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White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study

2019; Elsevier BV; Volume: 24; Linguagem: Inglês

10.1016/j.nicl.2019.102077

2213-1582

Carole H. Sudre, Martina Bocchetta, Carolin Heller, Rhian S. Convery, Mollie Neason, Katrina Moore, David M. Cash, David L. Thomas, Ione Woollacott, Martha Foiani, Amanda Heslegrave, Rachelle Shafei, Caroline Greaves, John C. van Swieten, Fermín Moreno, Raquel Sánchez‐Valle, Barbara Borroni, Robert Laforce, Mario Masellis, Maria Carmela Tartaglia, Caroline Graff, Daniela Galimberti, James B. Rowe, Elizabeth Finger, Matthis Synofzik, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Isabel Santana, Simon Ducharme, Christopher Butler, Alexander Gerhard, Johannes Levin, Adrian Danek, Giovanni B. Frisoni, Sandro Sorbi, Markus Otto, Henrik Zetterberg, Sébastien Ourselin, M. Jorge Cardoso, Jonathan D. Rohrer, Martin N. Rossor, Jason D. Warren, Nick C. Fox, Rita Guerreiro, José Brás, David L. Thomas, Jennifer Nicholas, Simon Mead, Lize C. Jiskoot, Lieke Meeter, Jessica Panman, Janne M. Papma, Rick van Minkelen, Yolanda Pijnenburg, Myriam Barandiarán, Begoña Indakoetxea, Alazne Gabilondo, Mikel Tainta, María de Arriba, Ana Gorostidi, Miren Zulaica, Jorge Villanúa, Zigor Díaz, Sergi Borrego‐Écija, Jaume Olives, Albert Lladó, Mircea Balasa, Anna Antonell, Núria Bargalló, Enrico Premi, Maura Cosseddu, Stefano Gazzina, Alessandro Padovani, Roberto Gasparotti, Silvana Archetti, Sandra E. Black, Sara Mitchell, Ekaterina Rogaeva, Morris Freedman, Ron Keren, David F. Tang‐Wai, Linn Öijerstedt, Christin Andersson, Vesna Jelić, Håkan Thonberg, Andrea Arighi, Chiara Fenoglio, Elio Scarpini, Giorgio Fumagalli, Thomas Cope, Carolyn Timberlake, Timothy Rittman, Christen Shoesmith, Robert Bartha, Rosa Rademakers, Carlo Wilke, Hans-Otto Karnarth, Benjamin Bender, Rose Bruffaerts, Philip Van Damme, Mathieu Vandenbulcke, Catarina B. Ferreira, Gabriel Miltenberger, Carolina Maruta, Ana Verdelho, Sónia Afonso, Ricardo Taipa, Paola Caroppo, Giuseppe Di Fede, Giorgio Giaccone, Sara Prioni, Veronica Redaelli, Giacomina Rossi, Pietro Tiraboschi, Diana Duro, Maria Rosário Almeida, Miguel Castelo‐Branco, Maria João Leitão, Miguel Tábuas‐Pereira, Beatriz Santiago, Serge Gauthier, Pedro Rosa‐Neto, Michele Veldsman, Toby Flanagan, Catharina Prix, Tobias Hoegen, Elisabeth Wlasich, Sandra Loosli, Sonja Schönecker, Elisa Semler, Sarah Anderl‐Straub, Luisa Benussi, Giuliano Binetti, Roberta Ghidoni, Michela Pievani, Gemma Lombardi, Benedetta Nacmias, Camilla Ferrari, Valentina Bessi,

Neurogenetic and Muscular Disorders Research

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative disorders with both sporadic and genetic forms. Mutations in the progranulin gene (GRN) are a common cause of genetic FTD, causing either a behavioural presentation or, less commonly, language impairment. Presence on T2-weighted images of white matter hyperintensities (WMH) has been previously shown to be more commonly associated with GRN mutations rather than other forms of FTD. The aim of the current study was to investigate the longitudinal change in WMH and the associations of WMH burden with grey matter (GM) loss, markers of neurodegeneration and cognitive function in GRN mutation carriers. 336 participants in the Genetic FTD Initiative (GENFI) study were included in the analysis: 101 presymptomatic and 32 symptomatic GRN mutation carriers, as well as 203 mutation-negative controls. 39 presymptomatic and 12 symptomatic carriers, and 73 controls also had longitudinal data available. Participants underwent MR imaging acquisition including isotropic 1 mm T1-weighted and T2-weighted sequences. WMH were automatically segmented and locally subdivided to enable a more detailed representation of the pathology distribution. Log-transformed WMH volumes were investigated in terms of their global and regional associations with imaging measures (grey matter volumes), biomarker concentrations (plasma neurofilament light chain, NfL, and glial fibrillary acidic protein, GFAP), genetic status (TMEM106B risk genotype) and cognition (tests of executive function). Analyses revealed that WMH load was higher in both symptomatic and presymptomatic groups compared with controls and this load increased over time. In particular, lesions were seen periventricularly in frontal and occipital lobes, progressing to medial layers over time. However, there was variability in the WMH load across GRN mutation carriers – in the symptomatic group 25.0% had none/mild load, 37.5% had medium and 37.5% had a severe load – a difference not fully explained by disease duration. GM atrophy was strongly associated with WMH load both globally and in separate lobes, and increased WMH burden in the frontal, periventricular and medial regions was associated with worse executive function. Furthermore, plasma NfL and to a lesser extent GFAP concentrations were seen to be associated with increased lesion burden. Lastly, the presence of the homozygous TMEM106B rs1990622 TT risk genotypic status was associated with an increased accrual of WMH per year. In summary, WMH occur in GRN mutation carriers and accumulate over time, but are variable in their severity. They are associated with increased GM atrophy and executive dysfunction. Furthermore, their presence is associated with markers of WM damage (NfL) and astrocytosis (GFAP), whilst their accrual is modified by TMEM106B genetic status. WMH load may represent a target marker for trials of disease modifying therapies in individual patients but the variability across the GRN population would prevent use of such markers as a global outcome measure across all participants in a trial.