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

Abstract

ObjectiveWe 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.MethodsOne 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.ResultsDiffusion 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.InterpretationThis 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.

Imaging Biomarkers for Neurodegeneration in Presymptomatic Familial Frontotemporal Lobar Degeneration

“…As indicated in sMRI, left-right asymmetry was also found in most white matter tracts of GRN mutation carriers. The most consistent asymmetry was reported in the uncinate fasciculus, retrolenticular part, and anterior limb of the internal capsule, as well as external capsule (36). However, the development of asymmetry over time may have different patterns in various white matter tracts.…”

“…White matter involvement from DTI studies in asymptomatic GRN mutation carriers showed reduced FA in the left uncinate fasciculus, left inferior occipitofrontal fasciculus, and the genu of the corpus callosum (55). Reduced FA and increased diffusivity in the internal capsule was also reported (36). Another DTI investigation did not find a difference in FA, MD, and RD, but reported increased AD in the right cingulum, superior longitudinal fasciculus, and corticospinal tract (25).…”

“…In asymptomatic MAPT mutation carriers, reduced FA and increased diffusivity were reported in bilateral uncinate fasciculus and cingulum in cross-sectional studies (7,36), while a longitudinal study only found increased MD in entorhinal white matter with accelerated increase in MD during followup (38). Furthermore, in a longitudinal study, lower FA in uncinate fasciculus and other white matter tracts were reported in MAPT and GRN mutations 2 years before symptom onset, while no difference in FA was found between the combined group of asymptomatic MAPT and GRN mutation carriers who remained asymptomatic and non-carriers (21).…”

“…Compared to FA, the diffusivity parameters such as MD appear to be more sensitive measures of the white matter integrity alterations in asymptomatic familial FTLD (36,38). One possible explanation is that FA is more influenced by the crossing fibers, which may limit its sensitivity to detect subtle white matter changes (74).…”

Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers

“…Our findings are consistent with the trajectories reported in a recent longitudinal study of converters with MAPT and GRN mutations, demonstrating that loss of white matter integrity and grey matter volume were present 2 years before symptom onset. 11 In addition, previous cross-sectional studies in asymptomatic MAPT mutation carriers report presence of 1 H MRS metabolite ratio abnormalities, 3 grey matter atrophy, 12 loss of white matter integrity, 13 and functional connectivity 14 with range of 5 to 30 years before the estimated age of symptom onset. It should be noted that the cross-sectional studies estimated the age of onset by the information available from the carriers of the MAPT mutation type.…”