://dx.doi.org/10.13039/100008914, Funder: Cambridge University Centre for Frontotemporal Dementia, Funder: EU Joint Programme – Neurodegenerative Disease Research; Id: http://dx.doi.org/10.13039/100013278, Funder: the Olav Thon Foundation; Id: http://dx.doi.org/10.13039/501100021720, Funder: Erling‐Persson Family Foundation; Id: http://dx.doi.org/10.13039/100007436, Funder: Stiftelsen för Gamla Tjänarinnor; Id: http://dx.doi.org/10.13039/100010815, Funder: Deutsche Forschungsgemeinschaft; Id: http://dx.doi.org/10.13039/501100001659, BACKGROUND: Neuroinflammation has been shown to be an important pathophysiological disease mechanism in frontotemporal dementia (FTD). This includes activation of microglia, a process that can be measured in life through assaying different glia-derived biomarkers in cerebrospinal fluid. However, only a few studies so far have taken place in FTD, and even fewer focusing on the genetic forms of FTD. METHODS: We investigated the cerebrospinal fluid concentrations of TREM2, YKL-40 and chitotriosidase using immunoassays in 183 participants from the Genetic FTD Initiative (GENFI) study: 49 C9orf72 (36 presymptomatic, 13 symptomatic), 49 GRN (37 presymptomatic, 12 symptomatic) and 23 MAPT (16 presymptomatic, 7 symptomatic) mutation carriers and 62 mutation-negative controls. Concentrations were compared between groups using a linear regression model adjusting for age and sex, with 95% bias-corrected bootstrapped confidence intervals. Concentrations in each group were correlated with the Mini-Mental State Examination (MMSE) score using non-parametric partial correlations adjusting for age. Age-adjusted z-scores were also created for the concentration of markers in each participant, investigating how many had a value above the 95th percentile of controls. RESULTS: Only chitotriosidase in symptomatic GRN mutation carriers had a concentration significantly higher than controls. No group had higher TREM2 or YKL-40 concentrations than controls after adjusting for age and sex. There was a significant negative correlation of chitotriosidase concentration with MMSE in presymptomatic GRN mutation carriers. In the symptomatic groups, for TREM2 31% of C9orf72, 25% of GRN, and 14% of MAPT mutation carriers had a concentration above the 95th percentile of controls. For YKL-40 this was 8% C9orf72, 8% GRN and 0% MAPT mutation carriers, whilst for chitotriosidase it was 23% C9orf72, 50% GRN, and 29% MAPT mutation carriers. CONCLUSIONS: Although chitotriosidase concentrations in GRN mutation carriers were the only significantly raised glia-derived biomarker as a group, a subset of mutation carriers in all three groups, particularly for chitotriosidase and TREM2, had elevated concentrations. Further work is required to understand the variability in concentrations and the extent of neuroinflammation across the genetic forms of FTD. However, the current findings suggest limited utility of these measures in forthcoming trials.
Published: 2022
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6. Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Author: Wilson, Katherine M, Katona, Eszter, Glaria, Idoia, Carcolé, Mireia, Swift, Imogen J, Sogorb-Esteve, Aitana, Heller, Carolin, Bouzigues, Arabella, Heslegrave, Amanda J, Keshavan, Ashvini, Knowles, Kathryn, Patil, Saurabh, Mohapatra, Susovan, Liu, Yuanjing, Goyal, Jaya, Sanchez-Valle, Raquel, Laforce, Robert, Synofzik, Matthis, Rowe, James B, Finger, Elizabeth, Vandenberghe, Rik, Butler, Christopher R, Gerhard, Alexander, Van Swieten, John C, Seelaar, Harro, Borroni, Barbara, Galimberti, Daniela, De Mendonça, Alexandre, Masellis, Mario, Tartaglia, M Carmela, Otto, Markus, Graff, Caroline, Ducharme, Simon, Schott, Jonathan M, Malaspina, Andrea, Zetterberg, Henrik, Boyanapalli, Ramakrishna, Rohrer, Jonathan D, Isaacs, Adrian M, Genetic FTD Initiative (GENFI), Carcolé, Mireia [0000-0001-5054-9016], Heller, Carolin [0000-0002-1934-6162], Synofzik, Matthis [0000-0002-2280-7273], Rowe, James B [0000-0001-7216-8679], Finger, Elizabeth [0000-0003-4461-7427], Gerhard, Alexander [0000-0002-8071-6062], Van Swieten, John C [0000-0001-6278-6844], Seelaar, Harro [0000-0003-1989-7527], Borroni, Barbara [0000-0001-9340-9814], Galimberti, Daniela [0000-0002-9284-5953], Ducharme, Simon [0000-0002-7309-1113], Schott, Jonathan M [0000-0003-2059-024X], Zetterberg, Henrik [0000-0003-3930-4354], Rohrer, Jonathan D [0000-0002-6155-8417], Isaacs, Adrian M [0000-0002-6820-5534], and Apollo - University of Cambridge Repository
Subjects: MOTOR NEURON DISEASE, DNA Repeat Expansion, C9orf72 Protein, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Humans, Biomarkers
Abstract: Funder: Bluefield Project, Funder: Fidelity Foundation; FundRef: http://dx.doi.org/10.13039/100005639, Funder: European Reference Network for Rare Neurological Diseases, Funder: Wellcome Trust; FundRef: http://dx.doi.org/10.13039/100010269, Funder: EU Joint Programme - Neurodegenerative Disease Research, OBJECTIVE: A GGGGCC repeat expansion in the C9orf72 gene is the most common cause of genetic frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). As potential therapies targeting the repeat expansion are now entering clinical trials, sensitive biomarker assays of target engagement are urgently required. Our objective was to develop such an assay. METHODS: We used the single molecule array (Simoa) platform to develop an immunoassay for measuring poly(GP) dipeptide repeat proteins (DPRs) generated by the C9orf72 repeat expansion in cerebrospinal fluid (CSF) of people with C9orf72-associated FTD/ALS. RESULTS AND CONCLUSIONS: We show the assay to be highly sensitive and robust, passing extensive qualification criteria including low intraplate and interplate variability, a high precision and accuracy in measuring both calibrators and samples, dilutional parallelism, tolerance to sample and standard freeze-thaw and no haemoglobin interference. We used this assay to measure poly(GP) in CSF samples collected through the Genetic FTD Initiative (N=40 C9orf72 and 15 controls). We found it had 100% specificity and 100% sensitivity and a large window for detecting target engagement, as the C9orf72 CSF sample with the lowest poly(GP) signal had eightfold higher signal than controls and on average values from C9orf72 samples were 38-fold higher than controls, which all fell below the lower limit of quantification of the assay. These data indicate that a Simoa-based poly(GP) DPR assay is suitable for use in clinical trials to determine target engagement of therapeutics aimed at reducing C9orf72 repeat-containing transcripts.
Published: 2022

7. The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

Author: Premi, Enrico, Calhoun, Vince D, Galimberti, Daniela, Panman, Jessica, Papma, Janne, Patzig, Maximilian, Pievani, Michela, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rittman, Tim, Rogaeva, Ekaterina, Sanchez-Valle, Raquel, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Scarpini, Elio, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Tábuas-Pereira, Miguel, Tainta, Mikel, Laforce, Robert, Tang-Wai, David, Thomas, David L, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Vandamme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Moreno, Fermin, Warren, Jason, Wilke, Carlo, Zetterberg, Henrik, Zulaica, Miren, Synofzik, Matthis, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James, Vandenberghe, Rik, Diano, Matteo, Finger, Elizabeth, Tagliavini, Fabrizio, de Mendonça, Alexandre, Santana, Isabel, Butler, Chris, Ducharme, Simon, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Otto, Markus, Gazzina, Stefano, Frisoni, Giovanni, Cappa, Stefano, Sorbi, Sandro, Padovani, Alessandro, Rohrer, Jonathan D, Borroni, Barbara, Genetic FTD Initiative, GENFI, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Cosseddu, Maura, Antonell, Anna, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Luisa, Binetti, Giuliano, Black, Sandra, Alberici, Antonella, Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Bruffaerts, Rose, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, de Arriba, María, Archetti, Silvana, Di Fede, Giuseppe, Díaz, Zigor, Dick, Katrina M, Duro, Diana, Fenoglio, Chiara, Ferreira, Carlos, Ferreira, Catarina B, Flanagan, Toby, Fox, Nick, Freedman, Morris, Paternicò, Donata, Fumagalli, Giorgio, Gabilondo, Alazne, Gauthier, Serge, Ghidoni, Roberta, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Gasparotti, Roberto, Indakoetxea, Begoña, Jelic, Vesna, Jiskoot, Lize, Karnath, Hans-Otto, Keren, Ron, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, van Swieten, John, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Nacmias, Benedetta, Neason, Mollie, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Neurology, National Institutes of Health (US), National Science Foundation (US), Wellcome Trust, and Repositório da Universidade de Lisboa
Subjects: Male, Time Factors, MOTION, Gene mutation, physiopathology [Frontotemporal Dementia], methods [Connectome], 0302 clinical medicine, C9orf72, physiopathology [Nerve Net], BEHAVIORAL VARIANT, Medicine, genetics [Frontotemporal Dementia], 11 Medical and Health Sciences, dult Connectome/*methods Female Frontotemporal Dementia/diagnostic imaging/genetics/*physiopathology Heterozygote Humans Magnetic Resonance Imaging Male Middle Aged Nerve Net/diagnostic imaging/*physiopathology *Prodromal Symptoms Time Factors C9orf72 Chronnectome Dynamic brain functional connectivity Frontotemporal dementia Granulin Microtuble associate protein tau Mutation resting-state fMRI, medicine.diagnostic_test, Radiology, Nuclear Medicine & Medical Imaging, 05 social sciences, Genetic FTD Initiative, GENFI, Middle Aged, Magnetic Resonance Imaging, Demência Frontotemporal, 17 Psychology and Cognitive Sciences, DYNAMIC FUNCTIONAL CONNECTIVITY, Chronnectome, Dynamic brain functional connectivity, Frontotemporal dementia, Granulin, Microtuble associate protein tau, Mutation, resting-state fMRI, Adult, Connectome, Female, Frontotemporal Dementia, Heterozygote, Humans, Nerve Net, Prodromal Symptoms, Neurology, SENSITIVITY, Life Sciences & Biomedicine, Cognitive Neuroscience, Neuroimaging, FREQUENCY, diagnostic imaging [Frontotemporal Dementia], Article, 050105 experimental psychology, 03 medical and health sciences, mental disorders, 0501 psychology and cognitive sciences, LOBAR DEGENERATION, ddc:610, Dynamic functional connectivity, RESTING-STATE NETWORKS, Neurology & Neurosurgery, Science & Technology, Resting state fMRI, SUBJECT, diagnostic imaging [Nerve Net], business.industry, Neurosciences, medicine.disease, FMRI DATA, PATTERNS, Neurosciences & Neurology, business, Functional magnetic resonance imaging, Neuroscience, 030217 neurology & neurosurgery
Abstract: © 2019 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Frontotemporal Dementia (FTD) is preceded by a long period of subtle brain changes, occurring in the absence of overt cognitive symptoms, that need to be still fully characterized. Dynamic network analysis based on resting-state magnetic resonance imaging (rs-fMRI) is a potentially powerful tool for the study of preclinical FTD. In the present study, we employed a "chronnectome" approach (recurring, time-varying patterns of connectivity) to evaluate measures of dynamic connectivity in 472 at-risk FTD subjects from the Genetic Frontotemporal dementia research Initiative (GENFI) cohort. We considered 249 subjects with FTD-related pathogenetic mutations and 223 mutation non-carriers (HC). Dynamic connectivity was evaluated using independent component analysis and sliding-time window correlation to rs-fMRI data, and meta-state measures of global brain flexibility were extracted. Results show that presymptomatic FTD exhibits diminished dynamic fluidity, visiting less meta-states, shifting less often across them, and travelling through a narrowed meta-state distance, as compared to HC. Dynamic connectivity changes characterize preclinical FTD, arguing for the desynchronization of the inner fluctuations of the brain. These changes antedate clinical symptoms, and might represent an early signature of FTD to be used as a biomarker in clinical trials., This work was supported in part by grants from the NIH (R01REB020407, P20GM103472), NSF grant 1539067 and the Well- come Trust grant (JBR 103838).
Published: 2019
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8. The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort

Author: Franklin, Hannah D, Russell, Lucy L, Jiskoot, Lize, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Moreno, Fermin, Padovani, Alessandro, Panman, Jessica, Papma, Janne M, Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Sanchez-Valle, Raquel, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Borroni, Barbara, Scarpini, Elio, Schönecker, Sonja, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Laforce, Robert, Tang-Wai, David, Thomas, David L, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Masellis, Mario, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Tartaglia, Maria Carmela, Graff, Caroline, Galimberti, Daniela, Rowe, James B, Peakman, Georgia, Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alex, Levin, Johannes, Greaves, Caroline V, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Rohrer, Jonathan D, Genetic FTD Initiative, GENFI, Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Bocchetta, Martina, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Nicholas, Jennifer, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Poos, Jackie, Cantoni, Valentina, Caroppo, Paola, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Convery, Rhian S, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Cash, David M, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans Otto, van Swieten, John, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Rohrer, Jonathan D. [0000-0002-6155-8417], Apollo - University of Cambridge Repository, Bocchetta, Martina [0000-0003-1814-5024], Rowe, James B [0000-0001-7216-8679], Rohrer, Jonathan D [0000-0002-6155-8417], Neurology, Clinical Psychology, Clinical Genetics, and Repositório da Universidade de Lisboa
Subjects: Social Cognition, Neurology, Medizin, RSMS, PROGRESSION, Audiology, genetics [Progranulins], 0302 clinical medicine, Progranulins, Familial, C9orf72, MAPT, Medicine, CDR® plus NACC FTLD, VBM, genetics [Frontotemporal Dementia], 11 Medical and Health Sciences, Socioemotional selectivity theory, 05 social sciences, Prodromal Stage, Genetic FTD Initiative, GENFI, Frontotemporal dementia, GRN, C9orf72 Protein, Humans, Magnetic Resonance Imaging, Mutation, tau Proteins, Frontotemporal Dementia, ORBITOFRONTAL CORTEX, Life Sciences & Biomedicine, RC321-571, medicine.medical_specialty, Cognitive Neuroscience, Clinical Neurology, Neurosciences. Biological psychiatry. Neuropsychiatry, genetics [Mutation], diagnostic imaging [Frontotemporal Dementia], 050105 experimental psychology, Temporal lobe, 03 medical and health sciences, mental disorders, 0501 psychology and cognitive sciences, ddc:610, RC346-429, genetics [C9orf72 Protein], Science & Technology, CDR (R) plus NACC FTLD, business.industry, Research, Neurosciences, medicine.disease, DYSFUNCTION, genetics [tau Proteins], Orbitofrontal cortex, Neurology. Diseases of the nervous system, Neurosciences & Neurology, Neurology (clinical), business, Insula, 030217 neurology & neurosurgery
Abstract: © The Author(s). 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data., Background: Although social cognitive dysfunction is a major feature of frontotemporal dementia (FTD), it has been poorly studied in familial forms. A key goal of studies is to detect early cognitive impairment using validated measures in large patient cohorts. Methods: We used the Revised Self-Monitoring Scale (RSMS) as a measure of socioemotional sensitivity in 730 participants from the genetic FTD initiative (GENFI) observational study: 269 mutation-negative healthy controls, 193 C9orf72 expansion carriers, 193 GRN mutation carriers and 75 MAPT mutation carriers. All participants underwent the standardised GENFI clinical assessment including the 'CDR® plus NACC FTLD' scale and RSMS. The RSMS total score and its two subscores, socioemotional expressiveness (EX score) and modification of self-presentation (SP score) were measured. Volumetric T1-weighted magnetic resonance imaging was available from 377 mutation carriers for voxel-based morphometry (VBM) analysis. Results: The RSMS was decreased in symptomatic mutation carriers in all genetic groups but at a prodromal stage only in the C9orf72 (for the total score and both subscores) and GRN (for the modification of self-presentation subscore) groups. RSMS score correlated with disease severity in all groups. The VBM analysis implicated an overlapping network of regions including the orbitofrontal cortex, insula, temporal pole, medial temporal lobe and striatum. Conclusions: The RSMS indexes socioemotional impairment at an early stage of genetic FTD and may be a suitable outcome measure in forthcoming trials., The Dementia Research Centre is supported by Alzheimer’s Research UK, Brain Research Trust and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility as well as an Alzheimer’s Society grant [AS-PG-16-007]. This work was also supported by the MRC UK GENFI grant [MR/M023664/1], the Italian Ministry of Health (CoEN015 and Ricerca Corrente) and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant, The Bluefield Project and the JPND GENFI-PROX grant [2019-02248]. 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], the Bluefield Project and the Association for Frontotemporal Degeneration. MB is supported by a Fellowship award from the Alzheimer’s Society, UK [AS-JF-19a-004-517]. JBR is supported by the Wellcome Trust [103838], the Medical Research Council and NIHR Cambridge Biomedical Research Centre. This work was also funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198]. Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510.
Published: 2021
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9. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

Author: Russell, Lucy L, Greaves, Caroline V, Bocchetta, Martina, Nicholas, Jennifer, Convery, Rhian S, Moore, Katrina, Cash, David M, van Swieten, John, Jiskoot, Lize, Moreno, Fermin, Sanchez-Valle, Raquel, Borroni, Barbara, Laforce, Robert, Masellis, Mario, Tartaglia, Maria Carmela, Graff, Caroline, Rotondo, Emanuela, Galimberti, Daniela, Rowe, James B, Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alex, Levin, Johannes, Danek, Adrian, Otto, Markus, Warren, Jason D, Rohrer, Jonathan D, Genetic FTD Initiative, GENFI, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: Social Cognition, Progranulin, C9orf72 Protein, Emotion processing, Magnetic Resonance Imaging, Progranulins, Theory of mind, Frontotemporal Dementia, C9orf72, Mutation, mental disorders, MAPT, Humans, Facial emotion recognition, Faux pas
Abstract: A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.
Published: 2020

10. Education modulates brain maintenance in presymptomatic frontotemporal dementia

Author: Gazzina, Stefano, Grassi, Mario, Laforce, Robert Jr, Pijnenburg, Yolande, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rittman, Tim, Rogaeva, Ekaterina, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Moreno, Fermin, Santiago, Beatriz, Scarpini, Elio, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Tábuas-Pereira, Miguel, Tainta, Mikel, Tang-Wai, David, Thomas, David L, Thonberg, Hakan, Synofzik, Matthis, Timberlake, Carolyn, Tiraboschi, Pietro, Vandamme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Wilke, Carlo, Zetterberg, Henrik, Zulaica, Miren, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Vandenberghe, Rik, Finger, Elizabeth, Tagliavini, Fabrizio, Premi, Enrico, de Mendonça, Alexandre, Santana, Isabel, Butler, Christopher R, Ducharme, Simon, Gerhard, Alex, Danek, Adrian, Levin, Johannes, Otto, Markus, Frisoni, Giovanni, Sorbi, Sandro, Cosseddu, Maura, Padovani, Alessandro, Rohrer, Jonathan D, Borroni, Barbara, Genetic FTD Initiative, GENFI, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Arighi, Andrea, Balasa, Mircea, Alberici, Antonella, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Luisa, Binetti, Giuliano, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Archetti, Silvana, Bruffaerts, Rose, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Convery, Rhian, Cope, Thomas, Arriba, María de, Di Fede, Giuseppe, Díaz, Zigor, Dick, Katrina M, Gasparotti, Roberto, Duro, Diana, Ferreira, Carlos, Ferreira, Catarina B, Flanagan, Toby, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gabilondo, Alazne, Gauthier, Serge, Ghidoni, Roberta, Van Swieten, John, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Jiskoot, Lize, Karnath, Hans-Otto, Galimberti, Daniela, Keren, Ron, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, Minkelen, Rick van, Sanchez-Valle, Raquel, Mitchell, Sara, Nacmias, Benedetta, Neason, Mollie, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Panman, Jessica, Papma, Janne, Patzig, Maximilian, Pievani, Michela, and Neurology
Subjects: Male, Longitudinal study, Audiology, genetics [Progranulins], Progranulins, 0302 clinical medicine, pathology [Brain], pathology [Gray Matter], pathology [White Matter], Gray Matter, genetics [Frontotemporal Dementia], Cerebrospinal Fluid, Cognitive reserve, Principal Component Analysis, 0303 health sciences, Brain, Cognition, Organ Size, Middle Aged, Mental Status and Dementia Tests, White Matter, psychology [Frontotemporal Dementia], diagnostic imaging [Cerebrospinal Fluid], Psychiatry and Mental health, medicine.anatomical_structure, Frontotemporal Dementia, Educational Status, Female, Frontotemporal dementia, Adult, medicine.medical_specialty, tau Proteins, Grey matter, diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [White Matter], 03 medical and health sciences, medicine, Humans, Dementia, Genetic Predisposition to Disease, ddc:610, diagnostic imaging [Brain], genetics [C9orf72 Protein], Pathological, 030304 developmental biology, Adult Frontotemporal dementia magnetic resonance imaging graph theory, Environmental enrichment, C9orf72 Protein, business.industry, diagnostic imaging [Gray Matter], medicine.disease, genetics [tau Proteins], Asymptomatic Diseases, Surgery, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: ObjectiveCognitively engaging lifestyles have been associated with reduced risk of conversion to dementia. Multiple mechanisms have been advocated, including increased brain volumes (ie, brain reserve) and reduced disease progression (ie, brain maintenance). In cross-sectional studies of presymptomatic frontotemporal dementia (FTD), higher education has been related to increased grey matter volume. Here, we examine the effect of education on grey matter loss over time.MethodsTwo-hundred twenty-nine subjects at-risk of carrying a pathogenic mutation leading to FTD underwent longitudinal cognitive assessment and T1-weighted MRI at baseline and at 1 year follow-up. The first principal component score of the graph-Laplacian Principal Component Analysis on 112 grey matter region-of-interest volumes was used to summarise the grey matter volume (GMV). The effects of education on cognitive performances and GMV at baseline and on the change between 1 year follow-up and baseline (slope) were tested by Structural Equation Modelling.ResultsHighly educated at-risk subjects had better cognition and higher grey matter volume at baseline; moreover, higher educational attainment was associated with slower loss of grey matter over time in mutation carriers.ConclusionsThis longitudinal study demonstrates that even in presence of ongoing pathological processes, education may facilitate both brain reserve and brain maintenance in the presymptomatic phase of genetic FTD.
Published: 2019
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11. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

Author: Barbara Borroni, Neil P. Oxtoby, Maria Carmela Tartaglia, Sandro Sorbi, Martina Bocchetta, Jonathan M. Schott, Razvan V. Marinescu, Mario Masellis, Alexandre de Mendonça, Alexandra L. Young, Robert Laforce, Caroline Graff, Katrina M. Dick, Alzheimer’s Disease Neuroimaging Initiative, John C. van Swieten, Giovanni B. Frisoni, Sebastian J. Crutch, David M. Cash, Daniel C. Alexander, Jorge Cardoso, Jason D. Warren, Keir Yong, Daniela Galimberti, Fabrizio Tagliavini, Nick C. Fox, David L. Thomas, Jonathan D. Rohrer, Nicholas C. Firth, Sebastien Ourselin, Genetic Ftd Initiative Genfi, Elizabeth Finger, James B. Rowe, Young, Alexandra L [0000-0002-7772-781X], Marinescu, Razvan V [0000-0003-4042-8493], Oxtoby, Neil P [0000-0003-0203-3909], Cash, David M [0000-0001-7833-616X], Thomas, David L [0000-0003-1491-1641], Cardoso, Jorge [0000-0003-1284-2558], Laforce, Robert [0000-0002-2031-490X], Schott, Jonathan M [0000-0003-2059-024X], Alexander, Daniel C [0000-0003-2439-350X], Apollo - University of Cambridge Repository, and Neurology
Subjects: Alzheimer Disease, Frontotemporal Dementia, Genotype, Humans, Models, Neurological, Neurodegenerative Diseases, Phenotype, Reproducibility of Results, Time Factors, Science, Neurodegenerative Diseases/classification/pathology, Inference, Disease, Computational biology, Biology, Frontotemporal Dementia/genetics/pathology, Article, 03 medical and health sciences, 0302 clinical medicine, Models, MD Multidisciplinary, medicine, Stage (cooking), lcsh:Science, 030304 developmental biology, 0303 health sciences, Neurodegeneration, Genetic FTD Initiative, Temporal complexity, Alzheimer Disease/genetics/pathology, Alzheimer’s Disease Neuroimaging Initiative, medicine.disease, Precision medicine, 3. Good health, ddc:618.97, Neurological, lcsh:Q, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique—Subtype and Stage Inference (SuStaIn)—able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer’s disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10−4) or temporal stage (p = 3.96 × 10−5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine., Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.
Published: 2018
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12. Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: results from the GENFI study

Author: Galimberti, Daniela, Fumagalli, Giorgio G, Fenoglio, Chiara, Cioffi, Sara MG, Arighi, Andrea, Serpente, Maria, Borroni, Barbara, Padovani, Alessandro, Tagliavini, Fabrizio, Masellis, Mario, Tartaglia, Maria Carmela, Van Swieten, John, Meeter, Lieke, Graff, Caroline, De Mendonça, Alexandre, Bocchetta, Martina, Rohrer, Jonathan D, Scarpini, Elio, Genetic FTD Initiative (GENFI), Galimberti, Daniela [0000-0002-9284-5953], Fumagalli, Giorgio G [0000-0003-0687-7199], Tagliavini, Fabrizio [0000-0003-1039-7315], Graff, Caroline [0000-0002-9949-2951], de Mendonça, Alexandre [0000-0002-0488-1453], Bocchetta, Martina [0000-0003-1814-5024], Rohrer, Jonathan D [0000-0002-6155-8417], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, Brain atrophy, Heterozygote, Nerve Tissue Proteins, Frontotemporal dementia (FTD), Sensitivity and Specificity, Cohort Studies, Young Adult, Plasma levels, Progranulins, mental disorders, Humans, Multicenter Studies as Topic, Genetic Testing, Gray Matter, Genetic Association Studies, Aged, Aged, 80 and over, Progranulin (GRN), Membrane Proteins, Biomarker, Middle Aged, Proximity marker, Frontotemporal Dementia, Mutation, Intercellular Signaling Peptides and Proteins, Female, Atrophy
Abstract: We investigated whether progranulin plasma levels are predictors of the presence of progranulin gene (GRN) null mutations or of the development of symptoms in asymptomatic at risk members participating in the Genetic Frontotemporal Dementia Initiative, including 19 patients, 64 asymptomatic carriers, and 77 noncarriers. In addition, we evaluated a possible role of TMEM106B rs1990622 as a genetic modifier and correlated progranulin plasma levels and gray-matter atrophy. Plasma progranulin mean ± SD plasma levels in patients and asymptomatic carriers were significantly decreased compared with noncarriers (30.5 ± 13.0 and 27.7 ± 7.5 versus 99.6 ± 24.8 ng/mL, p < 0.00001). Considering the threshold of >61.55 ng/mL, the test had a sensitivity of 98.8% and a specificity of 97.5% in predicting the presence of a mutation, independent of symptoms. No correlations were found between progranulin plasma levels and age, years from average age at onset in each family, or TMEM106B rs1990622 genotype (p > 0.05). Plasma progranulin levels did not correlate with brain atrophy. Plasma progranulin levels predict the presence of GRN null mutations independent of proximity to symptoms and brain atrophy.
Published: 2018
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13. Patterns of gray matter atrophy in genetic frontotemporal dementia: results from the GENFI study

