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Preparation, preliminary pharmacokinetic and brain targeting study of metformin encapsulated W/O/W composite submicron emulsions promoted by borneol.
Hong L, Li X, Bao Y, Duvall CL, Zhang C, Chen W, Peng C
(2019) Eur J Pharm Sci 133: 160-166
MeSH Terms: Animals, Bornanes, Brain, Drug Compounding, Drug Delivery Systems, Drug Liberation, Emulsions, Female, Hypoglycemic Agents, Male, Metformin, Rats, Sprague-Dawley
Show Abstract · Added April 10, 2019
Metformin hydrochloride (Met) is the first-line drug to treat type 2 diabetes and has shown high efficiency in reducing Alzheimer's disease in recent studies. Herein, a borneol W/O/W composite submicron emulsion containing Met (B-Met-W/O/W SE) was prepared, expecting longer in-vivo circulation time, better bioavailability and brain targeting of Met drug. In the optimized formulation, the mean droplets size, polydispersity index and encapsulation efficiency of the composite were 386.5 nm, 0.219 and 87.26%, respectively. FTIR analysis confirmed that Met interacted with carriers in B-Met-W/O/W SE. Compared with Met free drug, in-vitro release of Met in B-Met-W/O/W SE delivery system was much slower. In pharmacokinetic studies in rats, the AUC, MRT and t of the B-Met-W/O/W SE system were respectively 1.27, 2.49 and 4.02-fold higher than Met free drug system. The drug-targeting index of B-Met-W/O/W SE system to the brain tissue was also higher than that of Met free drug system and Met-W/O/W SE system. These results indicated that B-Met-W/O/W SE drug delivery system is a promising candidate in treating clinical Alzheimer's disease.
Copyright © 2019 Elsevier B.V. All rights reserved.
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12 MeSH Terms
Gene expression imputation across multiple brain regions provides insights into schizophrenia risk.
Huckins LM, Dobbyn A, Ruderfer DM, Hoffman G, Wang W, Pardiñas AF, Rajagopal VM, Als TD, T Nguyen H, Girdhar K, Boocock J, Roussos P, Fromer M, Kramer R, Domenici E, Gamazon ER, Purcell S, CommonMind Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, iPSYCH-GEMS Schizophrenia Working Group, Demontis D, Børglum AD, Walters JTR, O'Donovan MC, Sullivan P, Owen MJ, Devlin B, Sieberts SK, Cox NJ, Im HK, Sklar P, Stahl EA
(2019) Nat Genet 51: 659-674
MeSH Terms: Brain, Case-Control Studies, Gene Expression, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk, Schizophrenia, Transcriptome
Show Abstract · Added July 17, 2019
Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression.
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Registration-based image enhancement improves multi-atlas segmentation of the thalamic nuclei and hippocampal subfields.
Bao S, Bermudez C, Huo Y, Parvathaneni P, Rodriguez W, Resnick SM, D'Haese PF, McHugo M, Heckers S, Dawant BM, Lyu I, Landman BA
(2019) Magn Reson Imaging 59: 143-152
MeSH Terms: Algorithms, Brain Mapping, Hippocampus, Humans, Image Enhancement, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Temporal Lobe, Thalamic Nuclei
Show Abstract · Added March 26, 2019
Magnetic resonance imaging (MRI) is an important tool for analysis of deep brain grey matter structures. However, analysis of these structures is limited due to low intensity contrast typically found in whole brain imaging protocols. Herein, we propose a big data registration-enhancement (BDRE) technique to augment the contrast of deep brain structures using an efficient large-scale non-rigid registration strategy. Direct validation is problematic given a lack of ground truth data. Rather, we validate the usefulness and impact of BDRE for multi-atlas (MA) segmentation on two sets of structures of clinical interest: the thalamic nuclei and hippocampal subfields. The experimental design compares algorithms using T1-weighted 3 T MRI for both structures (and additional 7 T MRI for the thalamic nuclei) with an algorithm using BDRE. As baseline comparisons, a recent denoising (DN) technique and a super-resolution (SR) method are used to preprocess the original 3 T MRI. The performance of each MA segmentation is evaluated by the Dice similarity coefficient (DSC). BDRE significantly improves mean segmentation accuracy over all methods tested for both thalamic nuclei (3 T imaging: 9.1%; 7 T imaging: 15.6%; DN: 6.9%; SR: 16.2%) and hippocampal subfields (3 T T1 only: 8.7%; DN: 8.4%; SR: 8.6%). We also present DSC performance for each thalamic nucleus and hippocampal subfield and show that BDRE can help MA segmentation for individual thalamic nuclei and hippocampal subfields. This work will enable large-scale analysis of clinically relevant deep brain structures from commonly acquired T1 images.
