Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study.
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Authors
Jiskoot, Lize C
Bocchetta, Martina
Cash, David M
Thomas, David
Modat, Marc
Ourselin, Sebastien
Rombouts, Serge ARB
Dopper, Elise GP
Meeter, Lieke H
Panman, Jessica L
van Minkelen, Rick
van der Ende, Emma L
Donker Kaat, Laura
Pijnenburg, Yolande AL
Borroni, Barbara
Galimberti, Daniela
Masellis, Mario
Tartaglia, Maria Carmela
Rowe, James
Graff, Caroline
Tagliavini, Fabrizio
Frisoni, Giovanni B
Laforce, Robert
Finger, Elizabeth
de Mendonça, Alexandre
Sorbi, Sandro
Genetic Frontotemporal dementia Initiative (GENFI)
Papma, Janne M
van Swieten, John C
Rohrer, Jonathan D
Publication Date
2018-09Journal Title
Ann Clin Transl Neurol
ISSN
2328-9503
Publisher
Wiley
Volume
5
Issue
9
Pages
1025-1036
Language
eng
Type
Article
Physical Medium
Electronic-eCollection
Metadata
Show full item recordCitation
Jiskoot, L. C., Bocchetta, M., Nicholas, J. M., Cash, D. M., Thomas, D., Modat, M., Ourselin, S., et al. (2018). Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study.. Ann Clin Transl Neurol, 5 (9), 1025-1036. https://doi.org/10.1002/acn3.601
Abstract
OBJECTIVE: 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.
Keywords
Genetic Frontotemporal dementia Initiative (GENFI)
Sponsorship
Wellcome Trust (103838/Z/14/Z)
Medical Research Council (MR/J009482/1)
Medical Research Council (MC_U105597119)
Medical Research Council (MC_UU_00005/12)
Identifiers
External DOI: https://doi.org/10.1002/acn3.601
This record's URL: https://www.repository.cam.ac.uk/handle/1810/283447
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