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Title: White matter hyperintensities in progranulin-associated frontotemporal dementia: A longitudinal GENFI study
Authors: Sudre, Carole H.
Bocchetta, Martina
Heller, Carolin
Convery, Rhian
Neason, Mollie
Moore, Katrina M.
Cash, David M.
Thomas, David L.
Woollacott, Ione O. C.
Foiani, Martha
Heslegrave, Amanda
Shafei, Rachelle
Greaves, Caroline
van Swieten, John
Moreno, Fermin
Sánchez-Valle, Raquel 
Borroni, Barbara
Laforce, Robert
Masellis, Mario
Tartaglia, Maria Carmela
Graff, Caroline
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
Frisoni, Giovanni B
Sorbi, Sandro
Otto, Markus
Zetterberg, Henrik
Ourselin, Sebastien
Cardoso, M Jorge
Rohrer, Jonathan D. 
Keywords: Frontotemporal dementia; White matter hyperintensities; Dementia; Progranulin
Issue Date: 2019
Publisher: Elsevier
Project: info:eu-repo/grantAgreement/EC/FP7/601055/EU/VPH Dementia Research Enabled by IT 
Serial title, monograph or event: NeuroImage: Clinical
Volume: 24
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.
ISSN: 22131582
DOI: 10.1016/j.nicl.2019.102077
Rights: openAccess
Appears in Collections:FMUC Medicina - Artigos em Revistas Internacionais
I&D CNC - Artigos em Revistas Internacionais

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