Author: Cash, David M, Bocchetta, Martina, Thomas, David L, Dick, Katrina M, Van Swieten, John C, Borroni, Barbara, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James, Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni B, Laforce, Robert, Finger, Elizabeth, De Mendonça, Alexandre, Sorbi, Sandro, Rossor, Martin N, Ourselin, Sebastien, Rohrer, Jonathan D, Genetic FTD Initiative, GENFI, Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Cash, David M [0000-0001-7833-616X], Bocchetta, Martina [0000-0003-1814-5024], Thomas, David L [0000-0003-1491-1641], Galimberti, Daniela [0000-0002-9284-5953], Graff, Caroline [0000-0002-9949-2951], Tagliavini, Fabrizio [0000-0003-1039-7315], Frisoni, Giovanni B [0000-0002-6419-1753], Laforce, Robert [0000-0002-2031-490X], de Mendonça, Alexandre [0000-0002-0488-1453], Sorbi, Sandro [0000-0002-0380-6670], and Rohrer, Jonathan D [0000-0002-6155-8417]
Subjects: Adult, Male, Heterozygote, C9orf72 Protein, Genetic FTD Initiative, GENFI, tau Proteins, Organ Size, Voxel-based morphometry, Middle Aged, Magnetic Resonance Imaging, Cohort Studies, Progranulins, Frontotemporal Dementia, mental disorders, Mutation, Preclinical dementia, Humans, Intercellular Signaling Peptides and Proteins, Female, Atrophy, Gray Matter, Aged
Abstract: Frontotemporal dementia (FTD) is a highly heritable condition with multiple genetic causes. In this study, similarities and differences of gray matter (GM) atrophy patterns were assessed among 3 common forms of genetic FTD (mutations in C9orf72, GRN, and MAPT). Participants from the Genetic FTD Initiative (GENFI) cohort with a suitable volumetric T1 magnetic resonance imaging scan were included (319): 144 nonmutation carriers, 128 presymptomatic mutation carriers, and 47 clinically affected mutation carriers. Cross-sectional differences in GM volume between noncarriers and carriers were analyzed using voxel-based morphometry. In the affected carriers, each genetic mutation group exhibited unique areas of atrophy but also a shared network involving the insula, orbitofrontal lobe, and anterior cingulate. Presymptomatic GM atrophy was observed particularly in the thalamus and cerebellum in the C9orf72 group, the anterior and medial temporal lobes in MAPT, and the posterior frontal and parietal lobes as well as striatum in GRN. Across all presymptomatic carriers, there were significant decreases in the anterior insula. These results suggest that although there are important differences in atrophy patterns for each group (which can be seen presymptomatically), there are also similarities (a fronto-insula-anterior cingulate network) that help explain the clinical commonalities of the disease.
Published: 2018
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14. Distinct Neuroanatomical Correlates of Neuropsychiatric Symptoms in the Three Main Forms of Genetic Frontotemporal Dementia in the GENFI Cohort

Author: Sellami, Leila, Bocchetta, Martina, Masellis, Mario, Cash, David M, Dick, Katrina M, Van Swieten, John, Borroni, Barbara, Galimberti, Daniela, Tartaglia, Maria Carmela, Rowe, James B, Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni, Finger, Elizabeth, De Mendonça, Alexandre, Sorbi, Sandro, Warren, Jason D, Rohrer, Jonathan D, Laforce, Robert, Genetic FTD Initiative, GENFI, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, C9orf72 Protein, Brain, tau Proteins, Middle Aged, Magnetic Resonance Imaging, Cohort Studies, Progranulins, Psychotic Disorders, Frontotemporal Dementia, mental disorders, Mutation, Humans, genetics, neuropsychiatry, Female, Aged
Abstract: BACKGROUND: The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease-causing mutations. OBJECTIVE: We aimed to identify whether NPS could be driven by distinct structural correlates. METHODS: One hundred and sixty-seven mutation carriers (75 GRN, 60 C9orf72, and 32 MAPT) were included from the Genetic FTD Initiative (GENFI) study, a large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS. RESULTS: Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe. CONCLUSION: Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders.
Published: 2018

15. White matter hyperintensities are seen only inGRNmutation carriers in the GENFI cohort

Author: Sudre, Carole H, Bocchetta, Martina, Cash, David, Thomas, David L, Woollacott, Ione, Dick, Katrina M, van Swieten, John, Borroni, Barbara, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni, Laforce, Robert, Finger, Elizabeth, de Mendonça, Alexandre, Sorbi, Sandro, Ourselin, Sébastien, Cardoso, M Jorge, Rohrer, Jonathan D, Genetic FTD Initiative, GENFI, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: Adult, Male, TIV, Total Intracranial volume, C9orf72 Protein, CI, Confidence interval, IQR, Inter Quartile Range, tau Proteins, Middle Aged, behavioral disciplines and activities, Magnetic Resonance Imaging, White Matter, Cohort Studies, FTD, Frontotemporal dementia, PS, Presymptomatic, Frontotemporal Dementia, mental disorders, Humans, Intercellular Signaling Peptides and Proteins, Female, S, Symptomatic, WMH, White matter hyperintensity, Aged
Abstract: Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin(GRN), microtubule-associated protein tau (MAPT)and chromosome 9 open reading frame 72(C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7GRN, 13MAPTand 23C9orf72), 61 presymptomatic mutation carriers (25GRN, 8MAPTand 28C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomaticGRNgroup compared with the other groups with no differences in theMAPTorC9orf72groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in theGRNcohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in theGRNgroup compared with the other groups, with the lesions in theGRNgroup being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.
Published: 2017
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16. Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study

Author: Premi, Enrico, Grassi, Mario, Van Swieten, John, Galimberti, Daniela, Graff, Caroline, Masellis, Mario, Tartaglia, Carmela, Tagliavini, Fabrizio, Rowe, James B, Laforce, Robert, Finger, Elizabeth, Frisoni, Giovanni B, De Mendonça, Alexandre, Sorbi, Sandro, Gazzina, Stefano, Cosseddu, Maura, Archetti, Silvana, Gasparotti, Roberto, Manes, Marta, Alberici, Antonella, Cardoso, Manuel J, Bocchetta, Martina, Cash, David M, Ourselin, Sebastian, Padovani, Alessandro, Rohrer, Jonathan D, Borroni, Barbara, and Genetic FTD Initiative (GENFI)
Subjects: Adult, Male, Polymorphism, Genetic, Genotype, Membrane Proteins, Prodromal Symptoms, Nerve Tissue Proteins, Middle Aged, cognitive reserve, frontotemporal dementia, Magnetic Resonance Imaging, Cohort Studies, TMEM106b, Educational Status, Humans, genetics, Female, Atrophy, Gray Matter, 10. No inequality, structural MRI
Abstract: Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.

17. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

Author: Young, Alexandra L, Marinescu, Razvan V, Oxtoby, Neil P, Bocchetta, Martina, Yong, Keir, Firth, Nicholas C, Cash, David M, Thomas, David L, Dick, Katrina M, Cardoso, Jorge, Van Swieten, John, Borroni, Barbara, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B, Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni B, Laforce, Robert, Finger, Elizabeth, De Mendonça, Alexandre, Sorbi, Sandro, Warren, Jason D, Crutch, Sebastian, Fox, Nick C, Ourselin, Sebastien, Schott, Jonathan M, Rohrer, Jonathan D, Alexander, Daniel C, Genetic FTD Initiative (GENFI), and Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Subjects: Phenotype, Time Factors, Genotype, Alzheimer Disease, Frontotemporal Dementia, Models, Neurological, Humans, Reproducibility of Results, Neurodegenerative Diseases, 3. Good health
Abstract: The heterogeneity of neurodegenerative diseases is a key confound to disease understanding and treatment development, as study cohorts typically include multiple phenotypes on distinct disease trajectories. Here we introduce a machine-learning technique-Subtype and Stage Inference (SuStaIn)-able to uncover data-driven disease phenotypes with distinct temporal progression patterns, from widely available cross-sectional patient studies. Results from imaging studies in two neurodegenerative diseases reveal subgroups and their distinct trajectories of regional neurodegeneration. In genetic frontotemporal dementia, SuStaIn identifies genotypes from imaging alone, validating its ability to identify subtypes; further the technique reveals within-genotype heterogeneity. In Alzheimer's disease, SuStaIn uncovers three subtypes, uniquely characterising their temporal complexity. SuStaIn provides fine-grained patient stratification, which substantially enhances the ability to predict conversion between diagnostic categories over standard models that ignore subtype (p = 7.18 × 10-4) or temporal stage (p = 3.96 × 10-5). SuStaIn offers new promise for enabling disease subtype discovery and precision medicine.

18. Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

Author: Tsvetanov, Kamen A, Gazzina, Stefano, Jones, P Simon, Van Swieten, John, Borroni, Barbara, Sanchez-Valle, Raquel, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Synofzik, Matthis, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Finger, Elizabeth, Vandenberghe, Rik, De Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alexander, Danek, Adrian, Levin, Johannes, Otto, Markus, Frisoni, Giovanni, Ghidoni, Roberta, Sorbi, Sandro, Rohrer, Jonathan D, Rowe, James B, and Genetic FTD Initiative, GENFI
Subjects: Internationality, C9orf72 Protein, frontotemporal dementia (FTD), functional magnetic resonance imaging (fMRI), Brain, Prodromal Symptoms, network connectivity, tau Proteins, Middle Aged, Magnetic Resonance Imaging, 3. Good health, presymptomatic, Cognition, Frontotemporal Dementia, Mutation, Humans, Atrophy
Abstract: INTRODUCTION: The presymptomatic phase of neurodegenerative disease can last many years, with sustained cognitive function despite progressive atrophy. We investigate this phenomenon in familial frontotemporal dementia (FTD). METHODS: We studied 121 presymptomatic FTD mutation carriers and 134 family members without mutations, using multivariate data-driven approach to link cognitive performance with both structural and functional magnetic resonance imaging. Atrophy and brain network connectivity were compared between groups, in relation to the time from expected symptom onset. RESULTS: There were group differences in brain structure and function, in the absence of differences in cognitive performance. Specifically, we identified behaviorally relevant structural and functional network differences. Structure-function relationships were similar in both groups, but coupling between functional connectivity and cognition was stronger for carriers than for non-carriers, and increased with proximity to the expected onset of disease. DISCUSSION: Our findings suggest that the maintenance of functional network connectivity enables carriers to maintain cognitive performance.

19. Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers

Author: Finger, Elizabeth, Malik, Rubina, Bocchetta, Martina, Coleman, Kristy, Graff, Caroline, Borroni, Barbara, Masellis, Mario, Laforce, Robert, Greaves, Caroline V., Russell, Lucy L., Convery, Rhian S., Bouzigues, Arabella, Cash, David M., Otto, Markus, Synofzik, Matthis, Rowe, James B., Galimberti, Daniela, Tiraboschi, Pietro, Bartha, Robert, Shoesmith, Christen, Tartaglia, Maria Carmela, van Swieten, John C., Seelaar, Harro, Jiskoot, Lize C., Sorbi, Sandro, Butler, Chris R., Gerhard, Alexander, Sanchez-Valle, Raquel, De Mendonça, Alexandre, Moreno, Fermin, Vandenberghe, Rik, Le Ber, Isabelle, Levin, Johannes, Pasquier, Florence, Santana, Isabel, Rohrer, Jonathan D., Ducharme, Simon, Esteve, Aitana Sogorb, Heller, Carolin, Thomas, David L., Todd, Emily G., Nicholas, Jennifer, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J., Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger-Miltenyi, Gabriel, Simões Do Couto, Frederico, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Genetic FTD Initiative, GENFI, the Genetic FTD Initiative (GENFI), Repositório da Universidade de Lisboa, Bocchetta, Martina [0000-0003-1814-5024], Graff, Caroline [0000-0002-9949-2951], Borroni, Barbara [0000-0001-9340-9814], Cash, David M [0000-0001-7833-616X], Synofzik, Matthis [0000-0002-2280-7273], Seelaar, Harro [0000-0003-1989-7527], Jiskoot, Lize C [0000-0002-8120-7366], Gerhard, Alexander [0000-0002-8071-6062], Sanchez-Valle, Raquel [0000-0001-7750-896X], Vandenberghe, Rik [0000-0001-6237-2502], Pasquier, Florence [0000-0001-9880-9788], Ducharme, Simon [0000-0002-7309-1113], Apollo - University of Cambridge Repository, Neurology, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Esteve, Aitana Sogorb, Heller, Carolin, Thomas, David L, Todd, Emily G, Nicholas, Jennifer, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, and Borrego-Ecija, Sergi
Subjects: Adult, C9orf72 Protein, neurodevelopment, Nocturnal pulsed oximetry, Medizin, Brain, Neurodegenerative Diseases, tau Proteins, Amyotrophic lateral sclerosis, frontotemporal dementia, Phrenic nerve, Young Adult, Progranulins, Pick Disease of the Brain, Respiratory tests, Mutation, C9orf72, MAPT, Humans, ddc:610, Neurology (clinical), Human medicine, GRN, Respiratory function
Abstract: © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved., While frontotemporal dementia has been considered a neurodegenerative disease that starts in mid-life or later, it is now clearly established that cortical and subcortical volume loss is observed more than a decade prior to symptom onset and progresses with ageing. To test the hypothesis that genetic mutations causing frontotemporal dementia have neurodevelopmental consequences, we examined the youngest adults in the GENFI cohort of pre-symptomatic frontotemporal dementia mutation carriers who are between 19 and 30 years of age. Structural brain differences and improved performance on some cognitive tests were found for MAPT and GRN mutation carriers relative to familial non-carriers, while smaller volumes were observed in C9orf72 repeat expansion carriers at a mean age of 26 years. The detection of such early differences supports potential advantageous neurodevelopmental consequences of some frontotemporal dementia-causing genetic mutations. These results have implications for the design of therapeutic interventions for frontotemporal dementia. Future studies at younger ages are needed to identify specific early pathophysiologic or compensatory processes that occur during the neurodevelopmental period., This project was supported by Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, and by Canadian Institutes of Health Research operating grants (327387; 452843; 70797). The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the National Institute for Health Research (NIHR) Queen Square Dementia Biomedical Research Unit and the University College London Hospitals Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC), and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), the Alzheimer’s Society grant (AS-PG-16-007), the Bluefield Project and the EU Joint Programme – Neurodegenerative Disease Research (GENFI-PROX grant 2019-02248). M.B. is supported by a Fellowship award from the Alzheimer’s Society, UK (AS-JF-19a- 004-517). M.B.’s work was also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). J.B.R. is funded by the Wellcome Trust (103838) and the National Institute for Health Research Cambridge Biomedical Research Centre. This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). It is also funded by the Ministry of Health, Italy (S.S.). R.V.’s work is supported by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie. R.S.-V.’s work is supported by Instituto de Salud Carlos III (grant number 20/00448), cofunded by the EU. ANR-PRTS PrevdemALS study funding (I.L.B.). Several authors of this publication (J.C.vS., M.S., A.D., M.O., R.V., I.L.B., J.D.R.) are members of the European Reference Network for Rare Neurological Diseases (ERN-RND) - Project ID No 739510.
Published: 2023
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20. Loss of brainstem white matter predicts onset and motor neuron symptoms in C9orf72 expansion carriers: a GENFI study

Author: Pérez-Millan, Agnès, Borrego-Écija, Sergi, van Swieten, John C., Jiskoot, Lize, Moreno, Fermin, Laforce, Robert, Graff, Caroline, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, de Mendonça, Alexandre, Butler, Chris R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Tiraboschi, Pietro, Seelaar, Harro, Langheinrich, Tobias, Rohrer, Jonathan D., Sala-Llonch, Roser, Sánchez-Valle, Raquel, GENFI The Genetic FTD Initiative, Ullgren, Abbe, Rollin, Adeline, Camuzat, Agnès, Esteve, Aitana Sogorb, Gabilondo, Alazne, Lladó, Albert, Benussi, Alberto, Brice, Alexis, Gorostidi, Ana, Verdelho, Ana, Arighi, Andrea, Antonell, Anna, Bertrand, Anne, Engel, Annerose, Vogels, Annick, Bouzigues, Arabella, Funkiewiez, Aurélie, Nacmias, Benedetta, Bender, Benjamin, Ferrari, Camilla, Wilke, Carlo, Heller, Carolin, Maruta, Carolina, Greaves, Caroline V., Timberlake, Carolyn, Ferreira, Catarina B., Prix, Catharina, Fenoglio, Chiara, Shoesmith, Christen, Polito, Cristina, Rinaldi, Daisy, Saracino, Dario, Cash, David, Thomas, David L., Tang-Wai, David, Duro, Diana, Rogaeva, Ekaterina, Scarpini, Elio, Wlasich, Elisabeth, Buratti, Emanuele, Todd, Emily, Premi, Enrico, do Couto, Frederico Simões, Miltenberger, Gabriel, Lombardi, Gemma, Rossi, Giacomina, Fumagalli, Giorgio, Giaccone, Giorgio, Di Fede, Giuseppe, Kuchcinski, Gregory, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J., Poos, Jackie, M. Papma, Janne, Nicholas, Jennifer, Durães, João, Lombardi, Jolina, Juncà-Parella, Jordi, Sarto, Jordi, Villanua, Jorge, Samra, Kiran, Poesen, Koen, Öijerstedt, Linn, Graf, Lisa, Giannini, Lucia, Russell, Lucy L., Leitão, Maria João, Almeida, Maria Rosario, Serpente, Maria, Lima, Marisa, Cañada, Marta, Bocchetta, Martina, Polyakova, Maryna, Vandenbulcke, Mathieu, Bertoux, Maxime, Veldsman, Michele, Castelo-Branco, Miguel, Tábuas-Pereira, Miguel, Tainta, Mikel, Balasa, Mircea, Zulaica, Miren, Freedman, Morris, Barandiaran, Myriam, Bargalló, Nuria, Wagemann, Olivia, Colliot, Olivier, Caroppo, Paola, Alves, Patricia, Thompson, Paul, Rosa-Neto, Pedro, Van Damme, Philip, Shafei, Rachelle, Convery, Rhian S., van Minkelen, Rick, Bartha, Robart, Gasparotti, Roberto, Keren, Ron, Rademakers, Rosa, Bruffaerts, Rose, Sayah, Sabrina, Black, Sandra, Loosli, Sandra, Mitchell, Sara, Prioni, Sara, Anderl-Straub, Sarah, Gauthier, Serge, Afonso, Sónia, Schönecker, Sonja, Gazzina, Stefano, Lebouvier, Thibaud, Cope, Thomas, Rittman, Timothy, Hoegen, Tobias, Bessi, Valentina, Cantoni, Valentina, Redaelli, Veronica, Jelic, Vesna, Deramecourt, Vincent, Borracci, Vittoria, The Genetic FTD Initiative, GENFI, Almeida, Maria Rosario, Serpente, Maria, Lima, Marisa, Cañada, Marta, Bocchetta, Martina, Polyakova, Maryna, Vandenbulcke, Mathieu, Bertoux, Maxime, Veldsman, Michele, Castelo-Branco, Miguel, Tábuas-Pereira, Miguel, Tainta, Mikel, Balasa, Mircea, Zulaica, Miren, Freedman, Morris, Barandiaran, Myriam, Bargalló, Nuria, Wagemann, Olivia, Colliot, Olivier, Caroppo, Paola, Alves, Patricia, Thompson, Paul, Rosa-Neto, Pedro, Van Damme, Philip, Tiraboschi, Pietro, Shafei, Rachelle, Convery, Rhian S, van Minkelen, Rick, Bartha, Robart, Gasparotti, Roberto, Keren, Ron, Rademakers, Rosa, Bruffaerts, Rose, Sayah, Sabrina, Black, Sandra, Loosli, Sandra, Mitchell, Sara, Prioni, Sara, Anderl-Straub, Sarah, Gauthier, Serge, Afonso, Sónia, Schönecker, Sonja, Gazzina, Stefano, Lebouvier, Thibaud, Cope, Thomas, Rittman, Timothy, Hoegen, Tobias, Bessi, Valentina, Cantoni, Valentina, Redaelli, Veronica, Jelic, Vesna, Deramecourt, Vincent, Borracci, Vittoria, Ullgren, Abbe, Rollin, Adeline, Camuzat, Agnès, Esteve, Aitana Sogorb, Gabilondo, Alazne, Lladó, Albert, Benussi, Alberto, Brice, Alexis, Gorostidi, Ana, Verdelho, Ana, Arighi, Andrea, Antonell, Anna, Bertrand, Anne, Engel, Annerose, Vogels, Annick, Bouzigues, Arabella, Funkiewiez, Aurélie, Nacmias, Benedetta, Bender, Benjamin, Ferrari, Camilla, Wilke, Carlo, Heller, Carolin, Maruta, Carolina, Greaves, Caroline V, Timberlake, Carolyn, Ferreira, Catarina B, Prix, Catharina, Fenoglio, Chiara, Shoesmith, Christen, Polito, Cristina, Rinaldi, Daisy, Saracino, Dario, Cash, David, Thomas, David L, Tang-Wai, David, Duro, Diana, Rogaeva, Ekaterina, Scarpini, Elio, Wlasich, Elisabeth, Buratti, Emanuele, Todd, Emily, Premi, Enrico, do Couto, Frederico Simões, Miltenberger, Gabriel, Lombardi, Gemma, Rossi, Giacomina, Fumagalli, Giorgio, Giaccone, Giorgio, Di Fede, Giuseppe, Kuchcinski, Gregory, Benotmane, Hanya, Zetterberg, Henrik, Swift, Imogen J, Poos, Jackie, M Papma, Janne, Nicholas, Jennifer, Durães, João, Lombardi, Jolina, Juncà-Parella, Jordi, Sarto, Jordi, Villanua, Jorge, Samra, Kiran, Poesen, Koen, Öijerstedt, Linn, Graf, Lisa, Giannini, Lucia, Russell, Lucy L, and Leitão, Maria João
Subjects: diagnostic imaging [Brain Stem], pathology [Motor Neurons], diagnostic imaging [Motor Neuron Disease], diagnostic imaging [Frontotemporal Dementia], diagnostic imaging [White Matter], pathology [Brain Stem], Neurology, pathology [White Matter], pathology [Frontotemporal Dementia], Mutation, C9orf72, Humans, genetics [Motor Neuron Disease], ddc:610, Human medicine, Neurology (clinical), genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], Brainstem, GENFI, Frontotemporal dementia
Abstract: Background and objectives The C9orf72 expansion is the most common genetic cause of frontotemporal dementia (FTD) and/or motor neuron disease (MND). Corticospinal degeneration has been described in post-mortem neuropathological studies in these patients, especially in those with MND. We used MRI to analyze white matter (WM) volumes in presymptomatic and symptomatic C9orf72 expansion carriers and investigated whether its measure may be helpful in predicting the onset of symptoms. Methods We studied 102 presymptomatic C9orf72 mutation carriers, 52 symptomatic carriers: 42 suffering from FTD and 11 from MND, and 75 non-carriers from the Genetic Frontotemporal dementia Initiative (GENFI). All subjects underwent T1-MRI acquisition. We used FreeSurfer to estimate the volume proportion of WM in the brainstem regions (midbrain, pons, and medulla oblongata). We calculated group differences with ANOVA tests and performed linear and non-linear regressions to assess group-by-age interactions. Results A reduced WM ratio was found in all brainstem subregions in symptomatic carriers compared to both noncarriers and pre-symptomatic carriers. Within symptomatic carriers, MND patients presented a lower ratio in pons and medulla oblongata compared with FTD patients. No differences were found between presymptomatic carriers and non-carriers. Clinical severity was negatively associated with the WM ratio. C9orf72 carriers presented greater age-related WM loss than non-carriers, with MND patients showing significantly more atrophy in pons and medulla oblongata. Discussion We find consistent brainstem WM loss in C9orf72 symptomatic carriers with differences related to the clinical phenotype supporting the use of brainstem measures as neuroimaging biomarkers for disease tracking.
Published: 2022
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21. Motor symptoms in genetic frontotemporal dementia: developing a new module for clinical rating scales

