Structural MRI predicts clinical progression in presymptomatic genetic frontotemporal dementia: findings from the GENetic Frontotemporal dementia Initiative cohort
Authors: Bocchetta Martina , Todd Emily G , Bouzigues Arabella , Cash David M , Nicholas Jennifer M , Convery Rhian S , Russell Lucy L , Thomas David L , Malone Ian B , Iglesias Juan Eugenio , van Swieten John C , Jiskoot Lize C , Seelaar Harro , Borroni Barbara , Galimberti Daniela , Sanchez-Valle Raquel , Laforce Robert , Moreno Fermin , Synofzik Matthis , Graff Caroline , Masellis Mario , Tartaglia Maria Carmela , Rowe James B , Vandenberghe Rik , Finger Elizabeth , Tagliavini Fabrizio , de Mendonça Alexandre , Santana Isabel , Butler Chris R , Ducharme Simon , Gerhard Alexander , Danek Adrian , Levin Johannes , Otto Markus , Sorbi Sandro , Le Ber Isabelle , Pasquier Florence , Rohrer Jonathan D ,   Genetic Frontotemporal dementia Initiative (GENFI), Esteve Aitana Sogorb , Nelson Annabel , Heller Carolin , Greaves Caroline V , Benotmane Hanya , Zetterberg Henrik , Swift Imogen J , Samra Kiran , Shafei Rachelle , Timberlake Carolyn , Cope Thomas , Rittman Timothy , Benussi Alberto , Premi Enrico , Gasparotti Roberto , Archetti Silvana , Gazzina Stefano , Cantoni Valentina , Arighi Andrea , Fenoglio Chiara , Scarpini Elio , Fumagalli Giorgio , Borracci Vittoria , Rossi Giacomina , Giaccone Giorgio , Di Fede Giuseppe , Caroppo Paola , Tiraboschi Pietro , Prioni Sara , Redaelli Veronica , Tang-Wai David , Rogaeva Ekaterina , Castelo-Branco Miguel , Freedman Morris , Keren Ron , Black Sandra , Mitchell Sara , Shoesmith Christen , Bartha Robart , Rademakers Rosa , Poos Jackie , Papma Janne M , Giannini Lucia , van Minkelen Rick , Pijnenburg Yolande , Nacmias Benedetta , Ferrari Camilla , Polito Cristina , Lombardi Gemma , Bessi Valentina , Veldsman Michele , Andersson Christin , Thonberg Hakan , Öijerstedt Linn , Jelic Vesna , Thompson Paul , Langheinrich Tobias , Lladó Albert , Antonell Anna , Olives Jaume , Balasa Mircea , Bargalló Nuria , Borrego-Ecija Sergi , Verdelho Ana , Maruta Carolina , Ferreira Catarina B , Miltenberger Gabriel , Simões do Couto Frederico , Gabilondo Alazne , Gorostidi Ana , Villanua Jorge , Cañada Marta , Tainta Mikel , Zulaica Miren , Barandiaran Myriam , Alves Patricia , Bender Benjamin , Wilke Carlo , Graf Lisa , Vogels Annick , Vandenbulcke Mathieu , Van Damme Philip , Bruffaerts Rose , Poesen Koen , Rosa-Neto Pedro , Gauthier Serge , Camuzat Agnès , Brice Alexis , Bertrand Anne , Funkiewiez Aurélie , Rinaldi Daisy , Saracino Dario , Colliot Olivier , Sayah Sabrina , Prix Catharina , Wlasich Elisabeth , Wagemann Olivia , Loosli Sandra , Schönecker Sonja , Hoegen Tobias , Lombardi Jolina , Anderl-Straub Sarah , Rollin Adeline , Kuchcinski Gregory , Bertoux Maxime , Lebouvier Thibaud , Deramecourt Vincent , Santiago Beatriz , Duro Diana , Leitão Maria João , Almeida Maria Rosario , Tábuas-Pereira Miguel , Afonso Sónia 
Published: March 2023

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