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

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

Brain Communications(2023)

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