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

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.

Figure 1

Overview of participant in‐ and exclusion. A total of 365 subjects were eligible for study participation. Six subjects did not undergo MRI scanning, and were therefore excluded. Only 3T scans were considered; therefore, 1.5T (n = 34) scans were first excluded from further analysis. Visual quality control of the images resulted in exclusion of another 54 images, leading to a final dataset of 255 subjects (115 noncarriers (“nc”), 104 presymptomatic mutation carriers, 36 symptomatic carriers.

Figure 2

Gene‐specific differences in WM integrity between mutation carriers and noncarriers between minus 30 years before estimated onset until 10 years postestimated onset. Schematic overview of mean diffusion differences between noncarriers and C9orf72 (A), MAPT (B) and GRN mutation carriers (C) between minus 30 years before estimated symptom onset and plus 10 years after estimated onset (x‐axis), each row represents a different WM tract (y‐axis). Blue = where the difference between mutation carriers and noncarriers is negative; green = where the difference between mutation carriers and noncarriers is positive. NB: for FA, blue represents lower FA (=lower WM integrity) in mutation carriers than in noncarriers; for MD, RD, and AxD, green represents higher parameters (=lower WM integrity) in mutation carriers than in noncarriers. UF, uncinate fasciculus; SLF, superior longitudinal fasciculus; Sag.Stra., sagittal stratum; PTR, posterior thalamic radiation; PCR, posterior corona radiata; SCR, superior corona radiata; ACR, anterior corona radiata; EC, external capsule; RPIC, retrolenticular part of the internal capsule; PLIC, posterior limb of the internal capsule; ALIC, anterior limb of the internal capsule; sCC, splenium of the corpus callosum; bCC, body of the corpus callosum; gCC, genu of the corpus callosum.