PMID- 30424962 OWN - NLM STAT- MEDLINE DCOM- 20200225 LR - 20210930 IS - 1873-5150 (Electronic) IS - 0887-8994 (Print) IS - 0887-8994 (Linking) VI - 90 DP - 2019 Jan TI - Longitudinal Effects of Everolimus on White Matter Diffusion in Tuberous Sclerosis Complex. PG - 24-30 LID - S0887-8994(18)30926-3 [pii] LID - 10.1016/j.pediatrneurol.2018.10.005 [doi] AB - 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. CI - Copyright (c) 2018 Elsevier Inc. All rights reserved. FAU - Peters, Jurriaan M AU - Peters JM AD - 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. Electronic address: jurriaan.peters@childrens.harvard.edu. FAU - Prohl, Anna AU - Prohl A AD - Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. FAU - Kapur, Kush AU - Kapur K AD - Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. FAU - Nath, Audrey AU - Nath A AD - Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. FAU - Scherrer, Benoit AU - Scherrer B AD - Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. FAU - Clancy, Sean AU - Clancy S AD - Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. FAU - Prabhu, Sanjay P AU - Prabhu SP AD - Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. FAU - Sahin, Mustafa AU - Sahin M AD - Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. FAU - Franz, David Neal AU - Franz DN AD - Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. FAU - Warfield, Simon K AU - Warfield SK AD - Computational Radiology Laboratory, Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. FAU - Krueger, Darcy A AU - Krueger DA AD - Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. LA - eng SI - ClinicalTrials.gov/NCT00411619 GR - U01 NS092595/NS/NINDS NIH HHS/United States GR - U54 NS092090/NS/NINDS NIH HHS/United States GR - U01 NS082320/NS/NINDS NIH HHS/United States GR - UL1 TR000170/TR/NCATS NIH HHS/United States GR - U54 HD090255/HD/NICHD NIH HHS/United States GR - R01 NS079788/NS/NINDS NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20181018 PL - United States TA - Pediatr Neurol JT - Pediatric neurology JID - 8508183 RN - 0 (Antineoplastic Agents) RN - 9HW64Q8G6G (Everolimus) SB - IM MH - Adolescent MH - Antineoplastic Agents/*pharmacology/therapeutic use MH - Astrocytoma/diagnostic imaging/*drug therapy MH - Brain Neoplasms/diagnostic imaging/*drug therapy MH - Child MH - Child, Preschool MH - Diffusion Tensor Imaging MH - Everolimus/*pharmacology/therapeutic use MH - Female MH - Humans MH - Longitudinal Studies MH - Male MH - Neuroimaging MH - Treatment Outcome MH - Tuberous Sclerosis/diagnostic imaging/*drug therapy MH - White Matter/diagnostic imaging/*drug effects MH - Young Adult PMC - PMC6314307 MID - NIHMS1512238 OTO - NOTNLM OT - Children OT - Diffusion tensor imaging OT - Mechanistic target of rapamycin OT - Tuberous sclerosis complex OT - mTOR EDAT- 2018/11/15 06:00 MHDA- 2020/02/26 06:00 PMCR- 2020/01/01 CRDT- 2018/11/15 06:00 PHST- 2018/09/10 00:00 [received] PHST- 2018/10/10 00:00 [revised] PHST- 2018/10/14 00:00 [accepted] PHST- 2018/11/15 06:00 [pubmed] PHST- 2020/02/26 06:00 [medline] PHST- 2018/11/15 06:00 [entrez] PHST- 2020/01/01 00:00 [pmc-release] AID - S0887-8994(18)30926-3 [pii] AID - 10.1016/j.pediatrneurol.2018.10.005 [doi] PST - ppublish SO - Pediatr Neurol. 2019 Jan;90:24-30. doi: 10.1016/j.pediatrneurol.2018.10.005. Epub 2018 Oct 18.