Tracking white matter degeneration in asymptomatic and symptomatic MAPT mutation carriers

Abstract

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

Keywords: Asymptomatic; Diffusion tensor image; Frontotemporal dementia; Longitudinal; MAPT.

Conflict of interest statement

Disclosure

The authors have no actual or potential conflicts of interest.

Copyright © 2019 Elsevier Inc. All rights reserved.

Figures

Fig. 1.

Region of interest analysis. WM regions of interest with increased MD in asymptomatic and symptomatic MAPT mutation carriers compared with noncarriers are displayed on a rendered transparent brain from a single participant (colored in red). WM regions of interest with reduced FA in symptomatic MAPT mutation carriers compared with noncarriers are colored in green. MD and FA values from regions of interest that distinguished the MAPT mutation carriers from noncarriers with an area under the receiver operating characteristic curve (AUROC) of p < 0.05 after adjusting for age and correcting for multiple comparisons. Abbreviations: FA, fractional anisotropy; MAPT, microtubule-associated protein tau; MD, mean diffusivity; WM, white matter. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2.

Plots of age-adjusted FA and MD from entorhinal WM and the estimated or actual proximity to symptom onset. In the horizontal axis, 0 indicates the estimated age of symptom onset for asymptomatic MAPT mutation carriers based on the median age at the symptom onset in symptomatic MAPT mutation carriers from the same family. 0 indicates the age at actual symptom onset in symptomatic MAPT mutation carriers. Abbreviations: FA, fractional anisotropy; MD, mean diffusivity; MAPT, microtubule-associated protein tau; WM, white matter.

Fig. 3.

FA and MD values plotted against age at MRI. Data points for individual participants are shown in the top panel with asymptomatic (blue line) and symptomatic (red line) MAPT mutation carriers. The dash line in lower panel represents the average FA and MD value for all MAPT mutation carriers, the solid line shows the average FA and MD value for noncarriers. Abbreviations: FA, fractional anisotropy; MAPT, microtubule-associated protein tau; MD, mean diffusivity. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)