Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study.

TitlePresymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study.
Publication TypeJournal Article
Year of Publication2018
AuteursJiskoot, LC, Bocchetta, M, Nicholas, JM, Cash, DM, Thomas, D, Modat, M, Ourselin, S, Rombouts, SARB, Dopper, EGP, Meeter, LH, Panman, JL, van Minkelen, R, van der Ende, EL, Kaat, LDonker, Pijnenburg, YAL, Borroni, B, Galimberti, D, Masellis, M, Tartaglia, MCarmela, Rowe, J, Graff, C, Tagliavini, F, Frisoni, GB, Laforce, Jr, R, Finger, E, de Mendonça, A, Sorbi, S, Papma, JM, van Swieten, JC, Rohrer, JD
Corporate AuthorsGenetic Frontotemporal dementia Initiative (GENFI)
JournalAnn Clin Transl Neurol
Volume5
Issue9
Pagination1025-1036
Date Published2018 Sep
ISSN2328-9503
Abstract

Objective: We aimed to investigate mutation-specific white matter (WM) integrity changes in presymptomatic and symptomatic mutation carriers of the ,, and mutations by use of diffusion-weighted imaging within the Genetic Frontotemporal dementia Initiative (GENFI) study.Methods: One hundred and forty mutation carriers (54 , 30 , 56 ), 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 ,, and mutation carriers versus noncarriers. Post hoc analyses were performed on presymptomatic mutation carriers only, as well as left-right asymmetry analyses on mutation carriers versus noncarriers.Results: Diffusion changes in mutation carriers are present significantly earlier than both and 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. 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 . 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 , the uncinate fasciculus in presymptomatic , and the internal capsule (anterior and posterior limbs) in presymptomatic mutation carriers. In , 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.

DOI10.1002/acn3.601
Alternate JournalAnn Clin Transl Neurol
PubMed ID30250860
PubMed Central IDPMC6144447
Grant List / / Wellcome Trust / United Kingdom
MR/M023664/1 / / Medical Research Council / United Kingdom