Multimodal optical coherence tomography for in vivo imaging of brain tissue structure and microvascular network at glioblastoma

NASA Astrophysics Data System (ADS)

Yashin, Konstantin S.; Kiseleva, Elena B.; Gubarkova, Ekaterina V.; Matveev, Lev A.; Karabut, Maria M.; Elagin, Vadim V.; Sirotkina, Marina A.; Medyanik, Igor A.; Kravets, L. Y.; Gladkova, Natalia D.

2017-02-01

In the case of infiltrative brain tumors the surgeon faces difficulties in determining their boundaries to achieve total resection. The aim of the investigation was to evaluate the performance of multimodal OCT (MM OCT) for differential diagnostics of normal brain tissue and glioma using an experimental model of glioblastoma. The spectral domain OCT device that was used for the study provides simultaneously two modes: cross-polarization and microangiographic OCT. The comparative analysis of the both OCT modalities images from tumorous and normal brain tissue areas concurrently with histologic correlation shows certain difference between when accordingly to morphological and microvascular tissue features.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schwartz, C.; Gavin, P.

This report describes research performed at the WSU College of Veterinary Medicine in which a large animal model was developed and used to study the effects of boron neutron capture therapy (BNCT) on normal and neoplastic canine brain tissue. The studies were performed using borocaptate sodium (BSH) and epithermal neutrons and had two major foci: biodistribution of BSH in animals with spontaneously occurring brain tumors; and effects of BNCT in normal and neoplastic brain tissue.

Time-resolved fluorescence spectroscopy of human brain tumors

NASA Astrophysics Data System (ADS)

Marcu, Laura; Thompson, Reid C.; Garde, Smita; Sedrak, Mark; Black, Keith L.; Yong, William H.

2002-05-01

Fluorescence spectroscopy of the endogenous emission of brain tumors has been researched as a potentially important method for the intraoperative localization of brain tumor margins. In this study, we investigate the use of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) for demarcation of primary brain tumors by studying the time-resolved spectra of gliomas of different histologic grades. Time-resolved fluorescence (3 ns, 337 nm excitation) from excised human brain tumor show differences between the time-resolved emission of malignant glioma and normal brain tissue (gray and white matter). Our findings suggest that brain tumors can be differentiated from normal brain tissue based upon unique time-resolved fluorescence signature.

Brain tumor imaging of rat fresh tissue using terahertz spectroscopy

NASA Astrophysics Data System (ADS)

Yamaguchi, Sayuri; Fukushi, Yasuko; Kubota, Oichi; Itsuji, Takeaki; Ouchi, Toshihiko; Yamamoto, Seiji

2016-07-01

Tumor imaging by terahertz spectroscopy of fresh tissue without dye is demonstrated using samples from a rat glioma model. The complex refractive index spectrum obtained by a reflection terahertz time-domain spectroscopy system can discriminate between normal and tumor tissues. Both the refractive index and absorption coefficient of tumor tissues are higher than those of normal tissues and can be attributed to the higher cell density and water content of the tumor region. The results of this study indicate that terahertz technology is useful for detecting brain tumor tissue.

Dye-enhanced multimodal confocal imaging as a novel approach to intraoperative diagnosis of brain tumors.

PubMed

Snuderl, Matija; Wirth, Dennis; Sheth, Sameer A; Bourne, Sarah K; Kwon, Churl-Su; Ancukiewicz, Marek; Curry, William T; Frosch, Matthew P; Yaroslavsky, Anna N

2013-01-01

Intraoperative diagnosis plays an important role in accurate sampling of brain tumors, limiting the number of biopsies required and improving the distinction between brain and tumor. The goal of this study was to evaluate dye-enhanced multimodal confocal imaging for discriminating gliomas from nonglial brain tumors and from normal brain tissue for diagnostic use. We investigated a total of 37 samples including glioma (13), meningioma (7), metastatic tumors (9) and normal brain removed for nontumoral indications (8). Tissue was stained in 0.05 mg/mL aqueous solution of methylene blue (MB) for 2-5 minutes and multimodal confocal images were acquired using a custom-built microscope. After imaging, tissue was formalin fixed and paraffin embedded for standard neuropathologic evaluation. Thirteen pathologists provided diagnoses based on the multimodal confocal images. The investigated tumor types exhibited distinctive and complimentary characteristics in both the reflectance and fluorescence responses. Images showed distinct morphological features similar to standard histology. Pathologists were able to distinguish gliomas from normal brain tissue and nonglial brain tumors, and to render diagnoses from the images in a manner comparable to haematoxylin and eosin (H&E) slides. These results confirm the feasibility of multimodal confocal imaging for intravital intraoperative diagnosis. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

Cranial irradiation increases tumor growth in experimental breast cancer brain metastasis.

PubMed

Hamilton, Amanda M; Wong, Suzanne M; Wong, Eugene; Foster, Paula J

2018-05-01

Whole-brain radiotherapy is the standard of care for patients with breast cancer with multiple brain metastases and, although this treatment has been essential in the management of existing brain tumors, there are many known negative consequences associated with the irradiation of normal brain tissue. In our study, we used in vivo magnetic resonance imaging analysis to investigate the influence of radiotherapy-induced damage of healthy brain on the arrest and growth of metastatic breast cancer cells in a mouse model of breast cancer brain metastasis. We observed that irradiated, but otherwise healthy, neural tissue had an increased propensity to support metastatic growth compared with never-irradiated controls. The elucidation of the impact of irradiation on normal neural tissue could have implications in clinical patient management, particularly in patients with residual systemic disease or with residual radio-resistant brain cancer. Copyright © 2018 John Wiley & Sons, Ltd.

The biochemical, nanomechanical and chemometric signatures of brain cancer

NASA Astrophysics Data System (ADS)

Abramczyk, Halina; Imiela, Anna

2018-01-01

Raman spectroscopy and imaging combined with AFM topography and mechanical indentation by AFM have been shown to be an effective tool for analysis and discrimination of human brain tumors from normal structures. Raman methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n = 5) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma (IV grade), and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational spectra and Raman images we provide a real-time feedback that is label-free method to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, and proteins. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have shown that the ratio of Raman intensities I2930/I2845 at 2930 and 2845 cm- 1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the lipid and protein contents of tumorous brain tissue compared to the non-tumor tissue. Almost all brain tumors have the Raman intensity ratios significantly higher (1.99 ± 0.026) than that found in non-tumor brain tissue, which is 1.456 ± 0.02, and indicates that the relative amount of lipids compared to proteins is significantly higher in the normal brain tissue. Mechanical indentation using AFM on sliced human brain tissues (medulloblastoma, grade IV) revealed that the mechanical properties of this tissue are strongly heterogeneous, between 1.8 and 75.7 kPa, and the mean of 27.16 kPa. The sensitivity and specificity obtained directly from PLSDA and cross validation gives a sensitivity and specificity of 98.5% and 96% and 96.3% and 92% for cross-validation, respectively. The high sensitivity and specificity demonstrates usefulness for a proper decision for a Raman diagnostic test on biochemical alterations monitored by Raman spectroscopy related to brain cancer development.

Confocal laser endomicroscopy for brain tumor surgery: a milestone journey from microscopy to cellular surgery (Conference Presentation)

NASA Astrophysics Data System (ADS)

Charalampaki, Cleopatra

2017-02-01

The aim in brain tumor surgery is maximal tumor resection with minimal damage of normal neuronal tissue. Today diagnosis of tumor and definition of tumor borders intraoperatively is based on various visualization methods as well as on the histopathologic examination of a limited number of biopsy specimens via frozen sections. Unfortunately, intraoperative histopathology bears several shortcomings, and many biopsies are inconclusive. Therefore, the desirable treatment could be to have the ability to identify intraoperative cellular structures, and differentiate tumor from normal functional brain tissue on a cellular level. To achieve this goal new technological equipment integrated with new surgical concepts is needed.Confocal Laser Endomicroscopy (CLE) is an imaging technique which provides microscopic information of tissue in real-time. We are able to use these technique to perform intraoperative "optical biopsies" in bringing the microscope inside to the patients brain through miniaturized fiber-optic probes, and allow real-time histopathology. In our knowledge we are worldwide the only one neurosurgical group using CLE intraoperative for brain tumor surgery. We can detect and characterize intraoperative tumor cells, providing immediate online diagnosis without the need for frozen sections. It also provides delineation of borders between tumor and normal tissue on a cellular level, making surgical margins more accurate than ever before. The applications of CLE-assisted neurosurgery help to accurate the therapy by extending the resection borders and protecting the functionality of normal brain tissue in critical eloquent areas.

