1. White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study
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Rachelle Shafei, Albert Lladó, Benjamin Bender, Luisa Benussi, Elisabeth Wlasich, Martha S. Foiani, Isabel Santana, Christen Shoesmith, Ione O.C. Woollacott, Nick C. Fox, David L. Thomas, Jonathan D. Rohrer, Pietro Tiraboschi, Mario Masellis, Sergi Borrego-Écija, Giorgio G. Fumagalli, Ron Keren, Sandro Sorbi, Rick van Minkelen, Vesna Jelic, Ekaterina Rogaeva, Mollie Neason, Enrico Premi, Timothy Rittman, Lieke H.H. Meeter, Giacomina Rossi, Veronica Redaelli, Roberta Ghidoni, Begoña Indakoetxea, Johannes Levin, Håkan Thonberg, Rhian S Convery, Henrik Zetterberg, Gemma Lombardi, Giuseppe Di Fede, Chiara Fenoglio, Jose Bras, Daniela Galimberti, Simon Mead, Miren Zulaica, David M. Cash, Gabriel Miltenberger, Markus Otto, Simon Ducharme, Myriam Barandiaran, Katrina M. Moore, Alessandro Padovani, Thomas E. Cope, Elizabeth Finger, Maria Carmela Tartaglia, Martin N. Rossor, M. Jorge Cardoso, Sara Mitchell, Rik Vandenberghe, Pedro Rosa-Neto, John C. van Swieten, Sarah Anderl-Straub, Maria Rosário Almeida, Zigor Diaz, Robart Bartha, Maria de Arriba, Caroline V. Greaves, Philip Vandamme, Giorgio Giaccone, Adrian Danek, Miguel Tábuas-Pereira, Carolina Maruta, Roberto Gasparotti, Jennifer M. Nicholas, Martina Bocchetta, Elisa Semler, Valentina Bessi, C. Ferreira, Robert Laforce, Sandra V. Loosli, Ana Verdelho, Paola Caroppo, Jaume Olives, Giuliano Binetti, Carolin Heller, Jorge Villanua, Stefano Gazzina, Amanda Heslegrave, Alazne Gabilondo, Sandra E. Black, Y.A.L. Pijnenburg, Mikel Tainta, Carolyn Timberlake, Sónia Afonso, Matthis Synofzik, Janne M. Papma, Sebastien Ourselin, Núria Bargalló, Barbara Borroni, Ricardo Taipa, Hans-Otto Karnarth, Camilla Ferrari, David F. Tang-Wai, Diana Duro, Catharina Prix, Serge Gauthier, Sara Prioni, Carlo Wilke, Michele Veldsman, Alexandre de Mendonça, Andrea Arighi, Christopher C Butler, Raquel Sánchez-Valle, Toby Flanagan, Carole H. Sudre, Jason D. Warren, Rita Guerreiro, Linn Öijerstedt, Beatriz Santiago, Rosa Rademakers, Miguel Castelo-Branco, Fabrizio Tagliavini, Maria João Leitão, Anna Antonell, Mathieu Vandenbulcke, Rose Bruffaerts, Jessica L. Panman, Alexander Gerhard, Tobias Hoegen, Ana Gorostidi, Silvana Archetti, James B. Rowe, Michela Pievani, Elio Scarpini, Giovanni B. Frisoni, Benedetta Nacmias, Sonja Schönecker, Maura Cosseddu, Christin Andersson, Caroline Graff, Morris Freedman, Fermin Moreno, Mircea Balasa, Lize C. Jiskoot, Sudre, Carole H [0000-0001-5753-428X], Apollo - University of Cambridge Repository, Rowe, James [0000-0001-7216-8679], and Neurology
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Oncology ,Male ,SEGMENTATION ,PROTEIN ,physiopathology [Frontotemporal Dementia] ,DISEASE ,0302 clinical medicine ,White matter hyperintensities ,blood [Glial Fibrillary Acidic Protein] ,Longitudinal Studies ,education.field_of_study ,Regular Article ,Neurology ,Frontotemporal Dementia ,Disease Progression ,GRN ,medicine.medical_specialty ,lcsh:Computer applications to medicine. Medical informatics ,MRI, Magnetic Resonance Imaging ,White matter ,03 medical and health sciences ,AGE ,Humans ,neurofilament protein L ,education ,Aged ,CSF, Cerebrospinal fluid ,Science & Technology ,Trail Making Test ,Frontotemporal dementia ,Dementia ,Progranulin ,medicine.disease ,POLYMORPHISM ,Case-Control Studies ,Asymptomatic Diseases ,Mutation ,Neurosciences & Neurology ,Neurology (clinical) ,GENFI ,030217 neurology & neurosurgery ,Executive dysfunction ,blood [Frontotemporal Dementia] ,GFAP, Glial Fibrillary Acidic Protein ,blood [Neurofilament Proteins] ,lcsh:RC346-429 ,genetics [Progranulins] ,Executive Function ,Progranulins ,pathology [Gray Matter] ,Neurofilament Proteins ,BRAIN ATROPHY ,GM, Grey Matter ,Gray Matter ,genetics [Frontotemporal Dementia] ,genetics [Nerve Tissue Proteins] ,05 social sciences ,Organ Size ,Middle Aged ,Magnetic Resonance Imaging ,White Matter ,genetics [Membrane Proteins] ,medicine.anatomical_structure ,FTD, Frontotemporal dementia ,GENFI, GENetic Frontotemporal dementia Initiative ,lcsh:R858-859.7 ,Female ,Life Sciences & Biomedicine ,Adult ,Heterozygote ,Cognitive Neuroscience ,Population ,Prodromal Symptoms ,Neuroimaging ,PHENOTYPES ,Nerve Tissue Proteins ,MUTATION CARRIERS ,WM, White Matter ,Grey matter ,diagnostic imaging [Frontotemporal Dementia] ,050105 experimental psychology ,diagnostic imaging [White Matter] ,Atrophy ,TMEM106B protein, human ,Internal medicine ,mental disorders ,Glial Fibrillary Acidic Protein ,medicine ,0501 psychology and cognitive sciences ,Radiology, Nuclear Medicine and imaging ,ddc:610 ,lcsh:Neurology. Diseases of the nervous system ,business.industry ,GFAP protein, human ,WMH, White Matter Hyperintensity ,diagnostic imaging [Gray Matter] ,Membrane Proteins ,Hyperintensity ,GRN, Progranulin ,TMEM106B ,ddc:618.97 ,GRN protein, human ,business - Abstract
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. ispartof: NEUROIMAGE-CLINICAL vol:24 ispartof: location:Netherlands status: published
- Published
- 2019
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