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

Qin Chen, Bradley F Boeve, Nirubol Tosakulwong, Timothy Lesnick, Danielle Brushaber, Christina Dheel, Julie Fields, Leah Forsberg, Ralitza Gavrilova, Debra Gearhart, Dana Haley, Jeffrey L Gunter, Jonathan Graff-Radford, David Jones, David Knopman, Neill Graff-Radford, Ruth Kraft, Maria Lapid, Rosa Rademakers, Zbigniew K Wszolek, Howie Rosen, Adam L Boxer, Kejal Kantarci, Qin Chen, Bradley F Boeve, Nirubol Tosakulwong, Timothy Lesnick, Danielle Brushaber, Christina Dheel, Julie Fields, Leah Forsberg, Ralitza Gavrilova, Debra Gearhart, Dana Haley, Jeffrey L Gunter, Jonathan Graff-Radford, David Jones, David Knopman, Neill Graff-Radford, Ruth Kraft, Maria Lapid, Rosa Rademakers, Zbigniew K Wszolek, Howie Rosen, Adam L Boxer, Kejal Kantarci

Abstract

Background and purpose: The objective of this study was to longitudinally investigate the trajectory of change in 1 H MRS measurements in asymptomatic MAPT mutation carriers who became symptomatic during follow-up, and to determine the time at which the neurochemical alterations accelerated during disease progression.

Methods: We identified eight MAPT mutations carriers who transitioned from asymptomatic to symptomatic disease during follow-up. All participants were longitudinally followed with an average of 7.75 years (range 4-11 years) and underwent two or more single voxel 1 H MRS examinations from the posterior cingulate voxel, with a total of 60 examinations. The rate of longitudinal change for each metabolite was estimated using linear mixed models. A flex point model was used to estimate the flex time point of the change in slope.

Results: The decrease in the NAA/mI ratio accelerated 2.09 years prior to symptom onset, and continued to decline. A similar trajectory was observed in the presumed glial marker mI/Cr ratio accelerating 1.86 years prior to symptom onset.

Conclusions: Our findings support the potential use of longitudinal 1 H MRS for monitoring the neurodegenerative progression in MAPT mutation carriers starting from the asymptomatic stage.

Keywords: MAPT; MRS; converter; frontotemporal lobar degeneration; longitudinal.

© 2019 The Authors. Journal of Neuroimaging published by Wiley Periodicals, Inc. on behalf of American Society of Neuroimaging.

Figures

Figure 1
Figure 1
The flex point model for 1H MRS metabolite ratios. In the x axis, 0 indicates the actual age of symptom onset for converters with MAPT mutation. The metabolite ratios are in the y axis. The black line shows the predicted values calculated from the flex‐point models. NAA/Cr ratios did not have a “flex‐point” during the follow‐up time window (A). The increase of the presumed glial marker mI/Cr accelerated in 1.86 years prior to symptom onset, and continued to increase in time (B). A similar trajectory of decrease was observed the neuronal marker NAA/mI ratio 2.09 years prior to symptom onset (C). NAA = N‐acetylaspartate; Cr = creatine; mI = myo‐inositol.
Figure 2
Figure 2
Voxel location and representative 1H magnetic resonance spectra from a converter with MAPT mutation. Posterior cingulate voxel is placed on a mid‐sagittal 3‐dimensional T1‐weighted image (left). Example of 1H MRS for a converter with MAPT mutation at 2 years before symptom onset (A) and 2 year after symptom onset (B). The spectra are scaled to the creatine (Cr) peak as indicated with the dotted red line. During follow‐up, the myoinositol (mI) peak is elevated from 2 years before symptom onset with mI/Cr ratio of .48 (A) to 2 years after symptom onset with mI/Cr ratio of .57 (B). NAA = N‐acetylaspartate.

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