Integrin suppresses neurogenesis and regulates brain tissue assembly in planarian regeneration.

PubMed

Bonar, Nicolle A; Petersen, Christian P

2017-03-01

Animals capable of adult regeneration require specific signaling to control injury-induced cell proliferation, specification and patterning, but comparatively little is known about how the regeneration blastema assembles differentiating cells into well-structured functional tissues. Using the planarian Schmidtea mediterranea as a model, we identify β1-integrin as a crucial regulator of blastema architecture. β1-integrin(RNAi) animals formed small head blastemas with severe tissue disorganization, including ectopic neural spheroids containing differentiated neurons normally found in distinct organs. By mimicking aspects of normal brain architecture but without normal cell-type regionalization, these spheroids bore a resemblance to mammalian tissue organoids synthesized in vitro We identified one of four planarian integrin-alpha subunits inhibition of which phenocopied these effects, suggesting that a specific receptor controls brain organization through regeneration. Neoblast stem cells and progenitor cells were mislocalized in β1-integrin(RNAi) animals without significantly altered body-wide patterning. Furthermore, tissue disorganization phenotypes were most pronounced in animals undergoing brain regeneration and not homeostatic maintenance or regeneration-induced remodeling of the brain. These results suggest that integrin signaling ensures proper progenitor recruitment after injury, enabling the generation of large-scale tissue organization within the regeneration blastema. © 2017. Published by The Company of Biologists Ltd.

Mechanical characterization of human brain tumors from patients and comparison to potential surgical phantoms.

PubMed

Stewart, Daniel C; Rubiano, Andrés; Dyson, Kyle; Simmons, Chelsey S

2017-01-01

While mechanical properties of the brain have been investigated thoroughly, the mechanical properties of human brain tumors rarely have been directly quantified due to the complexities of acquiring human tissue. Quantifying the mechanical properties of brain tumors is a necessary prerequisite, though, to identify appropriate materials for surgical tool testing and to define target parameters for cell biology and tissue engineering applications. Since characterization methods vary widely for soft biological and synthetic materials, here, we have developed a characterization method compatible with abnormally shaped human brain tumors, mouse tumors, animal tissue and common hydrogels, which enables direct comparison among samples. Samples were tested using a custom-built millimeter-scale indenter, and resulting force-displacement data is analyzed to quantify the steady-state modulus of each sample. We have directly quantified the quasi-static mechanical properties of human brain tumors with effective moduli ranging from 0.17-16.06 kPa for various pathologies. Of the readily available and inexpensive animal tissues tested, chicken liver (steady-state modulus 0.44 ± 0.13 kPa) has similar mechanical properties to normal human brain tissue while chicken crassus gizzard muscle (steady-state modulus 3.00 ± 0.65 kPa) has similar mechanical properties to human brain tumors. Other materials frequently used to mimic brain tissue in mechanical tests, like ballistic gel and chicken breast, were found to be significantly stiffer than both normal and diseased brain tissue. We have directly compared quasi-static properties of brain tissue, brain tumors, and common mechanical surrogates, though additional tests would be required to determine more complex constitutive models.

High-sensitivity terahertz imaging of traumatic brain injury in a rat model

NASA Astrophysics Data System (ADS)

Zhao, Hengli; Wang, Yuye; Chen, Linyu; Shi, Jia; Ma, Kang; Tang, Longhuang; Xu, Degang; Yao, Jianquan; Feng, Hua; Chen, Tunan

2018-03-01

We demonstrated that different degrees of experimental traumatic brain injury (TBI) can be differentiated clearly in fresh slices of rat brain tissues using transmission-type terahertz (THz) imaging system. The high absorption region in THz images corresponded well with the injured area in visible images and magnetic resonance imaging results. The THz image and absorption characteristics of dehydrated paraffin-embedded brain slices and the hematoxylin and eosin (H&E)-stained microscopic images were investigated to account for the intrinsic differences in the THz images for the brain tissues suffered from different degrees of TBI and normal tissue aside from water. The THz absorption coefficients of rat brain tissues showed an increase in the aggravation of brain damage, particularly in the high-frequency range, whereas the cell density decreased as the order of mild, moderate, and severe TBI tissues compared with the normal tissue. Our results indicated that the different degrees of TBI were distinguishable owing to the different water contents and probable hematoma components distribution rather than intrinsic cell intensity. These promising results suggest that THz imaging has great potential as an alternative method for the fast diagnosis of TBI.

Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

PubMed

Yuan, Hong; Zhang, Lei; Frank, Jonathan E; Inscoe, Christina R; Burk, Laurel M; Hadsell, Mike; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

2015-09-01

Microbeam radiation treatment (MRT) using synchrotron radiation has shown great promise in the treatment of brain tumors, with a demonstrated ability to eradicate the tumor while sparing normal tissue in small animal models. With the goal of expediting the advancement of MRT research beyond the limited number of synchrotron facilities in the world, we recently developed a compact laboratory-scale microbeam irradiator using carbon nanotube (CNT) field emission-based X-ray source array technology. The focus of this study is to evaluate the effects of the microbeam radiation generated by this compact irradiator in terms of tumor control and normal tissue damage in a mouse brain tumor model. Mice with U87MG human glioblastoma were treated with sham irradiation, low-dose MRT, high-dose MRT or 10 Gy broad-beam radiation treatment (BRT). The microbeams were 280 μm wide and spaced at 900 μm center-to-center with peak dose at either 48 Gy (low-dose MRT) or 72 Gy (high-dose MRT). Survival studies showed that the mice treated with both MRT protocols had a significantly extended life span compared to the untreated control group (31.4 and 48.5% of life extension for low- and high-dose MRT, respectively) and had similar survival to the BRT group. Immunostaining on MRT mice demonstrated much higher DNA damage and apoptosis level in tumor tissue compared to the normal brain tissue. Apoptosis in normal tissue was significantly lower in the low-dose MRT group compared to that in the BRT group at 48 h postirradiation. Interestingly, there was a significantly higher level of cell proliferation in the MRT-treated normal tissue compared to that in the BRT-treated mice, indicating rapid normal tissue repairing process after MRT. Microbeam radiation exposure on normal brain tissue causes little apoptosis and no macrophage infiltration at 30 days after exposure. This study is the first biological assessment on MRT effects using the compact CNT-based irradiator. It provides an alternative technology that can enable widespread MRT research on mechanistic studies using a preclinical model, as well as further translational research towards clinical applications.

Dye-Enhanced Multimodal Confocal Imaging of Brain Cancers

NASA Astrophysics Data System (ADS)

Wirth, Dennis; Snuderl, Matija; Sheth, Sameer; Curry, William; Yaroslavsky, Anna

2011-04-01

Background and Significance: Accurate high resolution intraoperative detection of brain tumors may result in improved patient survival and better quality of life. The goal of this study was to evaluate dye enhanced multimodal confocal imaging for discriminating normal and cancerous brain tissue. Materials and Methods: Fresh thick brain specimens were obtained from the surgeries. Normal and cancer tissues were investigated. Samples were stained in methylene blue and imaged. Reflectance and fluorescence signals were excited at 658nm. Fluorescence emission and polarization were registered from 670 nm to 710 nm. The system provided lateral resolution of 0.6 μm and axial resolution of 7 μm. Normal and cancer specimens exhibited distinctively different characteristics. H&E histopathology was processed from each imaged sample. Results and Conclusions: The analysis of normal and cancerous tissues indicated clear differences in appearance in both the reflectance and fluorescence responses. These results confirm the feasibility of multimodal confocal imaging for intraoperative detection of small cancer nests and cells.

Reexpression of a developmentally regulated antigen in Down syndrome and Alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolozin, B.; Scicutella, A.; Davies, P.

1988-08-01

ALZ-50 is a monoclonal antibody that recognizes a protein of apparent molecular mass 68 kilodaltons (A68). The protein is present in the brains of patients with Alzheimer disease but is not detectable in normal adult brain tissue. The authors report that ALZ-50-reactive neurons are found in normal fetal and neonatal human brain and in brain tissue from neonatal individuals with Down syndrome. Reactive neurons decrease sharply in number after age 2 and reappear in older individuals with Down syndrome and in patients with Alzheimer disease.