Author: Samra, K, MacDougall, AM, Peakman, G, Bouzigues, A, Bocchetta, M, Cash, DM, Greaves, CV, Convery, RS, van Swieten, JC, Jiskoot, L, Seelaar, H, Butler, CR, Fenoglio, C, Rohrer, JD, Gerhard, A, Ducharme, S, Le Ber, I, Tiraboschi, P, Santana, I, Pasquier, F, Levin, J, Shoesmith, C, Otto, M, Russell, LL, Nelson, A, Cash, D, Thomas, DL, Todd, E, Ferrari, C, Benotmane, H, Timberlake, C, Gabilondo, A, Cope, T, Rittman, T, Benussi, A, Premi, E, Gasparotti, R, Thompson, P, Archetti, S, Fumagalli, G, do Couto, FS, Borracci, V, Polito, C, Rossi, G, Giaccone, G, Di Fede, G, Caroppo, P, Ferreira, CB, Prioni, S, Langheinrich, T, Redaelli, V, Lladó, A, Bartha, R, Tang-Wai, D, Rogaeva, E, Castelo-Branco, M, Freedman, M, Keren, R, Black, S, Mitchell, S, Miltenberger, G, Rademakers, R, Poos, J, Papma, JM, Giannini, L, van Minkelen, R, Pijnenburg, Y, Gauthier, S, Nacmias, B, Lombardi, G, Bessi, V, Veldsman, M, Andersson, C, Thonberg, H, Öijerstedt, L, Prix, C, Jelic, V, Antonell, A, Graff, C, Olives, J, Balasa, M, Bargalló, N, Borrego-Ecija, S, Verdelho, A, Kuchcinski, G, Maruta, C, Gorostidi, A, Laforce, R, Villanua, J, Wlasich, E, Cañada, M, Tainta, M, Zulaica, M, Barandiaran, M, Moreno, F, Alves, P, Bender, B, Bertoux, M, Wilke, C, Lebouvier, T, Camuzat, A, Graf, L, Vogels, A, Vandenbulcke, M, Van Damme, P, Bruffaerts, R, Poesen, K, Rosa-Neto, P, Sanchez-Valle, R, Brice, A, Bertrand, A, Funkiewiez, A, Rinaldi, D, Saracino, D, Colliot, O, Sorbi, S, Sayah, S, Wagemann, O, Loosli, S, Schönecker, S, Hoegen, T, Lombardi, J, Anderl-Straub, S, Nicholas, J, Rollin, A, Deramecourt, V, Arighi, A, Santiago, B, Duro, D, Leitão, MJ, Almeida, MR, Tábuas-Pereira, M, Gazzina, S, Afonso, S, Masellis, M, Tartaglia, C, Shafei, R, Rowe, JB, Borroni, B, Finger, E, Synofzik, M, Galimberti, D, Vandenberghe, R, de Mendonça, A, Cantoni, V, Genetic FTD Initiative (GENFI), Samra, Kiran [0000-0002-3105-7099], Apollo - University of Cambridge Repository, Maruta, Carolina, Ferreira, Catarina B, Miltenberger, Gabriel, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Nelson, Annabel, Bocchetta, Martina, Cash, David, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Samra, Kiran, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, and Verdelho, Ana
Subjects: Progranulin, Clinical Neurology, C9ORF72, tau Proteins, AMYOTROPHIC-LATERAL-SCLEROSIS, diagnosis [Frontotemporal Dementia], C9orf72, Tremor, Genetics, Humans, ddc:610, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], MUTATION, Science & Technology, C9orf72 Protein, HERITABILITY, Amyotrophic Lateral Sclerosis, PROGRESSIVE SUPRANUCLEAR PALSY, COGNITIVE IMPAIRMENT, REPEAT EXPANSION, genetics [tau Proteins], Motor, PATHOLOGICAL FEATURES, Neurology, FOS: Biological sciences, Frontotemporal Dementia, Mutation, Human medicine, Neurosciences & Neurology, Neurology (clinical), Tau, TAU, Life Sciences & Biomedicine, Frontotemporal dementia, PARKINSONISM
Abstract: Funder: CIBERNED, Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative, Funder: Italian Ministry of Health, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Mady Browaaeys Fund, Funder: Miriam Marks Brain Research UK, Funder: Bluefield Project, 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: 2022
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22. Language impairment in the genetic forms of behavioural variant frontotemporal dementia

Author: Samra, Kiran, MacDougall, Amy M., Bouzigues, Arabella, Bocchetta, Martina, Cash, David M., Greaves, Caroline V., Convery, Rhian S., van Swieten, John C., Seelaar, Harro, Jiskoot, Lize, Moreno, Fermin, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Sanchez-Valle, Raquel, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Laforce, Robert, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Graff, Caroline, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Masellis, Mario, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Tartaglia, Maria Carmela, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Galimberti, Daniela, Vandenberghe, Rik, De Mendonça, Alexandre, Butler, Christopher R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Tiraboschi, Pietro, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Russell, Lucy L., Nelson, Annabel, Thomas, David L., Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M., Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B., Miltenberger-Miltenyi, Gabriel, Simões Do Couto, Frederico, Neurology, Amsterdam Neuroscience - Neurodegeneration, Repositório da Universidade de Lisboa, Genetic FTD Initiative (GENFI), Erasmus MC other, Radiology & Nuclear Medicine, Clinical Genetics, Samra, Kiran [0000-0002-3105-7099], Apollo - University of Cambridge Repository, do Couto, Frederico Simões, Gabilondo, Alazne, Gorostidi, Ana, Villanua, Jorge, Cañada, Marta, Tainta, Mikel, Zulaica, Miren, Barandiaran, Myriam, Alves, Patricia, Bender, Benjamin, Wilke, Carlo, Graf, Lisa, Vogels, Annick, Vandenbulcke, Mathieu, Van Damme, Philip, Bruffaerts, Rose, Poesen, Koen, Rosa-Neto, Pedro, Gauthier, Serge, Camuzat, Agnès, Brice, Alexis, Bertrand, Anne, Funkiewiez, Aurélie, Rinaldi, Daisy, Saracino, Dario, Colliot, Olivier, Sayah, Sabrina, Prix, Catharina, Wlasich, Elisabeth, Wagemann, Olivia, Loosli, Sandra, Schönecker, Sonja, Hoegen, Tobias, Lombardi, Jolina, Anderl-Straub, Sarah, Rollin, Adeline, Kuchcinski, Gregory, Bertoux, Maxime, Lebouvier, Thibaud, Deramecourt, Vincent, Santiago, Beatriz, Duro, Diana, Leitão, Maria João, Almeida, Maria Rosario, Tábuas-Pereira, Miguel, Afonso, Sónia, Nelson, Annabel, Thomas, David L, Todd, Emily, Benotmane, Hanya, Nicholas, Jennifer, Shafei, Rachelle, Timberlake, Carolyn, Cope, Thomas, Rittman, Timothy, Benussi, Alberto, Premi, Enrico, Gasparotti, Roberto, Archetti, Silvana, Gazzina, Stefano, Cantoni, Valentina, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Fumagalli, Giorgio, Borracci, Vittoria, Rossi, Giacomina, Giaccone, Giorgio, Di Fede, Giuseppe, Caroppo, Paola, Tiraboschi, Pietro, Prioni, Sara, Redaelli, Veronica, Tang-Wai, David, Rogaeva, Ekaterina, Castelo-Branco, Miguel, Freedman, Morris, Keren, Ron, Black, Sandra, Mitchell, Sara, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Poos, Jackie, Papma, Janne M, Giannini, Lucia, van Minkelen, Rick, Pijnenburg, Yolande, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Veldsman, Michele, Andersson, Christin, Thonberg, Hakan, Öijerstedt, Linn, Jelic, Vesna, Thompson, Paul, Langheinrich, Tobias, Lladó, Albert, Antonell, Anna, Olives, Jaume, Balasa, Mircea, Bargalló, Nuria, Borrego-Ecija, Sergi, Verdelho, Ana, Maruta, Carolina, Ferreira, Catarina B, and Miltenberger, Gabriel
Subjects: Progranulin, Medizin, genetics [Mutation], tau Proteins, diagnostic imaging [Frontotemporal Dementia], frontotemporal dementia, Settore BIO/13 - Biologia Applicata, C9orf72, progranulin, Genetics, Humans, genetics, Language Development Disorders, ddc:610, tau, genetics [Frontotemporal Dementia], genetics [C9orf72 Protein], Frontotemporal dementia, Language, Tau, language, C9orf72 Protein, Magnetic Resonance Imaging, genetics [tau Proteins], Neurology, FOS: Biological sciences, Frontotemporal Dementia, Mutation, Human medicine, Neurology (clinical), Atrophy
Abstract: Funder: CIBERNED, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative Schorling Foundation, Funder: Swedish Alzheimer Foundation, Funder: Karolinska Institutet; doi: http://dx.doi.org/10.13039/501100004047, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Miriam Marks Brain Research UK, BACKGROUND: Behavioural variant fronto-temporal dementia (bvFTD) is characterised by a progressive change in personality in association with atrophy of the frontal and temporal lobes. Whilst language impairment has been described in people with bvFTD, little is currently known about the extent or type of linguistic difficulties that occur, particularly in the genetic forms. METHODS: Participants with genetic bvFTD along with healthy controls were recruited from the international multicentre Genetic FTD Initiative (GENFI). Linguistic symptoms were assessed using items from the Progressive Aphasia Severity Scale (PASS). Additionally, participants undertook the Boston Naming Test (BNT), modified Camel and Cactus Test (mCCT) and a category fluency test. Participants underwent a 3T volumetric T1-weighted MRI, with language network regional brain volumes measured and compared between the genetic groups and controls. RESULTS: 76% of the genetic bvFTD cohort had impairment in at least one language symptom: 83% C9orf72, 80% MAPT and 56% GRN mutation carriers. All three genetic groups had significantly impaired functional communication, decreased fluency, and impaired sentence comprehension. C9orf72 mutation carriers also had significantly impaired articulation and word retrieval as well as dysgraphia whilst the MAPT mutation group also had impaired word retrieval and single word comprehension. All three groups had difficulties with naming, semantic knowledge and verbal fluency. Atrophy in key left perisylvian language regions differed between the groups, with generalised involvement in the C9orf72 group and more focal temporal and insula involvement in the other groups. Correlates of language symptoms and test scores also differed between the groups. CONCLUSIONS: Language deficits exist in a substantial proportion of people with familial bvFTD across all three genetic groups. Significant atrophy is seen in the dominant perisylvian language areas and correlates with language impairments within each of the genetic groups. Improved understanding of the language phenotype in the main genetic bvFTD subtypes will be helpful in future studies, particularly in clinical trials where accurate stratification and monitoring of disease progression is required.
Published: 2023
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23. The CBI-R detects early behavioural impairment in genetic frontotemporal dementia

Author: Nelson, Annabel, Russell, Lucy L., Moreno, Fermin, Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Sanchez-Valle, Raquel, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Laforce, Robert, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Graff, Caroline, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L., Masellis, Mario, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Tartaglia, Maria Carmela, Warren, Jason, Wilke, Carlo, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Rowe, James B., Borroni, Barbara, Finger, Elizabeth, Synofzik, Matthis, Peakman, Georgia, Galimberti, Daniela, Vandenberghe, Rik, Mendonça, Alexandre, Butler, Chris R., Gerhard, Alexander, Ducharme, Simon, Le Ber, Isabelle, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Convery, Rhian S., Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Bouzigues, Arabella, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Greaves, Caroline V., Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Cash, David M., Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Swieten, John C., Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans Otto, Keren, Ron, Kuchcinski, Gregory, Jiskoot, Lize, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, Neurology, Clinical Genetics, Genetic FTD Initiative (GENFI), Russell, Lucy L [0000-0001-5023-5893], Bocchetta, Martina [0000-0003-1814-5024], Sanchez-Valle, Raquel [0000-0001-7750-896X], Laforce, Robert [0000-0002-2031-490X], Borroni, Barbara [0000-0001-9340-9814], Finger, Elizabeth [0000-0003-4461-7427], Synofzik, Matthis [0000-0002-2280-7273], Galimberti, Daniela [0000-0002-9284-5953], Ducharme, Simon [0000-0002-7309-1113], Le Ber, Isabelle [0000-0002-2508-5181], Rohrer, Jonathan D [0000-0002-6155-8417], Apollo - University of Cambridge Repository, and Amsterdam Neuroscience - Neurodegeneration
Subjects: FUNCTIONAL BRAIN CONNECTIVITY, Clinical Neurology, Medizin, PROGRESSION, tau Proteins, C9orf72 Protein, Humans, Progranulins, Frontotemporal Dementia, Pick Disease of the Brain, ATROPHY, genetics [Progranulins], diagnosis [Frontotemporal Dementia], mental disorders, ddc:610, genetics [C9orf72 Protein], genetics [Frontotemporal Dementia], Research Articles, Science & Technology, HEXANUCLEOTIDE REPEAT, MUTATIONS, General Neuroscience, TEMPORAL VARIANT, Neurosciences, genetics [tau Proteins], Neurosciences & Neurology, Neurology (clinical), TAU, FTLD, Life Sciences & Biomedicine, Research Article
Abstract: Funder: UK Dementia Research Institute, Funder: NIHR UCL/H Biomedical Research Centre, Funder: The Wolfson Foundation, Funder: Brain Research UK; Id: http://dx.doi.org/10.13039/100013790, Funder: Alzheimer’s Research UK; Id: http://dx.doi.org/10.13039/501100002283, INTRODUCTION: Behavioural dysfunction is a key feature of genetic frontotemporal dementia (FTD) but validated clinical scales measuring behaviour are lacking at present. METHODS: We assessed behaviour using the revised version of the Cambridge Behavioural Inventory (CBI-R) in 733 participants from the Genetic FTD Initiative study: 466 mutation carriers (195 C9orf72, 76 MAPT, 195 GRN) and 267 non-mutation carriers (controls). All mutation carriers were stratified according to their global CDR plus NACC FTLD score into three groups: asymptomatic (CDR = 0), prodromal (CDR = 0.5) and symptomatic (CDR = 1+). Mixed-effects models adjusted for age, education, sex and family clustering were used to compare between the groups. Neuroanatomical correlates of the individual domains were assessed within each genetic group. RESULTS: CBI-R total scores were significantly higher in all CDR 1+ mutation carrier groups compared with controls [C9orf72 mean 70.5 (standard deviation 27.8), GRN 56.2 (33.5), MAPT 62.1 (36.9)] as well as their respective CDR 0.5 groups [C9orf72 13.5 (14.4), GRN 13.3 (13.5), MAPT 9.4 (10.4)] and CDR 0 groups [C9orf72 6.0 (7.9), GRN 3.6 (6.0), MAPT 8.5 (13.3)]. The C9orf72 and GRN 0.5 groups scored significantly higher than the controls. The greatest impairment was seen in the Motivation domain for the C9orf72 and GRN symptomatic groups, whilst in the symptomatic MAPTgroup, the highest-scoring domains were Stereotypic and Motor Behaviours and Memory and Orientation. Neural correlates of each CBI-R domain largely overlapped across the different mutation carrier groups. CONCLUSIONS: The CBI-R detects early behavioural change in genetic FTD, suggesting that it could be a useful measure within future clinical trials.
Published: 2022
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24. Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort

Author: Peakman, Georgia, Russell, Lucy L., Convery, Rhian S., Nicholas, Jennifer M., van Swieten, John C., 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, Alex, Ducharme, Simon, Le Ber, Isabelle, Tagliavini, Fabrizio, Santana, Isabel, Pasquier, Florence, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Rohrer, Jonathan D., Afonso, Sónia, Almeida, Maria Rosario, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargalló, Nuria, Bartha, Robart, Bender, Benjamin, Benussi, Alberto, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Black, Sandra, Bocchetta, Martina, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Cantoni, Valentina, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Cope, Thomas, Deramecourt, Vincent, de Arriba, María, Di Fede, Giuseppe, Díez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, Ferreira, Catarina B., Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Gazzina, Stefano, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, Leitão, Maria João, Lladó, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Nacmias, Benedetta, Nelson, Annabel, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, Papma, Janne M., Pijnenburg, Yolande, Polito, Cristina, Premi, Enrico, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Shoesmith, Christen, Swift, Imogen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, Thomas, David L., Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Todd, Emily, van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Zetterberg, Henrik, Zulaica, Miren, Neurology, Amsterdam Neuroscience - Neurodegeneration, University College of London [London] (UCL), London School of Hygiene and Tropical Medicine (LSHTM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Donostia International Physics Center - DIPC (SPAIN), Donostia International Physics Center (DIPC), University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU)-University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Centre Hospitalier Université Laval [Quebec] (CHUL), CHU de Québec–Université Laval, Université Laval [Québec] (ULaval)-Université Laval [Québec] (ULaval), Karolinska Institutet [Stockholm], University of Toronto, University of Cambridge [UK] (CAM), University of Brescia, University of Western Ontario (UWO), Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Lusófona University [Lisbon], University of Oxford, University of Manchester [Manchester], McGill University = Université McGill [Montréal, Canada], Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Coimbra [Portugal] (UC), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ludwig-Maximilians-Universität München (LMU), University of Ulm (UUlm), Università degli Studi di Firenze = University of Florence (UniFI), HAL-SU, Gestionnaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Oxford [Oxford], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Sorbonne Université (SU), Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Peakman, Georgia [0000-0002-3319-138X], Convery, Rhian S [0000-0002-9477-1812], Van Swieten, John C [0000-0001-6278-6844], Jiskoot, Lize C [0000-0002-1120-1858], Rowe, James B [0000-0001-7216-8679], Borroni, Barbara [0000-0001-9340-9814], Finger, Elizabeth [0000-0003-4461-7427], Galimberti, Daniela [0000-0002-9284-5953], Gerhard, Alex [0000-0002-8071-6062], Ducharme, Simon [0000-0002-7309-1113], Le Ber, Isabelle [0000-0002-2508-5181], Danek, Adrian [0000-0001-8857-5383], Otto, Markus [0000-0002-6647-5944], Sorbi, Sandro [0000-0002-0380-6670], Rohrer, Jonathan D [0000-0002-6155-8417], Apollo - University of Cambridge Repository, and Genetic FTD Initiative (GENFI)
Subjects: Oncology, Medizin, LANGUAGE, Disease, Genetic FTD Initiative (GENFI), Cohort Studies, 0302 clinical medicine, diagnosis [Frontotemporal Dementia], ddc:150, C9orf72, CRITERIA, 030212 general & internal medicine, frontotemporal dementia, C9orf72 Protein, Cross-Sectional Studies, Disease Progression, Frontotemporal Dementia, Humans, Mutation, tau Proteins, Mental Status and Dementia Tests, VERSION, 11 Medical and Health Sciences, Psychiatry, UTILITY, DDC 150 / Psychology, biology, FTD, 17 Psychology and Cognitive Sciences, Psychiatry and Mental health, Mutation (genetic algorithm), Cohort, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, FTLD, Life Sciences & Biomedicine, Alzheimer’s disease, Frontotemporal dementia, medicine.medical_specialty, Clinical Dementia Rating, Tau protein, Clinical Neurology, Alzheimerkrankheit, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, DIAGNOSIS, Asymptomatic, VALIDATION, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Internal medicine, mental disorders, medicine, ddc:610, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurodegeneration, Science & Technology, Neurology & Neurosurgery, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], business.industry, MUTATIONS, medicine.disease, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, biology.protein, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Surgery, Neurology (clinical), Neurosciences & Neurology, business, 030217 neurology & neurosurgery
Abstract: BackgroundTherapeutic trials are now underway in genetic forms of frontotemporal dementia (FTD) but clinical outcome measures are limited. The two most commonly used measures, the Clinical Dementia Rating (CDR)+National Alzheimer’s Disease Coordinating Center (NACC) Frontotemporal Lobar Degeneration (FTLD) and the FTD Rating Scale (FRS), have yet to be compared in detail in the genetic forms of FTD.MethodsThe CDR+NACC FTLD and FRS were assessed cross-sectionally in 725 consecutively recruited participants from the Genetic FTD Initiative: 457 mutation carriers (77 microtubule-associated protein tau (MAPT), 187 GRN, 193 C9orf72) and 268 family members without mutations (non-carrier control group). 231 mutation carriers (51 MAPT, 92 GRN, 88 C9orf72) and 145 non-carriers had available longitudinal data at a follow-up time point.ResultsCross-sectionally, the mean FRS score was lower in all genetic groups compared with controls: GRN mutation carriers mean 83.4 (SD 27.0), MAPT mutation carriers 78.2 (28.8), C9orf72 mutation carriers 71.0 (34.0), controls 96.2 (7.7), p, publishedVersion
Published: 2022
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25. Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

Author: Young, Alexandra L, Bocchetta, Martina, Seelaar, Harro, Bruffaerts, Rose, Van Damme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B, Miltenberger, Gabriel, Maruta, Carolina, Verdelho, Ana, Afonso, Sónia, Taipa, Ricardo, Caroppo, Paola, Moreno, Fermin, Di Fede, Giuseppe, Giaccone, Giorgio, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Tiraboschi, Pietro, Duro, Diana, Almeida, Maria Rosario, Branco, Miguel Castelo, Leitão, Maria João, Sanchez-Valle, Raquel, Pereira, Miguel Tábuas, Santiago, Beatriz, Gauthier, Serge, Neto, Pedro Rosa, Veldsman, Michele, Thompson, Paul, Prix, Catharina, Hoegen, Tobias, Mag Rer Nat, Elisabeth Wlasich, Loosli, Sandra, Borroni, Barbara, Schönecker, Sonja, Dr Hum Bio, Elisa Semler, Psych, Dipl, Anderl-Straub, Sarah, Nacmias, Benedetta, Ferrari, Camilla, Polito, Cristina, Lombardi, Gemma, Bessi, Valentina, Laforce, Robert, Masellis, Mario, Tartaglia, Maria Carmela, Graff, Caroline, Galimberti, Daniela, Rowe, James B, Russell, Lucy L, Finger, Elizabeth, Synofzik, Matthis, Vandenberghe, Rik, de Mendonça, Alexandre, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris, Gerhard, Alex, Levin, Johannes, Convery, Rhian S, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Williams, Steven C R, Alexander, Daniel C, Rohrer, Jonathan D, Initiative, Genetic FTD, Rossor, Martin N, Fox, Nick C, Warren, Jason D, Peakman, Georgia, Woollacott, Ione, Shafei, Rachelle, Heller, Carolin, Swift, Imogen J, Moore, Katrina, Guerreiro, Rita, Bras, Jose, Thomas, David L, Nicholas, Jennifer, Mead, Simon, Todd, Emily, Meeter, Lieke, Panman, Jessica, Papma, Janne M, Poos, Jackie, van Minkelen, Rick, Pijnenburg, Yolande, Barandiaran, Myriam, Indakoetxea, Begoña, Gabilondo, Alazne, Tainta, Mikel, Cash, David M, de Arriba, María, Gorostidi, Ana, Zulaica, Miren, Villanua, Jorge, Díaz, Zigor, Borrego-Ecija, Sergi, Olives, Jaume, Lladó, Albert, Balasa, Mircea, Antonell, Anna, Greaves, Caroline V, Bargalló, Nuria, Premi, Enrico, Cosseddu, Maura, Gazzina, Stefano, Padovani, Alessandro, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Rogaeva, Ekaterina, van Swieten, John, Freedman, Morris, Keren, Ron, Tang-Wai, David, Öijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Thonberg, Hakan, Arighi, Andrea, Fenoglio, Chiara, Scarpini, Elio, Jiskoot, Lize, Fumagalli, Giorgio, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Karnath, Hans Otto, Bender, Benjamin, Young, Alexandra L [0000-0002-7772-781X], Todd, Emily [0000-0003-1551-5691], Cash, David M [0000-0001-7833-616X], Seelaar, Harro [0000-0003-1989-7527], Laforce, Robert [0000-0002-2031-490X], Galimberti, Daniela [0000-0002-9284-5953], Vandenberghe, Rik [0000-0001-6237-2502], Danek, Adrian [0000-0001-8857-5383], Otto, Markus [0000-0003-4273-4267], Williams, Steven CR [0000-0003-4299-1941], Apollo - University of Cambridge Repository, Genetic FTD Initiative (GENFI), Repositório da Universidade de Lisboa, and Neurology
Subjects: Male, Medizin, Hippocampus, volumetric MRI, frontotemporal dementia, Machine Learning, 0302 clinical medicine, pathology [Brain], 030212 general & internal medicine, genetics [Frontotemporal Dementia], Temporal cortex, pathology [Atrophy], Brain, Middle Aged, Magnetic Resonance Imaging, neuropsychological assessment, medicine.anatomical_structure, Frontotemporal Dementia, Disease Progression, CHAMELEON, Female, methods [Neuroimaging], Life Sciences & Biomedicine, Research Article, Frontotemporal dementia, genetics [Atrophy], Adult, Ventromedial prefrontal cortex, Clinical Neurology, Neuroimaging, MAPT protein, human, tau Proteins, methods [Image Interpretation, Computer-Assisted], Biology, Temporal lobe, 03 medical and health sciences, Atrophy, Image Interpretation, Computer-Assisted, Aged, Humans, Mutation, medicine, ddc:610, Science & Technology, MUTATIONS, medicine.disease, genetics [tau Proteins], association studies in genetics, pathology [Frontotemporal Dementia], Neurology (clinical), Neurosciences & Neurology, Neuroscience, Insula, 030217 neurology & neurosurgery, Executive dysfunction
Abstract: Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited., Background and objective: Mutations in the MAPT gene cause frontotemporal dementia (FTD). Most previous studies investigating the neuroanatomical signature of MAPT mutations have grouped all different mutations together and shown an association with focal atrophy of the temporal lobe. However, the variability in atrophy patterns between each particular MAPT mutation is less well characterised. We aimed to investigate whether there were distinct groups of MAPT mutation carriers based on their neuroanatomical signature. Methods: We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning technique that identifies groups of individuals with distinct progression patterns, to characterise patterns of regional atrophy in MAPT-associated FTD within the Genetic FTD Initiative (GENFI) cohort study. Results: 82 MAPT mutation carriers were analysed, the majority of whom had P301L, IVS10+16 or R406W mutations, along with 48 healthy non-carriers. SuStaIn identified two groups of MAPT mutation carriers with distinct atrophy patterns: a 'temporal' subtype in which atrophy was most prominent in the hippocampus, amygdala, temporal cortex and insula, and a 'frontotemporal' subtype in which atrophy was more localised to the lateral temporal lobe and anterior insula, as well as the orbitofrontal and ventromedial prefrontal cortex and anterior cingulate. There was a one-to-one mapping between IVS10+16 and R406W mutations and the temporal subtype, and a near one-to-one mapping between P301L mutations and the frontotemporal subtype. There were differences in clinical symptoms and neuropsychological test scores between subtypes: the temporal subtype was associated with amnestic symptoms, whereas the frontotemporal subtype was associated with executive dysfunction. Discussion: Our results demonstrate that different MAPT mutations give rise to distinct atrophy patterns and clinical phenotype, providing insights into the underlying disease biology, and potential utility for patient stratification in therapeutic trials., The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and Kings College London, as well as an Alzheimer's Society grant (AS-PG-16-007). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Italian Ministry of Health (CoEN015 and Ricerca Corrente), and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant, a Canadian Institutes of Health Research operating grant and The Bluefield Project, and the JPND GENFI-PROX grant (2019-02248). This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy ID 390857198). Nonfinancial support was also provided through the European Reference Network for Rare Neurologic Diseases (ERN-RND), 1 of 24 ERNs funded by the European Commission (ERNRND: 3HP 767231).
Published: 2021
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26. Progression of Behavioral Disturbances and Neuropsychiatric Symptoms in Patients With Genetic Frontotemporal Dementia

