White matter hyperintensities are seen only in GRN mutation carriers in the GENFI cohort

• Published in: NeuroImage clinical Vol. 15; pp. 171 - 180
• Main Authors: Sudre, Carole H., Bocchetta, Martina, Cash, David, Thomas, David L., Woollacott, Ione, Dick, Katrina M., van Swieten, John, Borroni, Barbara, Galimberti, Daniela, Masellis, Mario, Tartaglia, Maria Carmela, Rowe, James B., Graff, Caroline, Tagliavini, Fabrizio, Frisoni, Giovanni, Laforce, Robert, Finger, Elizabeth, de Mendonça, Alexandre, Sorbi, Sandro, Ourselin, Sébastien, Cardoso, M. Jorge, Rohrer, Jonathan D., Andersson, Christin, Archetti, Silvana, Arighi, Andrea, Benussi, Luisa, Binetti, Giuliano, Black, Sandra, Cosseddu, Maura, Fallström, Marie, Ferreira, Carlos, Fenoglio, Chiara, Fox, Nick C., Freedman, Morris, Fumagalli, Giorgio, Gazzina, Stefano, Ghidoni, Roberta, Grisoli, Marina, Jelic, Vesna, Jiskoot, Lize, Keren, Ron, Lombardi, Gemma, Maruta, Carolina, Mead, Simon, Meeter, Lieke, van Minkelen, Rick, Nacmias, Benedetta, Öijerstedt, Linn, Padovani, Alessandro, Panman, Jessica, Pievani, Michela, Polito, Cristina, Premi, Enrico, Prioni, Sara, Rademakers, Rosa, Redaelli, Veronica, Rogaeva, Ekaterina, Rossi, Giacomina, Rossor, Martin N., Scarpini, Elio, Tang-Wai, David, Thonberg, Hakan, Tiraboschi, Pietro, Verdelho, Ana, Warren, Jason D.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier 01-01-2017
• Subjects: Adult; Aged; C9orf72 Protein - genetics; Cohort Studies; Confidence interval; Female; Frontotemporal dementia; Frontotemporal Dementia - diagnostic imaging; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; FTD; Humans; Inter Quartile Range; Intercellular Signaling Peptides and Proteins - genetics; IQR; Magnetic Resonance Imaging; Male; Medicin och hälsovetenskap; Medicinsk genetik; Medicinska och farmaceutiska grundvetenskaper; Middle Aged; Neurovetenskaper; Presymptomatic; Progranulins; Regular; Symptomatic; tau Proteins - genetics; TIV; Total Intracranial volume; White Matter - diagnostic imaging; White Matter - pathology; White matter hyperintensity; WMH; PS, Presymptomatic; CI, Confidence interval; TIV, Total Intracranial volume; FTD, Frontotemporal dementia; IQR, Inter Quartile Range; WMH, White matter hyperintensity; S, Symptomatic
• ISSN: 2213-1582; 2213-1582
• DOI: 10.1016/j.nicl.2017.04.015

© 2017 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/BY/4.0/).
Genetic frontotemporal dementia is most commonly caused by mutations in the progranulin (GRN), microtubule-associated protein tau (MAPT) and chromosome 9 open reading frame 72 (C9orf72) genes. Previous small studies have reported the presence of cerebral white matter hyperintensities (WMH) in genetic FTD but this has not been systematically studied across the different mutations. In this study WMH were assessed in 180 participants from the Genetic FTD Initiative (GENFI) with 3D T1- and T2-weighed magnetic resonance images: 43 symptomatic (7 GRN, 13 MAPT and 23 C9orf72), 61 presymptomatic mutation carriers (25 GRN, 8 MAPT and 28 C9orf72) and 76 mutation negative non-carrier family members. An automatic detection and quantification algorithm was developed for determining load, location and appearance of WMH. Significant differences were seen only in the symptomatic GRN group compared with the other groups with no differences in the MAPT or C9orf72 groups: increased global load of WMH was seen, with WMH located in the frontal and occipital lobes more so than the parietal lobes, and nearer to the ventricles rather than juxtacortical. Although no differences were seen in the presymptomatic group as a whole, in the GRN cohort only there was an association of increased WMH volume with expected years from symptom onset. The appearance of the WMH was also different in the GRN group compared with the other groups, with the lesions in the GRN group being more similar to each other. The presence of WMH in those with progranulin deficiency may be related to the known role of progranulin in neuroinflammation, although other roles are also proposed including an effect on blood-brain barrier permeability and the cerebral vasculature. Future studies will be useful to investigate the longitudinal evolution of WMH and their potential use as a biomarker as well as post-mortem studies investigating the histopathological nature of the lesions.
This work was funded by the UK Medical Research Council, the Italian Ministry of Health, and the Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grant (CoEN015). The Dementia Research Centre is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit and the NIHR UCL/H Biomedical Research Centre. JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). KD is supported by an Alzheimer's Society PhD Studentship (AS-PhD-2015-005). JBR is supported by the Wellcome Trust (103838) and the NIHR Cambridge Biomedical Research Centre. MM is supported by the Canadian Institutes of Health Research and the Ontario Research Fund. RL is supported by Réseau de médecine génétique appliquée, Fonds de recherche du Québec—Santé (FRQS). FT is supported by the Italian Ministry of Health. DG is supported by the Fondazione Monzino and Italian Ministry of Health, Ricerca Corrente. SS is supported by Cassa di Risparmio di Firenze (CRF 2013/0199) and the Ministry of Health RF-2010-2319722. SO is supported by the Engineering and Physical Sciences Research Council (EP/H046410/1, EP/J020990/1, EP/K005278), the Medical Research Council (MR/J01107X/1), the EU-FP7 project VPH-DARE@IT (FP7-ICT-2011-9-601055), and the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative BW.mn.BRC10269). JvS is supported by The Netherlands Organisation for Health Research and Development Memorable grant (733050103) and Netherlands Alzheimer Foundation Memorable grant (733050103).