In vitro 3D regeneration-like growth of human patient brain tissue.

PubMed

Tang-Schomer, M D; Wu, W B; Kaplan, D L; Bookland, M J

2018-05-01

In vitro culture of primary neurons is widely adapted with embryonic but not mature brain tissue. Here, we extended a previously developed bioengineered three-dimensional (3D) embryonic brain tissue model to resected normal patient brain tissue in an attempt to regenerate human neurons in vitro. Single cells and small sized (diameter < 100 μm) spheroids from dissociated brain tissue were seeded into 3D silk fibroin-based scaffolds, with or without collagen or Matrigel, and compared with two-dimensional cultures and scaffold-free suspension cultures. Changes of cell phenotypes (neuronal, astroglial, neural progenitor, and neuroepithelial) were quantified with flow cytometry and analyzed with a new method of statistical analysis specifically designed for percentage comparison. Compared with a complete lack of viable cells in conventional neuronal cell culture condition, supplements of vascular endothelial growth factor-containing pro-endothelial cell condition led to regenerative growth of neurons and astroglial cells from "normal" human brain tissue of epilepsy surgical patients. This process involved delayed expansion of Nestin+ neural progenitor cells, emergence of TUJ1+ immature neurons, and Vimentin+ neuroepithelium-like cell sheet formation in prolonged cultures (14 weeks). Micro-tissue spheroids, but not single cells, supported the brain tissue growth, suggesting importance of preserving native cell-cell interactions. The presence of 3D scaffold, but not hydrogel, allowed for Vimentin+ cell expansion, indicating a different growth mechanism than pluripotent cell-based brain organoid formation. The slow and delayed process implied an origin of quiescent neural precursors in the neocortex tissue. Further optimization of the 3D tissue model with primary human brain cells could provide personalized brain disease models. Copyright © 2018 John Wiley & Sons, Ltd.

Multimodality Instrument for Tissue Characterization

NASA Technical Reports Server (NTRS)

Mah, Robert W. (Inventor); Andrews, Russell J. (Inventor)

2000-01-01

A system with multimodality instrument for tissue identification includes a computer-controlled motor driven heuristic probe with a multisensory tip is discussed. For neurosurgical applications, the instrument is mounted on a stereotactic frame for the probe to penetrate the brain in a precisely controlled fashion. The resistance of the brain tissue being penetrated is continually monitored by a miniaturized strain gauge attached to the probe tip. Other modality sensors may be mounted near the probe tip to provide real-time tissue characterizations and the ability to detect the proximity of blood vessels, thus eliminating errors normally associated with registration of pre-operative scans, tissue swelling, elastic tissue deformation, human judgement, etc., and rendering surgical procedures safer, more accurate, and efficient. A neural network, program adaptively learns the information on resistance and other characteristic features of normal brain tissue during the surgery and provides near real-time modeling. A fuzzy logic interface to the neural network program incorporates expert medical knowledge in the learning process. Identification of abnormal brain tissue is determined by the detection of change and comparison with previously learned models of abnormal brain tissues. The operation of the instrument is controlled through a user friendly graphical interface. Patient data is presented in a 3D stereographics display. Acoustic feedback of selected information may optionally be provided. Upon detection of the close proximity to blood vessels or abnormal brain tissue, the computer-controlled motor immediately stops probe penetration.

Mechanical characterization of human brain tumors from patients and comparison to potential surgical phantoms

PubMed Central

Rubiano, Andrés; Dyson, Kyle; Simmons, Chelsey S.

2017-01-01

While mechanical properties of the brain have been investigated thoroughly, the mechanical properties of human brain tumors rarely have been directly quantified due to the complexities of acquiring human tissue. Quantifying the mechanical properties of brain tumors is a necessary prerequisite, though, to identify appropriate materials for surgical tool testing and to define target parameters for cell biology and tissue engineering applications. Since characterization methods vary widely for soft biological and synthetic materials, here, we have developed a characterization method compatible with abnormally shaped human brain tumors, mouse tumors, animal tissue and common hydrogels, which enables direct comparison among samples. Samples were tested using a custom-built millimeter-scale indenter, and resulting force-displacement data is analyzed to quantify the steady-state modulus of each sample. We have directly quantified the quasi-static mechanical properties of human brain tumors with effective moduli ranging from 0.17–16.06 kPa for various pathologies. Of the readily available and inexpensive animal tissues tested, chicken liver (steady-state modulus 0.44 ± 0.13 kPa) has similar mechanical properties to normal human brain tissue while chicken crassus gizzard muscle (steady-state modulus 3.00 ± 0.65 kPa) has similar mechanical properties to human brain tumors. Other materials frequently used to mimic brain tissue in mechanical tests, like ballistic gel and chicken breast, were found to be significantly stiffer than both normal and diseased brain tissue. We have directly compared quasi-static properties of brain tissue, brain tumors, and common mechanical surrogates, though additional tests would be required to determine more complex constitutive models. PMID:28582392

Characterization of a Raman spectroscopy probe system for intraoperative brain tissue classification

PubMed Central

Desroches, Joannie; Jermyn, Michael; Mok, Kelvin; Lemieux-Leduc, Cédric; Mercier, Jeanne; St-Arnaud, Karl; Urmey, Kirk; Guiot, Marie-Christine; Marple, Eric; Petrecca, Kevin; Leblond, Frédéric

2015-01-01

A detailed characterization study is presented of a Raman spectroscopy system designed to maximize the volume of resected cancer tissue in glioma surgery based on in vivo molecular tissue characterization. It consists of a hand-held probe system measuring spectrally resolved inelastically scattered light interacting with tissue, designed and optimized for in vivo measurements. Factors such as linearity of the signal with integration time and laser power, and their impact on signal to noise ratio, are studied leading to optimal data acquisition parameters. The impact of ambient light sources in the operating room is assessed and recommendations made for optimal operating conditions. In vivo Raman spectra of normal brain, cancer and necrotic tissue were measured in 10 patients, demonstrating that real-time inelastic scattering measurements can distinguish necrosis from vital tissue (including tumor and normal brain tissue) with an accuracy of 87%, a sensitivity of 84% and a specificity of 89%. PMID:26203368

Dependence of normal brain integral dose and normal tissue complication probability on the prescription isodose values for γ-knife radiosurgery

NASA Astrophysics Data System (ADS)

Ma, Lijun

2001-11-01

A recent multi-institutional clinical study suggested possible benefits of lowering the prescription isodose lines for stereotactic radiosurgery procedures. In this study, we investigate the dependence of the normal brain integral dose and the normal tissue complication probability (NTCP) on the prescription isodose values for γ-knife radiosurgery. An analytical dose model was developed for γ-knife treatment planning. The dose model was commissioned by fitting the measured dose profiles for each helmet size. The dose model was validated by comparing its results with the Leksell gamma plan (LGP, version 5.30) calculations. The normal brain integral dose and the NTCP were computed and analysed for an ensemble of treatment cases. The functional dependence of the normal brain integral dose and the NCTP versus the prescribing isodose values was studied for these cases. We found that the normal brain integral dose and the NTCP increase significantly when lowering the prescription isodose lines from 50% to 35% of the maximum tumour dose. Alternatively, the normal brain integral dose and the NTCP decrease significantly when raising the prescribing isodose lines from 50% to 65% of the maximum tumour dose. The results may be used as a guideline for designing future dose escalation studies for γ-knife applications.

Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology.

