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dc.contributor.authorJiskoot, Lize C
dc.contributor.authorBocchetta, Martina
dc.contributor.authorNicholas, Jennifer M
dc.contributor.authorCash, David M
dc.contributor.authorThomas, David
dc.contributor.authorModat, Marc
dc.contributor.authorOurselin, Sebastien
dc.contributor.authorRombouts, Serge ARB
dc.contributor.authorDopper, Elise GP
dc.contributor.authorMeeter, Lieke H
dc.contributor.authorPanman, Jessica L
dc.contributor.authorvan Minkelen, Rick
dc.contributor.authorvan der Ende, Emma L
dc.contributor.authorDonker Kaat, Laura
dc.contributor.authorPijnenburg, Yolande AL
dc.contributor.authorBorroni, Barbara
dc.contributor.authorGalimberti, Daniela
dc.contributor.authorMasellis, Mario
dc.contributor.authorTartaglia, Maria Carmela
dc.contributor.authorRowe, James
dc.contributor.authorGraff, Caroline
dc.contributor.authorTagliavini, Fabrizio
dc.contributor.authorFrisoni, Giovanni B
dc.contributor.authorLaforce, Robert
dc.contributor.authorFinger, Elizabeth
dc.contributor.authorde Mendonça, Alexandre
dc.contributor.authorSorbi, Sandro
dc.contributor.authorGenetic Frontotemporal dementia Initiative (GENFI)
dc.contributor.authorPapma, Janne M
dc.contributor.authorvan Swieten, John C
dc.contributor.authorRohrer, Jonathan D
dc.date.accessioned2018-10-10T05:19:25Z
dc.date.available2018-10-10T05:19:25Z
dc.date.issued2018-09
dc.identifier.issn2328-9503
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283447
dc.description.abstractObjective: We aimed to investigate mutation-specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the C9orf72,MAPT, and GRN mutations by use of diffusion-weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study. Methods: One hundred and forty mutation carriers (54 C9orf72, 30 MAPT, 56 GRN), 104 presymptomatic and 36 symptomatic, and 115 noncarriers underwent 3T diffusion tensor imaging. Linear mixed effects models were used to examine the association between diffusion parameters and years from estimated symptom onset in C9orf72,MAPT, and GRN mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left-right asymmetry analyses on GRN mutation carriers versus noncarriers. Results: Diffusion changes in C9orf72 mutation carriers are present significantly earlier than both MAPT and GRN mutation carriers - characteristically in the posterior thalamic radiation and more posteriorly located tracts (e.g., splenium of the corpus callosum, posterior corona radiata), as early as 30 years before estimated symptom onset. MAPT mutation carriers showed early involvement of the uncinate fasciculus and cingulum, sparing the internal capsule, whereas involvement of the anterior and posterior internal capsule was found in GRN. Restricting analyses to presymptomatic mutation carriers only, similar - albeit less extensive - patterns were found: posteriorly located WM tracts (e.g., posterior thalamic radiation, splenium of the corpus callosum, posterior corona radiata) in presymptomatic C9orf72, the uncinate fasciculus in presymptomatic MAPT, and the internal capsule (anterior and posterior limbs) in presymptomatic GRN mutation carriers. In GRN, most tracts showed significant left-right differences in one or more diffusion parameter, with the most consistent results being found in the UF, EC, RPIC, and ALIC. Interpretation: This study demonstrates the presence of early and widespread WM integrity loss in presymptomatic FTD, and suggests a clear genotypic "fingerprint." Our findings corroborate the notion of FTD as a network-based disease, where changes in connectivity are some of the earliest detectable features, and identify diffusion tensor imaging as a potential neuroimaging biomarker for disease-tracking and -staging in presymptomatic to early-stage familial FTD.
dc.format.mediumElectronic-eCollection
dc.languageeng
dc.publisherWiley
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectGenetic Frontotemporal dementia Initiative (GENFI)
dc.titlePresymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study.
dc.typeArticle
prism.endingPage1036
prism.issueIdentifier9
prism.publicationDate2018
prism.publicationNameAnn Clin Transl Neurol
prism.startingPage1025
prism.volume5
dc.identifier.doi10.17863/CAM.30814
dc.identifier.doi10.17863/CAM.30814
dcterms.dateAccepted2018-06-08
rioxxterms.versionofrecord10.1002/acn3.601
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-09
dc.contributor.orcidNicholas, Jennifer M [0000-0001-6023-0391]
dc.contributor.orcidRowe, James [0000-0001-7216-8679]
dc.identifier.eissn2328-9503
rioxxterms.typeJournal Article/Review
pubs.funder-project-idWellcome Trust (103838/Z/14/Z)
pubs.funder-project-idMedical Research Council (MR/J009482/1)
pubs.funder-project-idMedical Research Council (MC_U105597119)
pubs.funder-project-idMedical Research Council (MC_UU_00005/12)
cam.issuedOnline2018-07-11


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International