eprintid: 10053325 rev_number: 31 eprint_status: archive userid: 608 dir: disk0/10/05/33/25 datestamp: 2018-11-16 12:32:51 lastmod: 2021-09-25 23:18:13 status_changed: 2018-11-16 12:32:51 type: article metadata_visibility: show creators_name: Jiskoot, LC creators_name: Bocchetta, M creators_name: Nicholas, JM creators_name: Cash, DM creators_name: Thomas, D creators_name: Modat, M creators_name: Ourselin, S creators_name: Rombouts, SARB creators_name: Dopper, EGP creators_name: Meeter, LH creators_name: Panman, JL creators_name: van Minkelen, R creators_name: van der Ende, EL creators_name: Kaat, LD creators_name: Pijnenburg, YAL creators_name: Borroni, B creators_name: Galimberti, D creators_name: Masellis, M creators_name: Tartaglia, MC creators_name: Rowe, J creators_name: Graff, C creators_name: Tagliavini, F creators_name: Frisoni, GB creators_name: Laforce, R creators_name: Finger, E creators_name: de Mendonca, A creators_name: Sorbi, S creators_name: Papma, JM creators_name: van Swieten, JC creators_name: Rohrer, JD title: Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study ispublished: pub subjects: UCH divisions: UCL divisions: B02 divisions: C07 divisions: DF9 divisions: FA5 divisions: D07 divisions: F82 divisions: F85 divisions: F86 note: © 2018 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 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. date: 2018-09 publisher: WILEY official_url: https://doi.org/10.1002/acn3.601 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green article_type_text: Article verified: verified_manual elements_id: 1571192 doi: 10.1002/acn3.601 lyricists_name: Bocchetta, Martina lyricists_name: Cash, David lyricists_name: Mead, Simon lyricists_name: Nicholas, Jennifer lyricists_name: Rohrer, Jonathan lyricists_name: Rossor, Martin lyricists_name: Thomas, David lyricists_id: MBOCC01 lyricists_id: DMCAS28 lyricists_id: SMEAD68 lyricists_id: JNICH85 lyricists_id: JDROH34 lyricists_id: MNROS52 lyricists_id: DTHOM65 actors_name: Bocchetta, Martina actors_id: MBOCC01 actors_role: owner full_text_status: public publication: Annals of Clinical and Translational Neurology volume: 5 number: 9 pagerange: 1025-1036 pages: 12 issn: 2328-9503 citation: Jiskoot, LC; Bocchetta, M; Nicholas, JM; Cash, DM; Thomas, D; Modat, M; Ourselin, S; ... Rohrer, JD; + view all <#> Jiskoot, 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, LD; Pijnenburg, YAL; Borroni, B; Galimberti, D; Masellis, M; Tartaglia, MC; Rowe, J; Graff, C; Tagliavini, F; Frisoni, GB; Laforce, R; Finger, E; de Mendonca, A; Sorbi, S; Papma, JM; van Swieten, JC; Rohrer, JD; - view fewer <#> (2018) Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study. Annals of Clinical and Translational Neurology , 5 (9) pp. 1025-1036. 10.1002/acn3.601 <https://doi.org/10.1002/acn3.601>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10053325/1/Jiskoot%2CAnnalsClinicalTransNeurol2018.pdf