PubMed

Macdonald, Ian R; Reid, G Andrew; Pottie, Ian R; Martin, Earl; Darvesh, Sultan

2016-02-01

Acetylcholinesterase and butyrylcholinesterase accumulate with brain β-amyloid (Aβ) plaques in Alzheimer disease (AD). The overall activity of acetylcholinesterase is found to decline in AD, whereas butyrylcholinesterase has been found to either increase or remain the same. Although some cognitively normal older adults also have Aβ plaques within the brain, cholinesterase-associated plaques are generally less abundant in such individuals. Thus, brain imaging of cholinesterase activity associated with Aβ plaques has the potential to distinguish AD from cognitively normal older adults, with or without Aβ accumulation, during life. Current Aβ imaging agents are not able to provide this distinction. To address this unmet need, synthesis and evaluation of a cholinesterase-binding ligand, phenyl 4-(123)I-iodophenylcarbamate ((123)I-PIP), is described. Phenyl 4-iodophenylcarbamate was synthesized and evaluated for binding potency toward acetylcholinesterase and butyrylcholinesterase using enzyme kinetic analysis. This compound was subsequently rapidly radiolabeled with (123)I and purified by high-performance liquid chromatography. Autoradiographic analyses were performed with (123)I-PIP using postmortem orbitofrontal cortex from cognitively normal and AD human brains. Comparisons were made with an Aβ imaging agent, 2-(4'-dimethylaminophenyl)-6-(123)I-iodo-imidazo[1,2-a]pyridine ((123)I-IMPY), in adjacent brain sections. Tissues were also stained for Aβ and cholinesterase activity to visualize Aβ plaque load for comparison with radioligand uptake. Synthesized and purified PIP exhibited binding to cholinesterases. (123)I was successfully incorporated into this ligand. (123)I-PIP autoradiography with human tissue revealed accumulation of radioactivity only in AD brain tissues in which Aβ plaques had cholinesterase activity. (123)I-IMPY accumulated in brain tissues with Aβ plaques from both AD and cognitively normal individuals. Radiolabeled ligands specific for cholinesterases have potential for use in neuroimaging AD plaques during life. The compound herein described, (123)I-PIP, can detect cholinesterases associated with Aβ plaques and can distinguish AD brain tissues from those of cognitively normal older adults with Aβ plaques. Imaging cholinesterase activity associated with Aβ plaques in the living brain may contribute to the definitive diagnosis of AD during life. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Differentiating pediatric epileptic brain tissue from normal brain tissue by using time-dependent diffuse reflectance spectroscopy in vivo: comprehensive data analysis method in the time domain

NASA Astrophysics Data System (ADS)

Oh, Sanghoon; Fernald, Bradley; Bhatia, Sanjiv; Ragheb, John; Sandberg, David; Johnson, Mahlon; Lin, Wei-Chiang

2009-05-01

This research investigated the feasibility of using time-dependent diffuse reflectance spectroscopy to differentiate pediatric epileptic brain tissue from normal brain tissue. The optical spectroscopic technique monitored the dynamic optical properties of the cerebral cortex that are associated with its physiological, morphological, and compositional characteristics. Due to the transient irregular epileptic discharge activity within the epileptic brain tissue it was hypothesized that the lesion would express abnormal dynamic optical behavior that would alter normal dynamic behavior. Thirteen pediatric epilepsy patients and seven pediatric brain tumor patients (normal controls) were recruited for this clinical study. Dynamic optical properties were obtained from the cortical surface intraoperatively using a timedependent diffuse reflectance spectroscopy system. This system consisted of a fiber-optic probe, a tungsten-halogen light source, and a spectrophotometer. It acquired diffuse reflectance spectra with a spectral range of 204 nm to 932 nm at a rate of 33 spectra per second for approximately 12 seconds. Biopsy samples were taken from electrophysiologically abnormal cortex and evaluated by a neuropathologist, which served as a gold standard for lesion classification. For data analysis, spectral intensity changes of diffuse reflectance in the time domain at two different wavelengths from each investigated site were compared. Negative correlation segment, defined by the periods where the intensity changes at the two wavelengths were opposite in their slope polarity, were extracted. The total duration of negative correlation, referred to as the "negative correlation time index", was calculated by integrating the negative correlation segments. The negative correlation time indices from all investigated sites were sub-grouped according to the corresponding histological classifications. The difference between the mean indices of two subgroups was evaluated by standard t-test. These comparison and calculation procedures were carried out for all possible wavelength combinations between 400 nm and 800 nm with 2 nm increments. The positive group consisted of seven pathologically abnormal test sites, and the negative group consisted of 13 normal test sites from non-epileptic tumor patients. A standard t-test showed significant difference between negative correlation time indices from the two groups at the wavelength combinations of 700-760 nm versus 550-580 nm. An empirical discrimination algorithm based on the negative correlation time indices in this range produced 100% sensitivity and 85% specificity. Based on these results time-dependent diffuse reflectance spectroscopy with optimized data analysis methods differentiates epileptic brain tissue from normal brain tissue adequately, therefore can be utilized for surgical guidance, and may enhance the surgical outcome of pediatric epilepsy surgery.

The biochemical, nanomechanical and chemometric signatures of brain cancer.

PubMed

Abramczyk, Halina; Imiela, Anna

2018-01-05

Raman spectroscopy and imaging combined with AFM topography and mechanical indentation by AFM have been shown to be an effective tool for analysis and discrimination of human brain tumors from normal structures. Raman methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n=5) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma (IV grade), and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational spectra and Raman images we provide a real-time feedback that is label-free method to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, and proteins. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have shown that the ratio of Raman intensities I2930/I2845 at 2930 and 2845cm -1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the lipid and protein contents of tumorous brain tissue compared to the non-tumor tissue. Almost all brain tumors have the Raman intensity ratios significantly higher (1.99±0.026) than that found in non-tumor brain tissue, which is 1.456±0.02, and indicates that the relative amount of lipids compared to proteins is significantly higher in the normal brain tissue. Mechanical indentation using AFM on sliced human brain tissues (medulloblastoma, grade IV) revealed that the mechanical properties of this tissue are strongly heterogeneous, between 1.8 and 75.7kPa, and the mean of 27.16kPa. The sensitivity and specificity obtained directly from PLSDA and cross validation gives a sensitivity and specificity of 98.5% and 96% and 96.3% and 92% for cross-validation, respectively. The high sensitivity and specificity demonstrates usefulness for a proper decision for a Raman diagnostic test on biochemical alterations monitored by Raman spectroscopy related to brain cancer development. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Autofluorescence of normal and neoplastic human brain tissue: an aid for intraoperative delineation of tumor resection margins

NASA Astrophysics Data System (ADS)

Bottiroli, Giovanni F.; Croce, Anna C.; Locatelli, Donata; Nano, Rosanna; Giombelli, Ermanno; Messina, Alberto; Benericetti, Eugenio

1998-01-01

Light-induced autofluorescence measurements were made on normal and tumor brain tissues to assess their spectroscopic properties and to verify the potential of this parameter for an intraoperative delineation of tumor resection margins. Spectrofluorometric analysis was performed both at the microscope on tissue sections from surgical resection, and on patients affected by glioblastoma, during surgical operation. Significant differences in autofluorescence emission properties were found between normal and tumor tissues in both ex vivo and in vivo measurements, indicating that the lesion can be distinguished from the informal surrounding tissues by the signal amplitude and the spectral shape. The non-invasiveness of the technique opens interesting prospects for improving the efficacy of neurosurgical operation, by allowing an intraoperative delimitation of tumor resection margins.

Preclinical studies of photodynamic therapy of intracranial tissues

NASA Astrophysics Data System (ADS)

Lilge, Lothar D.; Sepers, Marja; Park, Jane; O'Carroll, Cindy; Pournazari, Poupak; Prosper, Joe; Wilson, Brian C.

1997-05-01

The applicability and limitations of the photodynamic threshold model were investigated for an intracranial tumor (VX2) and normal brain tissues in a rabbit model. Photodynamic threshold values for four different photosensitizers, i.e., Photofrin, 5(delta) -aminolaevulinic acid (5(delta) -ALA) induced Protoporphyrin IX (PPIX), Tin Ethyl Etiopurpurin (SnET2), and chloroaluminum phthalocyanine (AlClPc), were determined based on measured light fluence distributions, macroscopic photosensitizer concentration in various brain structures, and histologically determined extent of tissue necrosis following PDT. For Photofrin, AlClPc, and SnET2, normal brain displayed a significantly lower threshold value than VX2 tumor. For 5(delta) -ALA induced PPIX and SnET2 no or very little white matter damage, equalling to very high or infinite threshold values, was observed. Additionally, the latter two photosensitizers showed significantly lower uptake in white matter compared to other brain structures and VX2 tumor. Normal brain structures lacking a blood- brain-barrier, such as the choroid plexus and the meninges, showed high photosensitizer uptake for all photosensitizers, and, hence, are at risk when exposed to light. Results to date suggest that the photodynamic threshold values iares valid for white matter, cortex and VX2 tumor. For clinical PDT of intracranial neoplasms 5(delta) -ALA induced PPIX and SnET2 appear to be the most promising for selective tumor necrosis.However, the photosensitizer concentration in each normal brain structure and the fluence distribution throughout the treatment volume and adjacent tissues at risk must be monitored to maximize the selectivity of PDT for intracranial tumors.