Copyright © 2019 Elsevier Inc. All rights reserved.
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9 MeSH Terms
Biophysical model-based parameters to classify tumor recurrence from radiation-induced necrosis for brain metastases.
Narasimhan S, Johnson HB, Nickles TM, Miga MI, Rana N, Attia A, Weis JA
(2019) Med Phys 46: 2487-2496
MeSH Terms: Brain Neoplasms, Humans, Magnetic Resonance Imaging, Models, Biological, Necrosis, Patient-Specific Modeling, Radiation Injuries, Radiosurgery, Recurrence, Retrospective Studies
Show Abstract · Added April 2, 2019
PURPOSE - Stereotactic radiosurgery (SRS) is used for local control treatment of patients with intracranial metastases. As a result of SRS, some patients develop radiation-induced necrosis. Radiographically, radiation-induced necrosis can appear similar to tumor recurrence in magnetic resonance (MR) T -weighted contrast-enhanced imaging, T -weighted MR imaging, and Fluid-Attenuated Inversion Recovery (FLAIR) MR imaging. Radiographic ambiguities often necessitate invasive brain biopsies to determine lesion etiology or cause delayed subsequent therapy initiation. We use a biomechanically coupled tumor growth model to estimate patient-specific model parameters and model-derived measures to noninvasively classify etiology of enhancing lesions in this patient population.
METHODS - In this initial, preliminary retrospective study, we evaluated five patients with tumor recurrence and five with radiation-induced necrosis. Longitudinal patient-specific MR imaging data were used in conjunction with the model to parameterize tumor cell proliferation rate and tumor cell diffusion coefficient, and Dice correlation coefficients were used to quantify degree of correlation between model-estimated mechanical stress fields and edema visualized from MR imaging.
RESULTS - Results found four statistically relevant parameters which can differentiate tumor recurrence and radiation-induced necrosis.
CONCLUSIONS - This preliminary investigation suggests potential of this framework to noninvasively determine the etiology of enhancing lesions in patients who previously underwent SRS for intracranial metastases.
© 2019 American Association of Physicists in Medicine.
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10 MeSH Terms
iNKT Cell Activation Exacerbates the Development of Huntington's Disease in R6/2 Transgenic Mice.
Park HJ, Lee SW, Im W, Kim M, Van Kaer L, Hong S
(2019) Mediators Inflamm 2019: 3540974
MeSH Terms: Animals, Brain, Cytokines, Disease Models, Animal, Disease Progression, Galactosylceramides, Genotype, Huntington Disease, Leukocytes, Lymphocyte Activation, Mice, Mice, Knockout, Natural Killer T-Cells
Show Abstract · Added March 26, 2019
Huntington's disease (HD) is an inherited neurodegenerative disorder which is caused by a mutation of the huntingtin (HTT) gene. Although the pathogenesis of HD has been associated with inflammatory responses, if and how the immune system contributes to the onset of HD is largely unknown. Invariant natural killer T (iNKT) cells are a group of innate-like regulatory T lymphocytes that can rapidly produce various cytokines such as IFN and IL4 upon stimulation with the glycolipid -galactosylceramide (-GalCer). By employing both R6/2 Tg mice (murine HD model) and J18 KO mice (deficient in iNKT cells), we investigated whether alterations of iNKT cells affect the development of HD in R6/2 Tg mice. We found that J18 KO R6/2 Tg mice showed disease progression comparable to R6/2 Tg mice, indicating that the absence of iNKT cells did not have any significant effects on HD development. However, repeated activation of iNKT cells with -GalCer facilitated HD progression in R6/2 Tg mice, and this was associated with increased infiltration of iNKT cells in the brain. Taken together, our results demonstrate that repeated -GalCer treatment of R6/2 Tg mice accelerates HD progression, suggesting that immune activation can affect the severity of HD pathogenesis.
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13 MeSH Terms
Linear Accelerator-Based Stereotactic Radiosurgery for Cranial Intraparenchymal Metastasis of a Malignant Peripheral Nerve Sheath Tumor: Case Report and Review of the Literature.