Author: Benussi, Alberto, Premi, Enrico, Laforce, Robert, Lladò, Albert, Lombardi, Gemma, Loosli, Sandra, Maruta, Carolina, Mead, Simon, Meeter, Lieke, Miltenberger, Gabriel, van Minkelen, Rick, Mitchell, Sara, Moore, Katrina, Graff, Caroline, Nacmias, Benedetta, Nicholas, Jennifer, Öijerstedt, Linn, Olives, Jaume, Ourselin, Sebastien, Padovani, Alessandro, Panman, Jessica, M Papma, Janne, Pievani, Michela, Pijnenburg, Yolande, Synofzik, Matthis, Polito, Cristina, Prioni, Sara, Prix, Catharina, Rademakers, Rosa, Redaelli, Veronica, Rinaldi, Daisy, Rittman, Tim, Rogaeva, Ekaterina, Rollin, Adeline, Rosa-Neto, Pedro, Galimberti, Daniela, Rossi, Giacomina, Rossor, Martin, Santiago, Beatriz, Saracino, Dario, Sayah, Sabrina, Scarpini, Elio, Schönecker, Sonja, Seelaar, Harro, Semler, Elisa, Shafei, Rachelle, Masellis, Mario, Shoesmith, Christen, Tábuas-Pereira, Miguel, Tainta, Mikel, Taipa, Ricardo, Tang-Wai, David, L Thomas, David, Thompson, Paul, Thonberg, Hakan, Timberlake, Carolyn, Tiraboschi, Pietro, Tartaglia, Carmela, Todd, Emily, Van Damme, Philip, Vandenbulcke, Mathieu, Veldsman, Michele, Verdelho, Ana, Villanua, Jorge, Warren, Jason, Wilke, Carlo, Woollacott, Ione, Wlasich, Elisabeth, Rowe, James B, Zetterberg, Henrik, Zulaica, Miren, Finger, Elizabeth, Vandenberghe, Rik, de Mendonça, Alexandre, Gazzina, Stefano, Tagliavini, Fabrizio, Santana, Isabel, Ducharme, Simon, Butler, Chris R, Gerhard, Alexander, Levin, Johannes, Danek, Adrian, Otto, Markus, Frisoni, Giovanni, Ghidoni, Roberta, Brattini, Chiara, Sorbi, Sandro, Le Ber, Isabelle, Pasquier, Florence, Peakman, Georgia, Bocchetta, Martina, Rohrer, Jonathan D, Borroni, Barbara, Initiative, Genetic FTD, Afonso, Sònia, Bonomi, Elisa, Rosario Almeida, Maria, Anderl-Straub, Sarah, Andersson, Christin, Antonell, Anna, Archetti, Silvana, Arighi, Andrea, Balasa, Mircea, Barandiaran, Myriam, Bargallò, Nuria, Bartha, Robart, Alberici, Antonella, Bender, Benjamin, Benussi, Luisa, Bertoux, Maxime, Bertrand, Anne, Bessi, Valentina, Binetti, Giuliano, Black, Sandra, Borrego-Ecija, Sergi, Bras, Jose, Brice, Alexis, Jiskoot, Lize, Bruffaerts, Rose, Camuzat, Agnès, Cañada, Marta, Caroppo, Paola, Cash, David, Castelo-Branco, Miguel, Colliot, Olivier, Convery, Rhian, Cope, Thomas, Cosseddu, Maura, van Swieten, John C, Deramecourt, Vincent, de Arriba, Marìa, Di Fede, Giuseppe, Dìez, Alina, Duro, Diana, Fenoglio, Chiara, Ferrari, Camilla, B Ferreira, Catarina, Fox, Nick, Freedman, Morris, Sanchez-Valle, Raquel, Fumagalli, Giorgio, Funkiewiez, Aurélie, Gabilondo, Alazne, Gasparotti, Roberto, Gauthier, Serge, Giaccone, Giorgio, Gorostidi, Ana, Greaves, Caroline, Guerreiro, Rita, Moreno, Fermin, Heller, Carolin, Hoegen, Tobias, Indakoetxea, Begoña, Jelic, Vesna, Karnath, Hans-Otto, Keren, Ron, Kuchcinski, Gregory, Langheinrich, Tobias, Lebouvier, Thibaud, João Leitão, Maria, Genetic FTD Initiative (GENFI), Repositório da Universidade de Lisboa, Neurology, Rowe, James [0000-0001-7216-8679], and Apollo - University of Cambridge Repository
Subjects: Male, Longitudinal study, Pediatrics, Hallucinations, FEATURES, VARIANT, Medizin, Anxiety, physiopathology [Frontotemporal Dementia], 0302 clinical medicine, Interquartile range, Medicine, Apathy, Longitudinal Studies, genetics [Frontotemporal Dementia], Depression (differential diagnoses), Granulins, Original Investigation, Depression, Aged, C9orf72 Protein, Canada, Compulsive Behavior, Disease Progression, Europe, Female, Humans, Middle Aged, tau Proteins, Frontotemporal Dementia, General Medicine, 3. Good health, Online Only, Neurology, Compulsive behavior, medicine.symptom, Life Sciences & Biomedicine, Frontotemporal dementia, Cohort study, medicine.medical_specialty, genetics [Granulins], DIAGNOSTIC-CRITERIA, epidemiology [Frontotemporal Dementia], MAPT protein, human, 03 medical and health sciences, Medicine, General & Internal, 030225 pediatrics, General & Internal Medicine, mental disorders, ddc:610, LOBAR DEGENERATION, genetics [C9orf72 Protein], Science & Technology, business.industry, Research, DISEASE PROGRESSION, Correction, medicine.disease, genetics [tau Proteins], ONSET, Other, C9orf72 protein, human, business, 030217 neurology & neurosurgery
Abstract: © 2021 Benussi A et al. JAMA Network Open. This is an open access article distributed under the terms of the CC-BY License., Importance: Behavioral disturbances are core features of frontotemporal dementia (FTD); however, symptom progression across the course of disease is not well characterized in genetic FTD. Objective: To investigate behavioral symptom frequency and severity and their evolution and progression in different forms of genetic FTD. Design, setting, and participants: This longitudinal cohort study, the international Genetic FTD Initiative (GENFI), was conducted from January 30, 2012, to May 31, 2019, at 23 multicenter specialist tertiary FTD research clinics in the United Kingdom, the Netherlands, Belgium, France, Spain, Portugal, Italy, Germany, Sweden, Finland, and Canada. Participants included a consecutive sample of 232 symptomatic FTD gene variation carriers comprising 115 with variations in C9orf72, 78 in GRN, and 39 in MAPT. A total of 101 carriers had at least 1 follow-up evaluation (for a total of 400 assessments). Gene variations were included only if considered pathogenetic. Main outcomes and measures: Behavioral and neuropsychiatric symptoms were assessed across disease duration and evaluated from symptom onset. Hierarchical generalized linear mixed models were used to model behavioral and neuropsychiatric measures as a function of disease duration and variation. Results: Of 232 patients with FTD, 115 (49.6%) had a C9orf72 expansion (median [interquartile range (IQR)] age at evaluation, 64.3 [57.5-69.7] years; 72 men [62.6%]; 115 White patients [100%]), 78 (33.6%) had a GRN variant (median [IQR] age, 63.4 [58.3-68.8] years; 40 women [51.3%]; 77 White patients [98.7%]), and 39 (16.8%) had a MAPT variant (median [IQR] age, 56.3 [49.9-62.4] years; 25 men [64.1%]; 37 White patients [94.9%]). All core behavioral symptoms, including disinhibition, apathy, loss of empathy, perseverative behavior, and hyperorality, were highly expressed in all gene variant carriers (>50% patients), with apathy being one of the most common and severe symptoms throughout the disease course (51.7%-100% of patients). Patients with MAPT variants showed the highest frequency and severity of most behavioral symptoms, particularly disinhibition (79.3%-100% of patients) and compulsive behavior (64.3%-100% of patients), compared with C9orf72 carriers (51.7%-95.8% of patients with disinhibition and 34.5%-75.0% with compulsive behavior) and GRN carriers (38.2%-100% with disinhibition and 20.6%-100% with compulsive behavior). Alongside behavioral symptoms, neuropsychiatric symptoms were very frequently reported in patients with genetic FTD: anxiety and depression were most common in GRN carriers (23.8%-100% of patients) and MAPT carriers (26.1%-77.8% of patients); hallucinations, particularly auditory and visual, were most common in C9orf72 carriers (10.3%-54.5% of patients). Most behavioral and neuropsychiatric symptoms increased in the early-intermediate phases and plateaued in the late stages of disease, except for depression, which steadily declined in C9orf72 carriers, and depression and anxiety, which surged only in the late stages in GRN carriers. Conclusions and relevance: This cohort study suggests that behavioral and neuropsychiatric disturbances differ between the common FTD gene variants and have different trajectories throughout the course of disease. These findings have crucial implications for counseling patients and caregivers and for the design of disease-modifying treatment trials in genetic FTD., This work is supported by the Joint Programme–Neurodegenerative Disease Research grant no. JPND2019-466-090 “GENFI-prox” (Drs Synofzik, van Swieten, Otto, Graff, Rohrer, and Borroni), the Centre d’Investigation Clinique grant no. ANR/DGOS PRTS 2015-2019 PREV-DEMALS (Dr Le Ber), the Centre pour l’Acquisition et le Traitement des Images platform grant no. ANR-10-IAIHU-06 (Dr Le Ber), the UK Medical Research Council grant no. MR/M023664/1 (Dr Rohrer), the Italian Ministry of Health grant no. 733051042 (Dr Galimberti), and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant no. MOP 327387 (Dr Masellis), a Canadian Institutes of Health Research operating grant.
Published: 2021
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27. Impairment of episodic memory in genetic frontotemporal dementia

Author: Poos, Jackie M, Russell, Lucy L, Pijnenburg, Yolande A L, Bender, Benjamin, Bruffaerts, Rose, Vandamme, Philip, Vandenbulcke, Mathieu, Ferreira, Catarina B, Miltenberger, Gabriel, Maruta, Carolina, Verdelho, Ana, Afonso, Sónia, Taipa, Ricardo, Borroni, Barbara, Caroppo, Paola, Di Fede, Giuseppe, Giaccone, Giorgio, Prioni, Sara, Redaelli, Veronica, Rossi, Giacomina, Tiraboschi, Pietro, Duro, Diana, Almeida, Maria Rosario, Castelo-Branco, Miguel, Sanchez-Valle, Raquel, Leitão, Maria João, Tabuas-Pereira, Miguel, Santiago, Beatriz, Gauthier, Serge, Rosa-Neto, Pedro, Veldsman, Michele, Thompson, Paul, Langheinrich, Tobias, Prix, Catharina, Hoegen, Tobias, Moreno, Fermin, Wlasich, Elisabeth, Loosli, Sandra, Schonecker, Sonja, Anderl-Straub, Sarah, Lombardi, Jolina, Bargalló, Nuria, Benussi, Alberto, Cantoni, Valentina, Bertoux, Maxime, Bertrand, Anne, Laforce, Robert, Brice, Alexis, Camuzat, Agnès, Colliot, Olivier, Sayah, Sabrina, Funkiewiez, Aurélie, Rinaldi, Daisy, Lombardi, Gemma, Nacmias, Benedetta, Saracino, Dario, Bessi, Valentina, Graff, Caroline, Ferrari, Camilla, Cañada, Marta, Deramecourt, Vincent, Kuchcinski, Gregory, Lebouvier, Thibaud, Ourselin, Sebastien, Polito, Cristina, Rollin, Adeline, Synofzik, Matthias, Galimberti, Daniela, Rowe, James B, Masellis, Mario, Peakman, Georgia, Tartaglia, Carmela, Finger, Elizabeth, Vandenberghe, Rik, de Medonça, Alexandre, Tagliavini, Fabrizio, Butler, Chris R, Santana, Isabel, Ber, Isabelle Le, Gerhard, Alex, Ducharme, Simon, Bocchetta, Martina, Levin, Johannes, Danek, Adrian, Otto, Markus, Sorbi, Sandro, Pasquier, Florence, van Swieten, John C, Rohrer, Jonathan D, Genetic FTD Initiative, GENF, Rossor, Martin N, Fox, Nick C, Greaves, Caroline V, Warren, Jason D, Moore, Katrina, Convery, Rhian, Swift, Imogen J, Shafei, Rachelle, Heller, Carolin, Todd, Emily, Bouzigues, Arabella, Cash, David, Woollacott, Ione, Jiskoot, Lize C, Zetterberg, Henrik, Nelson, Annabel, Nicholas, Jennifer, Guerreiro, Rita, Bras, Jose, Thomas, David L, Mead, Simon, Meeter, Lieke, Panman, Jessica, van Minkelen, Rick, van der Ende, Emma L, Barandiaran, Myriam, Indakoetxea, Begoña, Gabilondo, Alazne, Tainta, Mikel, Gorostidi, Ana, Zulaica, Miren, Díez, Alina, Villanua, Jorge, Borrego-Ecija, Sergi, Jaume, Olives, Seelaar, Harro, Lladó, Albert, Balasa, Mircea, Antonell, Anna, Bargallo, Nuria, Premi, Enrico, Gazzina, Stefano, Gasparotti, Roberto, Archetti, Silvana, Black, Sandra, Mitchell, Sara, Papma, Janne M, Rogaeva, Ekaterina, Freedman, Morris, Keren, Ron, Tang-Wai, David, Thonberg, Hakan, Öijerstedt, Linn, Andersson, Christin, Jelic, Vesna, Arighi, Andrea, Fenoglio, Chiara, van den Berg, Esther, Scarpini, Elio, Fumagalli, Giorgio, Cope, Thomas, Timberlake, Carolyn, Rittman, Timothy, Shoesmith, Christen, Bartha, Robart, Rademakers, Rosa, Wilke, Carlo, Karnarth, Hans-Otto, Apollo - University of Cambridge Repository, Repositório da Universidade de Lisboa, Rowe, James [0000-0001-7216-8679], Rowe, James B [0000-0001-7216-8679], Neurology, Amsterdam Neuroscience - Neurodegeneration, Genetic FTD Initiative, GENFI, Radiology & Nuclear Medicine, Neurosurgery, Clinical Psychology, and Clinical Genetics
Subjects: cognition, Medizin, neuropsychology, Audiology, frontotemporal dementia, DISEASE, 0302 clinical medicine, COGNITIVE & BEHAVIORAL ASSESSMENT, C9orf72, BEHAVIORAL VARIANT, CRITERIA, voxel‐based morphometry, ALZHEIMERS, Episodic memory, 0303 health sciences, episodic memory, CARRIERS, frontal lobe, Psychiatry and Mental health, Frontal lobe, Life Sciences & Biomedicine, Frontotemporal dementia, temporal lobe, Cognition, Executive function, Genetic disorders, Neuropsychology, Temporal lobe, Voxel-based morphometry, medicine.medical_specialty, Clinical Neurology, DIAGNOSIS, RESEARCH ARTICLE, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Memory impairment, voxel-based morphometry, genetic disorders, ddc:610, PROGRANULIN, RC346-429, 030304 developmental biology, 0604 Genetics, Science & Technology, Recall, business.industry, RC952-954.6, Neurosciences, PROFILES, medicine.disease, executive function, Geriatrics, VOLUME, Genetic FTD Initiative, GENF, Neurology (clinical), Neurology. Diseases of the nervous system, Neurosciences & Neurology, business, 1109 Neurosciences, 030217 neurology & neurosurgery
Abstract: © 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., Introduction: We aimed to assess episodic memory in genetic frontotemporal dementia (FTD) with the Free and Cued Selective Reminding Test (FCSRT). Methods: The FCSRT was administered in 417 presymptomatic and symptomatic mutation carriers (181 chromosome 9 open reading frame 72 [C9orf72], 163 progranulin [GRN], and 73 microtubule-associated protein tau [MAPT]) and 290 controls. Group differences and correlations with other neuropsychological tests were examined. We performed voxel-based morphometry to investigate the underlying neural substrates of the FCSRT. Results: All symptomatic mutation carrier groups and presymptomatic MAPT mutation carriers performed significantly worse on all FCSRT scores compared to controls. In the presymptomatic C9orf72 group, deficits were found on all scores except for the delayed total recall task, while no deficits were found in presymptomatic GRN mutation carriers. Performance on the FCSRT correlated with executive function, particularly in C9orf72 mutation carriers, but also with memory and naming tasks in the MAPT group. FCSRT performance also correlated with gray matter volumes of frontal, temporal, and subcortical regions in C9orf72 and GRN, but mainly temporal areas in MAPT mutation carriers. Discussion: The FCSRT detects presymptomatic deficits in C9orf72- and MAPT-associated FTD and provides important insight into the underlying cause of memory impairment in different forms of FTD., The Dementia Research Centre is supported by Alzheimer's Research UK, Alzheimer's Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the 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. J. D. Rohrer 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; the JPND GENFI-PROX grant (2019-02248); the Dioraphte Foundation (grant numbers 09-02-00); the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO; grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie, project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). J. M. Poos is supported by a Fellowship award from Alzheimer Nederland (WE.15-2019.02). This work was conducted using the MRC Dementias Platform UK (MR/L023784/1 and MR/009076/1). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510.
Published: 2021
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28. Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