Correlation of tissue-plasma partition coefficients between normal tissues and subcutaneous xenografts of human tumor cell lines in mouse as a prediction tool of drug penetration in tumors.

PubMed

Poulin, Patrick; Hop, Cornelis Eca; Salphati, Laurent; Liederer, Bianca M

2013-04-01

Understanding drug distribution and accumulation in tumors would be informative in the assessment of efficacy in targeted therapy; however, existing methods for predicting tissue drug distribution focus on normal tissues and do not incorporate tumors. The main objective of this study was to describe the relationships between tissue-plasma concentration ratios (Kp ) of normal tissues and those of subcutaneous xenograft tumors under nonsteady-state conditions, and establish regression equations that could potentially be used for the prediction of drug levels in several human tumor xenografts in mouse, based solely on a Kp value determined in a normal tissue (e.g., muscle). A dataset of 17 compounds was collected from the literature and from Genentech. Tissue and plasma concentration data in mouse were obtained following oral gavage or intraperitoneal administration. Linear regression analyses were performed between Kp values in several normal tissues (muscle, lung, liver, or brain) and those in human tumor xenografts (CL6, EBC-1, HT-29, PC3, U-87, MCF-7-neo-Her2, or BT474M1.1). The tissue-plasma ratios in normal tissues reasonably correlated with the tumor-plasma ratios in CL6, EBC-1, HT-29, U-87, BT474M1.1, and MCF-7-neo-Her2 xenografts (r(2) in the range 0.62-1) but not with the PC3 xenograft. In general, muscle and lung exhibited the strongest correlation with tumor xenografts, followed by liver. Regression coefficients from brain were low, except between brain and the glioblastoma U-87 xenograft (r(2) in the range 0.62-0.94). Furthermore, reasonably strong correlations were observed between muscle and lung and between muscle and liver (r(2) in the range 0.67-0.96). The slopes of the regressions differed depending on the class of drug (strong vs. weak base) and type of tissue (brain vs. other tissues and tumors). Overall, this study will contribute to our understanding of tissue-plasma partition coefficients for tumors and facilitate the use of physiologically based pharmacokinetics (PBPK) modeling for chemotherapy in oncology studies. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1355-1369, 2013. Copyright © 2013 Wiley Periodicals, Inc.

Fiber-probe optical spectroscopy discriminates normal brain from focal cortical dysplasia in pediatric subjects

NASA Astrophysics Data System (ADS)

Anand, Suresh; Cicchi, Riccardo; Giordano, Flavio; Conti, Valerio; Buccoliero, Anna Maria; Guerrini, Renzo; Pavone, Francesco S.

2017-02-01

Focal cortical dysplasia (FCD) is an abnormality in the cerebral cortex that is caused by malformations during cortical development. Currently, magnetic resonance imaging (MRI) and electro-corticography (ECoG) are used for detecting FCD. On the downside, MRI is very much insensitive to small malformations in the brain, while ECoG is an invasive and time consuming procedure. Recently, optical techniques were widely exploited as a minimally invasive and quantitative approaches for disease diagnosis. These techniques include fluorescence and Raman spectroscopy. The aim of this investigation is to study the diagnostic performances of optical spectroscopy incorporating fluorescence (at 378 nm and 445 nm excitation wavelengths) and Raman spectroscopy (at 785 nm excitation) for the discrimination of FCD from normal brain in pediatric subjects. The study included 10 normal and 17 FCD tissue sites from 3 normal and 7 FCD samples. The emission spectra of FCD at 378 nm excitation wavelength presented a blue-shifted peak with respect to normal tissue. Prominent spectral differences between normal and FCD tissue were observed at 1298 cm-1, 1302 cm-1, 1445 cm-1 and 1660 cm-1 using Raman spectroscopy. Tissue classification models were developed using a multivariate statistical method, principal component analysis. This study demonstrates that a combined spectroscopic approach can provide a better diagnostic capability for classifying normal and FCD tissues. Further, the implementation of the technology within a fiber probe could open the way for in vivo diagnostics and intra-operative surgical guidance.

Potential application of a handheld confocal endomicroscope imaging system using a variety of fluorophores in experimental gliomas and normal brain.

PubMed

Martirosyan, Nikolay L; Georges, Joseph; Eschbacher, Jennifer M; Cavalcanti, Daniel D; Elhadi, Ali M; Abdelwahab, Mohammed G; Scheck, Adrienne C; Nakaji, Peter; Spetzler, Robert F; Preul, Mark C

2014-02-01

The authors sought to assess the feasibility of a handheld visible-wavelength confocal endomicroscope imaging system (Optiscan 5.1, Optiscan Pty., Ltd.) using a variety of rapid-acting fluorophores to provide histological information on gliomas, tumor margins, and normal brain in animal models. Mice (n = 25) implanted with GL261 cells were used to image fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA), acridine orange (AO), acriflavine (AF), and cresyl violet (CV). A U251 glioma xenograft model in rats (n = 5) was used to image sulforhodamine 101 (SR101). A swine (n = 3) model with AO was used to identify confocal features of normal brain. Images of normal brain, obvious tumor, and peritumoral zones were collected using the handheld confocal endomicroscope. Histological samples were acquired through biopsies from matched imaging areas. Samples were visualized with a benchtop confocal microscope. Histopathological features in corresponding confocal images and photomicrographs of H & E-stained tissues were reviewed. Fluorescence induced by FNa, 5-ALA, AO, AF, CV, and SR101 and detected with the confocal endomicroscope allowed interpretation of histological features. Confocal endomicroscopy revealed satellite tumor cells within peritumoral tissue, a definitive tumor border, and striking fluorescent cellular and subcellular structures. Fluorescence in various tumor regions correlated with standard histology and known tissue architecture. Characteristic features of different areas of normal brain were identified as well. Confocal endomicroscopy provided rapid histological information precisely related to the site of microscopic imaging with imaging characteristics of cells related to the unique labeling features of the fluorophores. Although experimental with further clinical trial validation required, these data suggest that intraoperative confocal imaging can help to distinguish normal brain from tumor and tumor margin and may have application in improving intraoperative decisions during resection of brain tumors.

EFFECTS OF IRRADIATION ON BRAIN VASCULATURE USING AN IN SITU TUMOR MODEL

PubMed Central

Zawaski, Janice A.; Gaber, M. Waleed; Sabek, Omaima M.; Wilson, Christy M.; Duntsch, Christopher D.; Merchant, Thomas E.

2013-01-01

Purpose Damage to normal tissue is a limiting factor in clinical radiotherapy (RT). We tested the hypothesis that the presence of tumor alters the response of normal tissues to irradiation using a rat in situ brain tumor model. Methods and Materials Intravital microscopy was used with a rat cranial window to assess the in situ effect of rat C6 glioma on peritumoral tissue with and without RT. The RT regimen included 40 Gy at 8 Gy/day starting Day 5 after tumor implant. Endpoints included blood–brain barrier permeability, clearance index, leukocyte-endothelial interactions and staining for vascular endothelial growth factor (VEGF) glial fibrillary acidic protein, and apoptosis. To characterize the system response to RT, animal survival and tumor surface area and volume were measured. Sham experiments were performed on similar animals implanted with basement membrane matrix absent of tumor cells. Results The presence of tumor alone increases permeability but has little effect on leukocyte–endothelial interactions and astrogliosis. Radiation alone increases tissue permeability, leukocyte-endothelial interactions, and astrogliosis. The highest levels of permeability and cell adhesion were seen in the model that combined tumor and irradiation; however, the presence of tumor appeared to reduce the volume of rolling leukocytes. Unirradiated tumor and peritumoral tissue had poor clearance. Irradiated tumor and peritumoral tissue had a similar clearance index to irradiated and unirradiated sham-implanted animals. Radiation reduces the presence of VEGF in peritumoral normal tissues but did not affect the amount of apoptosis in the normal tissue. Apoptosis was identified in the tumor tissue with and without radiation. Conclusions We developed a novel approach to demonstrate that the presence of the tumor in a rat intracranial model alters the response of normal tissues to irradiation. PMID:22197233

SU-E-T-326: Dosimetric Impact of Beam Energies and Jaw Tracking On Intracranial Tumors Using RapidArc

