Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts; Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Pediatr Neurol. 2019 Jan;90:24-30. doi: 10.1016/j.pediatrneurol.2018.10.005. Epub 2018 Oct 18.
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).
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.
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.
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.
我们研究了哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂依维莫司对结节性硬化症（TSC）患者胼胝体弥散张量成像（DTI）的纵向影响。
来自依维莫司治疗室管膜下巨细胞星形细胞瘤的开放标签、I/II 期试验（NCT00411619）和开放性扩展阶段的 28 例依维莫司治疗患者和 25 例未治疗对照患者的 9 年系列影像学数据，共 481 次 MRI 扫描。严格的质量控制导致所有弥散加权成像数据少于 15 个方向或 8 个以上伪影体积的扫描以及所有手术后的扫描均被排除。我们对其余 125 次扫描（17 次治疗，24 次对照）应用线性混合效应模型进行纵向分析，以评估手动绘制胼胝体感兴趣区的每个 DTI 指标。
在人群水平上，mTOR 抑制与平均弥散度降低相关。此外，仅在治疗组患者中观察到径向弥散度降低，而在未治疗组患者中仅观察到轴向弥散度增加。在年龄小于 10 岁的患者中，效应大小始终更大，且更长的治疗时间与更大的弥散变化率相关。DTI 指标与室管膜下巨细胞星形细胞瘤体积减少或依维莫司血清水平之间无相关性。
通过 mTOR 的药理抑制，改变了 TSC 中白质微观结构完整性的 mTOR 过度活跃的影响。这些变化随时间持续存在，在快速白质成熟期间，治疗时间更长且患者年龄更小，变化更大。
