Longitudinal Effects of Everolimus on White Matter Diffusion in Tuberous Sclerosis Complex

Abstract

Objective: We studied the longitudinal effects of everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), on callosal white matter diffusion tensor imaging (DTI) in patients with tuberous sclerosis complex (TSC).

Methods: Serial imaging data spanning nine years were used from the open label, Phase I/II trial (NCT00411619) and open-ended extension phase of everolimus for the treatment of subependymal giant cell astrocytoma associated with TSC. From 28 patients treated with everolimus and 25 untreated control patients, 481 MRI scans were available. Rigorous quality control resulted in omission of all scans with diffusion weighted imaging data in less than 15 directions or more than eight artifacted volumes, and all postsurgical scans. We applied a linear mixed-effects model to the remaining 125 scans (17 treated, 24 controls) for longitudinal analysis of each DTI metric of manually drawn callosal regions of interest.

Results: On a population level, mTOR inhibition was associated with a decrease in mean diffusivity. In addition, in treated patients only, a decrease of radial diffusivity was observed; in untreated patients only, an increase of axial diffusivity was seen. In patients below age 10, effect-sizes were consistently greater, and longer treatment was associated with greater rate of diffusion change. There was no correlation between DTI metrics and reduction of subependymal giant cell astrocytoma volume, or everolimus serum levels.

Conclusions: Effects from mTOR overactivity on white matter microstructural integrity in TSC were modified through pharmacologic inhibition of mTOR. These changes sustained over time, were greater with longer treatment and in younger patients during a time of rapid white matter maturation.

Keywords: Children; Diffusion tensor imaging; Mechanistic target of rapamycin; Tuberous sclerosis complex; mTOR.

Copyright © 2018 Elsevier Inc. All rights reserved.

Figures

Figure 1.. MRI quality assurance and data selection process.

Of the 481 scans available for all patients, 125 of 17 patients treated with everolimus and 24 intreated controls with TSC were included in data analysis after rigorous quality assurance. Scans with only some artifacted volumes could often be salvaged through reconstruction of the tensor data after omitting bad volumes. DWI diffusion-weighted imaging; mTOR mechanistic target of rapamycin

Figure 2.. Longitudinal diffusion changes, treated (mTOR) vs. untreated, ≤ 10 years.

Diffusion changes over time in treated group (mTOR, red) and untreated group (controls, blue). Orange and blue shaded areas indicate confidence intervals. On the y-axis, the four different DTI metrics. Note that for the analysis, FA was multiplied by a scale factor of 10, and DTI MD, RD, and AD were multiplied scaled by a scale factor of 1,000. On the x-axis, age is expressed a ratio: For example, if the subject is 2 years at time-point 1.0, the patient will be 5 years old at time-point 2.5. FA fractional anisotropy; MD mean diffusivity; RD radial diffusivity; AD axial diffusivity