Fenlon JB, Khattab MH, Ferguson DC, Luo G, Keedy VL, Chambless LB, Kirschner AN
(2019) World Neurosurg 123: 123-127
MeSH Terms: Adult, Brain Neoplasms, Humans, Magnetic Resonance Imaging, Male, Nerve Sheath Neoplasms, Neurofibrosarcoma, Particle Accelerators, Positron-Emission Tomography, Radiosurgery
Show Abstract · Added April 2, 2019
BACKGROUND - Malignant peripheral nerve sheath tumors (MPNSTs) are rare, aggressive soft tissue sarcomas. MPNST intracranial metastasis is exceedingly rare with only 22 documented cases in the literature and, to our knowledge, only 1 case with intraparenchymal brain metastasis. Most have been managed surgically; however, 2 documented cases were treated with Gamma Knife radiosurgery. Excluding this case report, there are no other documented cases of linear accelerator-based stereotactic radiosurgery (SRS) to treat MPNST brain metastasis.
CASE DESCRIPTION - A 41-year-old man with MPNST of the lung initially underwent tumor resection. He developed multiple systemic metastases that were managed with directed radiation therapy. A parietal brain metastasis was treated with linear accelerator-based SRS. Following SRS therapy, the patient was treated with a tropomyosin receptor kinase inhibitor. Complete resolution of brain metastasis was seen on brain magnetic resonance imaging 5 months after treatment with SRS. At 11 months after SRS, there was no evidence of recurrence or progression of the intraparenchymal disease. The patient continued to have stable extracranial disease on his ninth cycle of systemic treatment.
CONCLUSIONS - This report provides important insights into efficacy of linear accelerator-based SRS to treat MPNST brain metastases.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Challenges in diffusion MRI tractography - Lessons learned from international benchmark competitions.
Schilling KG, Daducci A, Maier-Hein K, Poupon C, Houde JC, Nath V, Anderson AW, Landman BA, Descoteaux M
(2019) Magn Reson Imaging 57: 194-209
MeSH Terms: Algorithms, Benchmarking, Brain, Diffusion Tensor Imaging, Humans, Internationality, Neuroimaging, Reproducibility of Results
Show Abstract · Added March 26, 2019
Diffusion MRI (dMRI) fiber tractography has become a pillar of the neuroimaging community due to its ability to noninvasively map the structural connectivity of the brain. Despite widespread use in clinical and research domains, these methods suffer from several potential drawbacks or limitations. Thus, validating the accuracy and reproducibility of techniques is critical for sound scientific conclusions and effective clinical outcomes. Towards this end, a number of international benchmark competitions, or "challenges", has been organized by the diffusion MRI community in order to investigate the reliability of the tractography process by providing a platform to compare algorithms and results in a fair manner, and evaluate common and emerging algorithms in an effort to advance the state of the field. In this paper, we summarize the lessons from a decade of challenges in tractography, and give perspective on the past, present, and future "challenges" that the field of diffusion tractography faces.
Copyright © 2018 Elsevier Inc. All rights reserved.
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8 MeSH Terms
Deep Brain Stimulation Versus Peripheral Denervation for Cervical Dystonia: A Systematic Review and Meta-Analysis.
Ravindran K, Ganesh Kumar N, Englot DJ, Wilson TJ, Zuckerman SL
(2019) World Neurosurg 122: e940-e946
MeSH Terms: Deep Brain Stimulation, Denervation, Humans, Torticollis
Show Abstract · Added June 22, 2019
BACKGROUND - Cervical dystonia is a disabling medical condition that drastically decreases quality of life. Surgical treatment consists of peripheral nerve denervation procedures with or without myectomies or deep brain stimulation (DBS). The current objective was to compare the efficacy of peripheral denervation versus DBS in improving the severity of cervical dystonia through a systematic review and meta-analysis.
METHODS - A search of PubMed, MEDLINE, EMBASE, and Web of Science electronic databases was conducted in accordance with PRISMA guidelines. Preoperative and postoperative Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores were used to generate standardized mean differences and 95% confidence intervals (CIs), which were combined in a random-effects model. Both mean percentage and absolute reduction in TWSTRS scores were calculated. Absolute reduction was used for forest plots.
RESULTS - Eighteen studies met the inclusion criteria, comprising 870 patients with 180 (21%) undergoing DBS and 690 (79%) undergoing peripheral denervation procedures. The mean follow-up time was 31.5 months (range, 12-38 months). In assessing the efficacy of each intervention, forest plots revealed significant absolute reduction in total postoperative TWSTRS scores for both peripheral denervation (standardized mean difference 1.54; 95% CI 1.42-1.66) and DBS (standardized mean difference 2.07; 95% CI 1.43-2.71). On subgroup analysis, DBS therapy was significantly associated with improvement in postoperative TWSTRS severity (standardized mean difference 2.08; 95% CI 1.66-2.50) and disability (standardized mean difference 2.12; 95% CI 1.57-2.68) but not pain (standardized mean difference 1.18; 95% CI 0.80-1.55).