Author: Altmann, A., Cash, D. M., Bocchetta, M., Heller, C., Reynolds, R., Moore, K., Convery, R. S., Thomas, D. L., Van Swieten, J. C., Moreno, F., Sanchez-Valle, R., Borroni, B., Laforce, R., Masellis, M., Tartaglia, M. C., Graff, C., Galimberti, D., Rowe, J. B., Finger, E., Synofzik, M., Vandenberghe, R., De Mendonca, A., Tagliavini, F., Santana, I., Ducharme, S., Butler, C. R., Gerhard, A., Levin, J., Danek, A., Frisoni, G., Ghidoni, R., Sorbi, S., Otto, M., Ryten, M., Rohrer, J. D., Greaves, C., Peakman, G., Shafei, R., Todd, E., Rossor, M. N., Warren, J. D., Fox, N. C., Zetterberg, H., Guerreiro, R., Bras, J., Nicholas, J., Mead, S., Jiskoot, L., Meeter, L., Panman, J., Papma, J. M., Van Minkelen, R., Pijnenburg, Y., Barandiaran, M., Indakoetxea, B., Gabilondo, A., Tainta, M., De Arriba, M., Gorostidi, A., Zulaica, M., Villanua, J., Diaz, Z., Borrego-Ecija, S., Olives, J., Llado, A., Balasa, M., Antonell, A., Bargallo, N., Premi, E., Cosseddu, M., Gazzina, S., Padovani, A., Gasparotti, R., Archetti, S., Black, S., Mitchell, S., Rogaeva, E., Freedman, M., Keren, R., Tang-Wai, D., Oijerstedt, L., Andersson, C., Jelic, V., Thonberg, H., Arighi, A., Fenoglio, C., Scarpini, E., Fumagalli, G., Cope, T., Timberlake, C., Rittman, T., Shoesmith, C., Bartha, R., Rademakers, R., Wilke, C., Karnarth, H. -O., Bender, B., Bruffaerts, R., Van Damme, P., Vandenbulcke, M., Ferreira, C. B., Miltenberger, G., Maruta, C., Verdelho, A., Afonso, S., Taipa, R., Caroppo, P., Di Fede, G., Giaccone, G., Prioni, S., Redaelli, V., Rossi, G., Tiraboschi, P., Duro, D., Almeida, M. R., Castelo-Branco, M., Leitao, M. J., Tabuas-Pereira, M., Santiago, B., Gauthier, S., Rosa-Neto, P., Veldsman, M., Thompson, P., Langheinrich, T., Prix, C., Hoegen, T., Wlasich, E., Loosli, S., Schonecker, S., Semler, E., Anderl-Straub, S., Benussi, L., Binetti, G., Pievani, M., Lombardi, G., Nacmias, B., Ferrari, C., Bessi, V., Polito, C., Rowe, James [0000-0001-7216-8679], Apollo - University of Cambridge Repository, Medical Research Council, and Genetic FTD Initiative, GENFI
Subjects: 0301 basic medicine, Cell type, Imaging genetics, Clinical Neurology, Medizin, Biology, Article, DISEASE, 03 medical and health sciences, 0302 clinical medicine, Atrophy, atrophy, C9orf72, Gene expression, medicine, Astrocytes, Frontotemporal dementia, ddc:610, 10. No inequality, Gene, 030304 developmental biology, Genetics, 0303 health sciences, Science & Technology, TREM2, AcademicSubjects/SCI01870, Neurodegeneration, General Engineering, C9orf72 Gene, Neurosciences, astrocytes, Genetic FTD Initiative, GENFI, medicine.disease, C9orf72 Protein, 030104 developmental biology, gene expression, imaging genetics, Original Article, AcademicSubjects/MED00310, Human medicine, Neurosciences & Neurology, Life Sciences & Biomedicine, 030217 neurology & neurosurgery
Abstract: Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood–brain barrier, respectively., Altmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that elevated gene expression of endothelial cell and astrocyte-related genes in regions with atrophy, suggesting a role of these cell types in the aetiology of frontotemporal dementia., Graphical Abstract Graphical Abstract
Published: 2020
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29. Spatiotemporal analysis for detection of pre-symptomatic shape changes in neurodegenerative diseases: Initial application to the GENFI cohort

Author: Cury, Claire, Durrleman, Stanley, Cash, David M., Lorenzi, Marco, Nicholas, Jennifer M., Bocchetta, Martina, van Swieten, John C., Borroni, Barbara, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni B., Laforce, Robert, Finger, Elizabeth, De Mendonça, Alexandre, Sorbi, Sandro, Ourselin, Sebastien, Rohrer, Jonathan D., Modat, Marc, Andersson, Christin, Archetti, Silvana, Arighi, Andrea, Benussi, Luisa, Black, Sandra, Cosseddu, Maura, Fallstrm, Marie, Ferreira, Carlos, Fenoglio, Chiara, Fox, Nick, Freedman, Morris, Fumagalli, Giorgio, Gazzina, Stefano, Ghidoni, Roberta, Grisoli, Marina, Jelic, Vesna, Jiskoot, Lize, Keren, Ron, Lombardi, Gemma, Maruta, Carolina, Meeter, Lieke, van Minkelen, Rick, Nacmias, Benedetta, ijerstedt, Linn, Padovani, Alessandro, Panman, Jessica, Pievani, Michela, Polito, Cristina, Premi, Enrico, Prioni, Sara, Rademakers, Rosa, Redaelli, Veronica, Rogaeva, Ekaterina, Rossi, Giacomina, Rossor, Martin, Scarpini, Elio, Tang-Wai, David, Tartaglia, Carmela, Thonberg, Hakan, Tiraboschi, Pietro, Verdelho, Ana, Warren, Jason, Genetic FTD Initiative GENFI, and Repositório da Universidade de Lisboa
Subjects: Computer. Automation, Computational anatomy, Thalamus, Clustering, Parallel transport, Shape analysis, Spatiotemporal geodesic regression, Neurology, Cognitive Neuroscience, Human medicine
Abstract: © 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), Brain atrophy as measured from structural MR images, is one of the primary imaging biomarkers used to track neurodegenerative disease progression. In diseases such as frontotemporal dementia or Alzheimer's disease, atrophy can be observed in key brain structures years before any clinical symptoms are present. Atrophy is most commonly captured as volume change of key structures and the shape changes of these structures are typically not analysed despite being potentially more sensitive than summary volume statistics over the entire structure. In this paper we propose a spatiotemporal analysis pipeline based on Large Diffeomorphic Deformation Metric Mapping (LDDMM) to detect shape changes from volumetric MRI scans. We applied our framework to a cohort of individuals with genetic variants of frontotemporal dementia and healthy controls from the Genetic FTD Initiative (GENFI) study. Our method, take full advantage of the LDDMM framework, and relies on the creation of a population specific average spatiotemporal trajectory of a relevant brain structure of interest, the thalamus in our case. The residuals from each patient data to the average spatiotemporal trajectory are then clustered and studied to assess when presymptomatic mutation carriers differ from healthy control subjects. We found statistical differences in shape in the anterior region of the thalamus at least five years before the mutation carrier subjects develop any clinical symptoms. This region of the thalamus has been shown to be predominantly connected to the frontal lobe, consistent with the pattern of cortical atrophy seen in the disease., Claire Cury is supported by the EU-FP7 project VPH-DARE@IT (FP7-ICT-2011-9-601055). Stanley Durrleman has received funding from the program Investissements d'avenir ANR-10-IAIHU-06 and the European Unions Horizon 2020 research and innovation programme EuroPOND under grant agreement No 666992, and is funded by the European Research Council (ERC) under grant agreement No 678304. Marco Lorenzi received funding from the EPSRC (EP/J020990/1). Jennifer Nicholas is supported by UK Medical Research Council (grant MR/M023664/1). David Cash is supported by grants from the Alzheimer Society (AS-PG-15-025), Alzheimer’s Research UK (ARUK-PG2014-1946) and Medical Research Council UK (MR/M023664/1). JBR is supported by the Wellcome Trust (103838). Jonathan D. Rohrer is an MRC Clinician Scientist and has received funding from the NIHR Rare Diseases Translational Research Collaboration. Sebastien Ourselin receives funding from the EPSRC (EP/H046410/1, EP/K005278), the MRC (MR/J01107X/1), the NIHR Biomedical Research Unit (Dementia) at UCL and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative- BW.mn.BRC10269). Marc Modat is supported by the UCL Leonard Wolfson Experimental Neurology Centre (PR/ylr/18575) and Alzheimer's Society UK (AS-PG-15-025).
Published: 2019

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29 results on '"The Genetic FTD Initiative, GENFI"'

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

2. Language impairment in the genetic forms of behavioural variant frontotemporal dementia

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

4. CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia

5. CSF glial markers are elevated in a subset of patients with genetic frontotemporal dementia

6. Development of a sensitive trial-ready poly(GP) CSF biomarker assay for C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

7. The inner fluctuations of the brain in presymptomatic Frontotemporal Dementia: The chronnectome fingerprint

8. The Revised Self-Monitoring Scale detects early impairment of social cognition in genetic frontotemporal dementia within the GENFI cohort

9. Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort

10. Education modulates brain maintenance in presymptomatic frontotemporal dementia

11. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

12. Progranulin plasma levels predict the presence of GRN mutations in asymptomatic subjects and do not correlate with brain atrophy: results from the GENFI study

13. Patterns of gray matter atrophy in genetic frontotemporal dementia: results from the GENFI study

14. Distinct Neuroanatomical Correlates of Neuropsychiatric Symptoms in the Three Main Forms of Genetic Frontotemporal Dementia in the GENFI Cohort

15. White matter hyperintensities are seen only inGRNmutation carriers in the GENFI cohort

16. Cognitive reserve and TMEM106B genotype modulate brain damage in presymptomatic frontotemporal dementia: a GENFI study

17. Uncovering the heterogeneity and temporal complexity of neurodegenerative diseases with Subtype and Stage Inference

18. Brain functional network integrity sustains cognitive function despite atrophy in presymptomatic genetic frontotemporal dementia

19. Neurodevelopmental effects of genetic frontotemporal dementia in young adult mutation carriers

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

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

22. Language impairment in the genetic forms of behavioural variant frontotemporal dementia

23. The CBI-R detects early behavioural impairment in genetic frontotemporal dementia

24. Comparison of clinical rating scales in genetic frontotemporal dementia within the GENFI cohort

25. Characterizing the Clinical Features and Atrophy Patterns of MAPT-Related Frontotemporal Dementia With Disease Progression Modeling

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

27. Impairment of episodic memory in genetic frontotemporal dementia

28. Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

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

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29 results on '"The Genetic FTD Initiative, GENFI"'

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