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hossain, S; Keeling, V; Ali, I

2015-06-15

Purpose: To determine the dosimetric impact of jaw tracking and beam energies on dose conformity and normal-brain-tissue doses for intracranial tumors using VMAT (RapidArc). Methods: Seven patients with 1–2 and three patients with 4–6 intracranial tumors were planned using RapidArc for Varian TrueBeam STx machine with beam energies 6MV-FFF (Flattening-Filter-Free), 8MV, 10MV, and 10MV-FFF. The prescription dose ranged from 14–23Gy. Between 2 and 8 arcs were used with the following geometries: 2 full coplanar arcs and the non-coplanar half arcs. Plans were optimized (jaw tracking ON) with a high priority to Normal-Tissue-Objective and normal-brain-tissue. Plans were calculated on 1mm gridmore » size using AAA algorithm and then normalized so that 99% of each target volume received the prescription dose. Plans for the 6MV-FFF were also optimized without jaw tracking (No-JT) for comparison. Plan quality was assessed by target coverage using Paddick Conformity Index (PCI), sparing of normal-brain-tissue through analysis of V4Gy, V8Gy and V12Gy, and integral dose. Results: The average PCI ± standard deviation was 0.76±0.21 and 0.76±0.22 for 6MV-FFF and 10 MV-FFF, respectively. The average ratio in normal brain tissue volume (reported as follows V4,V8,V12) were (1.12±0.07,1.12±0.07,1.14±0.04), (1.12±0.08,1.12±0.09,1.13±0.06), (1.19±0.10,1.18±0.10,1.20±0.04), and (1.04±0.03,1.03±0.03,1.03±0.04) for 8MV/6MV-FFF, 10MV-FFF/6MV-FFF, 10MV/6MV-FFF, 6MV-FFF No-JT/6MV-FFF, respectively. Statistically significant differences in normal-brain-tissue for V4, V8, and V12 were observed in all cases for the different energies (p-values <0.05). V4 data shows significant differences in JT vs. No-JT (p=0.04), however no difference was found for V8 and V12. Brain tissue sparing from best to worst occurred in this order 6MV-FFF, 6MV-FFF no-JT, 10MV-FFF, 8MV, and 10MV. The average ratio of integral brain dose was 1.05±0.04 (p=0.21), 1.04±0.05 (p=0.33), 1.09±0.06 (p=0.04), and 1.02±0.06 (p=0.61) for 8MV/6MV-FFF, 10MV-FFF/6MV-FFF, 10MV/6MV-FFF, and 6MV-FFF No-JT/6MV-FFF, respectively. Conclusion: Normal brain tissue and integral dose improved using the lower energy and FFF beams, though plan conformity showed energy independence.« less

Integrity of normal-appearing white matter: Influence of age, visible lesion burden and hypertension in patients with small-vessel disease.

PubMed

Muñoz Maniega, Susana; Chappell, Francesca M; Valdés Hernández, Maria C; Armitage, Paul A; Makin, Stephen D; Heye, Anna K; Thrippleton, Michael J; Sakka, Eleni; Shuler, Kirsten; Dennis, Martin S; Wardlaw, Joanna M

2017-02-01

White matter hyperintensities accumulate with age and occur in patients with stroke, but their pathogenesis is poorly understood. We measured multiple magnetic resonance imaging biomarkers of tissue integrity in normal-appearing white matter and white matter hyperintensities in patients with mild stroke, to improve understanding of white matter hyperintensities origins. We classified white matter into white matter hyperintensities and normal-appearing white matter and measured fractional anisotropy, mean diffusivity, water content (T1-relaxation time) and blood-brain barrier leakage (signal enhancement slope from dynamic contrast-enhanced magnetic resonance imaging). We studied the effects of age, white matter hyperintensities burden (Fazekas score) and vascular risk factors on each biomarker, in normal-appearing white matter and white matter hyperintensities, and performed receiver-operator characteristic curve analysis. Amongst 204 patients (34.3-90.9 years), all biomarkers differed between normal-appearing white matter and white matter hyperintensities ( P < 0.001). In normal-appearing white matter and white matter hyperintensities, mean diffusivity and T1 increased with age ( P < 0.001), all biomarkers varied with white matter hyperintensities burden ( P < 0.001; P = 0.02 signal enhancement slope), but only signal enhancement slope increased with hypertension ( P = 0.028). Fractional anisotropy showed complex age-white matter hyperintensities-tissue interactions; enhancement slope showed white matter hyperintensities-tissue interactions. Mean diffusivity distinguished white matter hyperintensities from normal-appearing white matter best at all ages. Blood-brain barrier leakage increases with hypertension and white matter hyperintensities burden at all ages in normal-appearing white matter and white matter hyperintensities, whereas water mobility and content increase as tissue damage accrues, suggesting that blood-brain barrier leakage mediates small vessel disease-related brain damage.

Compression Stiffening of Brain and its Effect on Mechanosensing by Glioma Cells

NASA Astrophysics Data System (ADS)

Pogoda, Katarzyna

The stiffness of tissues, often characterized by their time-dependent elastic properties, is tightly controlled under normal condition and central nervous system tissue is among the softest tissues. Changes in tissue and organ stiffness occur in some physiological conditions and are frequently symptoms of diseases such as fibrosis, cardiovascular disease and many forms of cancer. Primary cells isolated from various tissues often respond to changes in the mechanical properties of their substrates, and the range of stiffness over which these responses occur appear to be limited to the tissue elastic modulus from which they are derived. Our goal was to test the hypotheses that the stiffness of tumors derived from CNS tissue differs from that of normal brain, and that transformed cells derived from such tumors exhibit mechanical responses that differ from those of normal glial cells. Unlike breast and some other cancers where the stroma and the tumor itself is substantially stiffer than the surrounding normal tissue, our data suggest that gliomas can arise without a gross change in the macroscopic tissue stiffness when measured at low strains without compression. However, both normal brain and glioma samples stiffen with compression, but not in elongation and increased shear strains. On the other hand, different classes of immortalized cells derived from human glioblastoma show substantially different responses to the stiffness of substrates in vitrowhen grown on soft polyacrylamide and hyaluronic acid gels. This outcome supports the hypothesis that compression stiffening, which might occur with increased vascularization and interstitial pressure gradients that are characteristic of tumors, effectively stiffens the environment of glioma cells, and that in situ, the elastic resistance these cells sense might be sufficient to trigger the same responses that are activated in vitro by increased substrate stiffness.

Alternative Polyadenylation in Glioblastoma Multiforme and Changes in Predicted RNA Binding Protein Profiles

PubMed Central

Shao, Jiaofang; Zhang, Jing; Zhang, Zengming; Jiang, Huawei; Lou, Xiaoyan; Foltz, Gregory; Lan, Qing; Huang, Qiang

2013-01-01

Abstract Alternative polyadenylation (APA) is widely present in the human genome and plays a key role in carcinogenesis. We conducted a comprehensive analysis of the APA products in glioblastoma multiforme (GBM, one of the most lethal brain tumors) and normal brain tissues and further developed a computational pipeline, RNAelements (http://sysbio.zju.edu.cn/RNAelements/), using covariance model from known RNA binding protein (RBP) targets acquired by RNA Immunoprecipitation (RIP) analysis. We identified 4530 APA isoforms for 2733 genes in GBM, and found that 182 APA isoforms from 148 genes showed significant differential expression between normal and GBM brain tissues. We then focused on three genes with long and short APA isoforms that show inconsistent expression changes between normal and GBM brain tissues. These were myocyte enhancer factor 2D, heat shock factor binding protein 1, and polyhomeotic homolog 1 (Drosophila). Using the RNAelements program, we found that RBP binding sites were enriched in the alternative regions between the first and the last polyadenylation sites, which would result in the short APA forms escaping regulation from those RNA binding proteins. To the best of our knowledge, this report is the first comprehensive APA isoform dataset for GBM and normal brain tissues. Additionally, we demonstrated a putative novel APA-mediated mechanism for controlling RNA stability and translation for APA isoforms. These observations collectively lay a foundation for novel diagnostics and molecular mechanisms that can inform future therapeutic interventions for GBM. PMID:23421905

3D variational brain tumor segmentation using Dirichlet priors on a clustered feature set.