CONCLUSIONS - Both peripheral denervation and DBS are associated with a significant reduction in absolute TWSTRS total score, with no significant difference in the magnitude of reduction observed between the 2 treatments. Further comparative data are needed to better evaluate the long-term results of both interventions.
Copyright © 2018 Elsevier Inc. All rights reserved.
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Limits to anatomical accuracy of diffusion tractography using modern approaches.
Schilling KG, Nath V, Hansen C, Parvathaneni P, Blaber J, Gao Y, Neher P, Aydogan DB, Shi Y, Ocampo-Pineda M, Schiavi S, Daducci A, Girard G, Barakovic M, Rafael-Patino J, Romascano D, Rensonnet G, Pizzolato M, Bates A, Fischi E, Thiran JP, Canales-Rodríguez EJ, Huang C, Zhu H, Zhong L, Cabeen R, Toga AW, Rheault F, Theaud G, Houde JC, Sidhu J, Chamberland M, Westin CF, Dyrby TB, Verma R, Rathi Y, Irfanoglu MO, Thomas C, Pierpaoli C, Descoteaux M, Anderson AW, Landman BA
(2019) Neuroimage 185: 1-11
MeSH Terms: Brain, Brain Mapping, Diffusion Tensor Imaging, Humans, Image Processing, Computer-Assisted, Neural Pathways
Show Abstract · Added March 26, 2019
Diffusion MRI fiber tractography is widely used to probe the structural connectivity of the brain, with a range of applications in both clinical and basic neuroscience. Despite widespread use, tractography has well-known pitfalls that limits the anatomical accuracy of this technique. Numerous modern methods have been developed to address these shortcomings through advances in acquisition, modeling, and computation. To test whether these advances improve tractography accuracy, we organized the 3-D Validation of Tractography with Experimental MRI (3D-VoTEM) challenge at the ISBI 2018 conference. We made available three unique independent tractography validation datasets - a physical phantom and two ex vivo brain specimens - resulting in 176 distinct submissions from 9 research groups. By comparing results over a wide range of fiber complexities and algorithmic strategies, this challenge provides a more comprehensive assessment of tractography's inherent limitations than has been reported previously. The central results were consistent across all sub-challenges in that, despite advances in tractography methods, the anatomical accuracy of tractography has not dramatically improved in recent years. Taken together, our results independently confirm findings from decades of tractography validation studies, demonstrate inherent limitations in reconstructing white matter pathways using diffusion MRI data alone, and highlight the need for alternative or combinatorial strategies to accurately map the fiber pathways of the brain.
Copyright © 2018 Elsevier Inc. All rights reserved.
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6 MeSH Terms
Anatomical accuracy of standard-practice tractography algorithms in the motor system - A histological validation in the squirrel monkey brain.
Schilling KG, Gao Y, Stepniewska I, Janve V, Landman BA, Anderson AW
(2019) Magn Reson Imaging 55: 7-25
MeSH Terms: Algorithms, Animals, Brain, Brain Mapping, Diffusion Tensor Imaging, Image Processing, Computer-Assisted, Models, Anatomic, Motor Cortex, Probability, Reproducibility of Results, Saimiri, Sensitivity and Specificity, Software, White Matter
Show Abstract · Added March 26, 2019
For two decades diffusion fiber tractography has been used to probe both the spatial extent of white matter pathways and the region to region connectivity of the brain. In both cases, anatomical accuracy of tractography is critical for sound scientific conclusions. Here we assess and validate the algorithms and tractography implementations that have been most widely used - often because of ease of use, algorithm simplicity, or availability offered in open source software. Comparing forty tractography results to a ground truth defined by histological tracers in the primary motor cortex on the same squirrel monkey brains, we assess tract fidelity on the scale of voxels as well as over larger spatial domains or regional connectivity. No algorithms are successful in all metrics, and, in fact, some implementations fail to reconstruct large portions of pathways or identify major points of connectivity. The accuracy is most dependent on reconstruction method and tracking algorithm, as well as the seed region and how this region is utilized. We also note a tremendous variability in the results, even though the same MR images act as inputs to all algorithms. In addition, anatomical accuracy is significantly decreased at increased distances from the seed. An analysis of the spatial errors in tractography reveals that many techniques have trouble properly leaving the gray matter, and many only reveal connectivity to adjacent regions of interest. These results show that the most commonly implemented algorithms have several shortcomings and limitations, and choices in implementations lead to very different results. This study should provide guidance for algorithm choices based on study requirements for sensitivity, specificity, or the need to identify particular connections, and should serve as a heuristic for future developments in tractography.
Copyright © 2018 Elsevier Inc. All rights reserved.
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14 MeSH Terms