PubMed

Popuri, Karteek; Cobzas, Dana; Murtha, Albert; Jägersand, Martin

2012-07-01

Brain tumor segmentation is a required step before any radiation treatment or surgery. When performed manually, segmentation is time consuming and prone to human errors. Therefore, there have been significant efforts to automate the process. But, automatic tumor segmentation from MRI data is a particularly challenging task. Tumors have a large diversity in shape and appearance with intensities overlapping the normal brain tissues. In addition, an expanding tumor can also deflect and deform nearby tissue. In our work, we propose an automatic brain tumor segmentation method that addresses these last two difficult problems. We use the available MRI modalities (T1, T1c, T2) and their texture characteristics to construct a multidimensional feature set. Then, we extract clusters which provide a compact representation of the essential information in these features. The main idea in this work is to incorporate these clustered features into the 3D variational segmentation framework. In contrast to previous variational approaches, we propose a segmentation method that evolves the contour in a supervised fashion. The segmentation boundary is driven by the learned region statistics in the cluster space. We incorporate prior knowledge about the normal brain tissue appearance during the estimation of these region statistics. In particular, we use a Dirichlet prior that discourages the clusters from the normal brain region to be in the tumor region. This leads to a better disambiguation of the tumor from brain tissue. We evaluated the performance of our automatic segmentation method on 15 real MRI scans of brain tumor patients, with tumors that are inhomogeneous in appearance, small in size and in proximity to the major structures in the brain. Validation with the expert segmentation labels yielded encouraging results: Jaccard (58%), Precision (81%), Recall (67%), Hausdorff distance (24 mm). Using priors on the brain/tumor appearance, our proposed automatic 3D variational segmentation method was able to better disambiguate the tumor from the surrounding tissue.

Resonance Raman imaging for detecting and monitoring molecular pathological changes in human brain tumors related to Warburg effect

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Zhu, Ke; Zhang, Chunyuan; Yang, Yang; Yu, Xinguang; Hu, Hailong; Cheng, Gangge; Wu, Binlin; Shi, Lingyan; Alfano, Robert R.

2018-02-01

The goal of the research is to determine the prognostic molecular pathological changes in components and composition, for human brain glioma gradings in comparison with normal tissues in three-dimensional Raman imaging profiles by visible Resonance Raman (VRR) imaging. VRR images from twenty-five specimens including three healthy tissues, one normal control, and twenty-one glioma tissues of grades II, II-III and III-IV with histology examination were measured and investigated using WITec300R confocal micro Raman imaging system with laser excitation of 532nm. Two-dimensional RR spectral mappings performed in 20μm x 20μm generated 400 images which integrated the intensity of the specific biochemical bonds as the third dimension. The three-dimension (3D) map demonstrated the spatial distributions of three selected sets of RR spectra of molecular biomarkers, and revealed significant differences in the spectra between normal and glioma tissues of different grades due to the composition changes in key molimageecules. These RR molecular spectral fingerprints have displayed: a clear enhancement of RR vibrational modes at 1129-1131cm-1 and 2934cm-1 which are supposed to be arising from lipoproteins; evident decreased RR vibrational modes at 1442cm-1 and 2854cm-1 which are from saturated fatty acids bonds in all-grades of glioma brain tissues compared with normal tissues; and the enhanced RR spectral modes of 1129 cm-1 and 2938cm-1 which suggest contribution from lactate. These findings may provide a novel proof for anaerobic glycolysis metabolic process in brain glioma cancer tissues that has been explained by Warburg effects.

Disruptions of brain structural network in end-stage renal disease patients with long-term hemodialysis and normal-appearing brain tissues.

PubMed

Chou, Ming-Chung; Ko, Chih-Hung; Chang, Jer-Ming; Hsieh, Tsyh-Jyi

2018-05-04

End-stage renal disease (ESRD) patients on hemodialysis were demonstrated to exhibit silent and invisible white-matter alterations which would likely lead to disruptions of brain structural networks. Therefore, the purpose of this study was to investigate the disruptions of brain structural network in ESRD patients. Thiry-three ESRD patients with normal-appearing brain tissues and 29 age- and gender-matched healthy controls were enrolled in this study and underwent both cognitive ability screening instrument (CASI) assessment and diffusion tensor imaging (DTI) acquisition. Brain structural connectivity network was constructed using probabilistic tractography with automatic anatomical labeling template. Graph-theory analysis was performed to detect the alterations of node-strength, node-degree, node-local efficiency, and node-clustering coefficient in ESRD patients. Correlational analysis was performed to understand the relationship between network measures, CASI score, and dialysis duration. Structural connectivity, node-strength, node-degree, and node-local efficiency were significantly decreased, whereas node-clustering coefficient was significantly increased in ESRD patients as compared with healthy controls. The disrupted local structural networks were generally associated with common neurological complications of ESRD patients, but the correlational analysis did not reveal significant correlation between network measures, CASI score, and dialysis duration. Graph-theory analysis was helpful to investigate disruptions of brain structural network in ESRD patients with normal-appearing brain tissues. Copyright © 2018. Published by Elsevier Masson SAS.

Detection of experimental brain tumors using time-resolved laser-induced fluorescence spectroscopy

NASA Astrophysics Data System (ADS)

Thompson, Reid C.; Black, Keith L.; Kateb, Babak; Marcu, Laura

2002-05-01

Time-Resolved Laser-Induced Fluorescence Spectroscopy (TR-LIFS) has the potential to provide a non- invasive characterization and detection of tumors. We utilized TR-LIFS to detect gliomas in-vivo in the rat C6 glioma model. Time-resolved emission spectra of both normal brain and tumor were analyzed to determine if unique fluorescence signatures could be used to distinguish the two. Fluorescence parameters derived from both spectral and time domain were used for tissue characterization. Our results show that in the rat C6 glioma model, TR-LIFS can be used to differentiate brain tumors from normal tissue (gray and white mater) based upon time- resolved fluorescence signatures seen in brain tumors.

FDG-PET reproducibility in tumor-bearing mice: comparing a traditional SUV approach with a tumor-to-brain tissue ratio approach.

PubMed

Busk, Morten; Munk, Ole L; Jakobsen, Steen; Frøkiær, Jørgen; Overgaard, Jens; Horsman, Michael R

2017-05-01

Current [F-18]-fluorodeoxyglucose positron emission tomography (FDG-PET) procedures in tumor-bearing mice typically includes fasting, anesthesia, and standardized uptake value (SUV)-based quantification. Such procedures may be inappropriate for prolonged multiscan experiments. We hypothesize that normalization of tumor FDG retention relative to a suitable reference tissue may improve accuracy as this method may be less susceptible to uncontrollable day-to-day changes in blood glucose levels, physical activity, or unnoticed imperfect tail vein injections. Fed non-anesthetized tumor-bearing mice were administered FDG intravenously (i.v.) or intraperitoneally (i.p.) and PET scanned on consecutive days using a Mediso nanoScan PET/magnetic resonance imaging (MRI). Reproducibility of various PET-deduced measures of tumor FDG retention, including normalization to FDG signal in reference organs and a conventional SUV approach, was evaluated. Day-to-day variability in i.v. injected mice was lower when tumor FDG retention was normalized to brain signal (T/B), compared to normalization to other tissues or when using SUV-based normalization. Assessment of tissue radioactivity in dissected tissues confirmed the validity of PET-derived T/B ratios. Mean T/B and SUV values were similar in i.v. and i.p. administered animals, but SUV normalization was more robust in the i.p. group than in the i.v. group. Multimodality scanners allow tissue delineation and normalization of tumor FDG uptake relative to reference tissues. Normalization to brain, but not liver or kidney, improved scan reproducibility considerably and was superior to traditional SUV quantification in i.v. tracer-injected animals. Day-to-day variability in SUV's was lower in i.p. than in i.v. injected animals, and i.p. injections may therefore be a valuable alternative in prolonged rodent studies, where repeated vein injections are undesirable.

Neocortical Transplants in the Mammalian Brain Lack a Blood-Brain Barrier to Macromolecules

NASA Astrophysics Data System (ADS)

Rosenstein, Jeffrey M.

1987-02-01

In order to determine whether the blood-brain barrier was present in transplants of central nervous tissue, fetal neocortex, which already possesses blood-brain and blood-cerebrospinal fluid barriers to protein, was grafted into the undamaged fourth ventricle or directly into the neocortex of recipient rats. Horseradish peroxidase or a conjugated human immunoglobulin G-peroxidase molecule was systemically administered into the host. These proteins were detected within the cortical transplants within 2 minutes regardless of the age of the donor or postoperative time. At later times these compounds, which normally do not cross the blood-brain barrier, inundated the grafts and adjacent host brain and also entered the cerebrospinal fluid. Endogenous serum albumin detected immunocytochemically in untreated hosts had a comparable although less extensive distribution. Thus, transplants of fetal central nervous tissue have permanent barrier dysfunction, probably due to microvascular changes, and are not integrated physiologically within the host. Blood-borne compounds, either systemically administered or naturally occurring, which should never contact normal brain tissue, have direct access to these transplants and might affect neuronal function.

Extracting morphologies from third harmonic generation images of structurally normal human brain tissue.

PubMed

Zhang, Zhiqing; Kuzmin, Nikolay V; Groot, Marie Louise; de Munck, Jan C

2017-06-01

The morphologies contained in 3D third harmonic generation (THG) images of human brain tissue can report on the pathological state of the tissue. However, the complexity of THG brain images makes the usage of modern image processing tools, especially those of image filtering, segmentation and validation, to extract this information challenging. We developed a salient edge-enhancing model of anisotropic diffusion for image filtering, based on higher order statistics. We split the intrinsic 3-phase segmentation problem into two 2-phase segmentation problems, each of which we solved with a dedicated model, active contour weighted by prior extreme. We applied the novel proposed algorithms to THG images of structurally normal ex-vivo human brain tissue, revealing key tissue components-brain cells, microvessels and neuropil, enabling statistical characterization of these components. Comprehensive comparison to manually delineated ground truth validated the proposed algorithms. Quantitative comparison to second harmonic generation/auto-fluorescence images, acquired simultaneously from the same tissue area, confirmed the correctness of the main THG features detected. The software and test datasets are available from the authors. z.zhang@vu.nl. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy

PubMed Central

Butte, Pramod V.; Fang, Qiyin; Jo, Javier A.; Yong, William H.; Pikul, Brian K.; Black, Keith L.; Marcu, Laura

2010-01-01

The goal of this study is to determine the potential of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as an adjunctive tool for delineation of brain tumor from surrounding normal tissue in order to assist the neurosurgeon in near-complete tumor excision. A time-domain TR-LIFS prototype apparatus (gated photomultiplier detection, fast digitizer) was used for recording tissue autofluorescence in normal cortex (NC), normal white matter (NWM), and various grades of gliomas intraoperatively. Tissue fluorescence was induced with a pulsed nitrogen laser (337nm, 700ps), and the intensity decay profiles were recorded in the 360-to550-nm spectral range (10-nm interval). Histopathological analysis (hematoxylin & eosin) of the biopsy samples taken from the site of TR-LIFS measurements was used for validation of spectroscopic results. Preliminary results on 17 patients demonstrate that normal cortex (N=16) and normal white matter (N=3) show two peaks of fluorescence emission at 390nm(lifetime=1.8±0.3ns) and 460nm(lifetime=0.8±0.1ns). The 390-nm emission peak is absent in low-grade glioma (N=5; lifetime=1.1ns) and reduced in high-grade glioma (N=9; lifetime=1.7±0.4ns). The emission characteristics at 460nm in all tissues correlated with the nicotinamide adenine dinucleotide fluorescence (peak: 440to460nm; lifetime: 0.8to1.0ns). These findings demonstrate the potential of using TR-LIFS as a tool for enhanced delineation of brain tumors during surgery. In addition, this study evaluates similarities and differences between TR-LIFS signatures of brain tumors obtained in vivo and those previously reported in ex vivo brain tumor specimens. PMID:20459282

Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy.

PubMed

Butte, Pramod V; Fang, Qiyin; Jo, Javier A; Yong, William H; Pikul, Brian K; Black, Keith L; Marcu, Laura

2010-01-01

The goal of this study is to determine the potential of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as an adjunctive tool for delineation of brain tumor from surrounding normal tissue in order to assist the neurosurgeon in near-complete tumor excision. A time-domain TR-LIFS prototype apparatus (gated photomultiplier detection, fast digitizer) was used for recording tissue autofluorescence in normal cortex (NC), normal white matter (NWM), and various grades of gliomas intraoperatively. Tissue fluorescence was induced with a pulsed nitrogen laser (337 nm, 700 ps), and the intensity decay profiles were recorded in the 360- to 550-nm spectral range (10-nm interval). Histopathological analysis (hematoxylin & eosin) of the biopsy samples taken from the site of TR-LIFS measurements was used for validation of spectroscopic results. Preliminary results on 17 patients demonstrate that normal cortex (N=16) and normal white matter (N=3) show two peaks of fluorescence emission at 390 nm (lifetime=1.8+/-0.3 ns) and 460 nm (lifetime=0.8+/-0.1 ns). The 390-nm emission peak is absent in low-grade glioma (N=5; lifetime=1.1 ns) and reduced in high-grade glioma (N=9; lifetime=1.7+/-0.4 ns). The emission characteristics at 460 nm in all tissues correlated with the nicotinamide adenine dinucleotide fluorescence (peak: 440 to 460 nm; lifetime: 0.8 to 1.0 ns). These findings demonstrate the potential of using TR-LIFS as a tool for enhanced delineation of brain tumors during surgery. In addition, this study evaluates similarities and differences between TR-LIFS signatures of brain tumors obtained in vivo and those previously reported in ex vivo brain tumor specimens.

Intraoperative delineation of primary brain tumors using time-resolved fluorescence spectroscopy

NASA Astrophysics Data System (ADS)

Butte, Pramod V.; Fang, Qiyin; Jo, Javier A.; Yong, William H.; Pikul, Brian K.; Black, Keith L.; Marcu, Laura

2010-03-01

The goal of this study is to determine the potential of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as an adjunctive tool for delineation of brain tumor from surrounding normal tissue in order to assist the neurosurgeon in near-complete tumor excision. A time-domain TR-LIFS prototype apparatus (gated photomultiplier detection, fast digitizer) was used for recording tissue autofluorescence in normal cortex (NC), normal white matter (NWM), and various grades of gliomas intraoperatively. Tissue fluorescence was induced with a pulsed nitrogen laser (337 nm, 700 ps), and the intensity decay profiles were recorded in the 360- to 550-nm spectral range (10-nm interval). Histopathological analysis (hematoxylin & eosin) of the biopsy samples taken from the site of TR-LIFS measurements was used for validation of spectroscopic results. Preliminary results on 17 patients demonstrate that normal cortex (N=16) and normal white matter (N=3) show two peaks of fluorescence emission at 390 nm (lifetime=1.8+/-0.3 ns) and 460 nm (lifetime=0.8+/-0.1 ns). The 390-nm emission peak is absent in low-grade glioma (N=5; lifetime=1.1 ns) and reduced in high-grade glioma (N=9; lifetime=1.7+/-0.4 ns). The emission characteristics at 460 nm in all tissues correlated with the nicotinamide adenine dinucleotide fluorescence (peak: 440 to 460 nm lifetime: 0.8 to 1.0 ns). These findings demonstrate the potential of using TR-LIFS as a tool for enhanced delineation of brain tumors during surgery. In addition, this study evaluates similarities and differences between TR-LIFS signatures of brain tumors obtained in vivo and those previously reported in ex vivo brain tumor specimens.

Metastasis Infiltration: An Investigation of the Postoperative Brain-Tumor Interface

DOE Office of Scientific and Technical Information (OSTI.GOV)

Raore, Bethwel; Schniederjan, Matthew; Prabhu, Roshan

Purpose: This study aims to evaluate brain infiltration of metastatic tumor cells past the main tumor resection margin to assess the biological basis for the use of stereotactic radiosurgery treatment of the tumor resection cavity and visualized resection edge or clinical target volume. Methods and Materials: Resection margin tissue was obtained after gross total resection of a small group of metastatic lesions from a variety of primary sources. The tissue at the border of the tumor and brain tissue was carefully oriented and processed to evaluate the presence of tumor cells within brain tissue and their distance from the resectionmore » margin. Results: Microscopic assessment of the radially oriented tissue samples showed no tumor cells infiltrating the surrounding brain tissue. Among the positive findings were reactive astrocytosis observed on the brain tissue immediately adjacent to the tumor resection bed margin. Conclusions: The lack of evidence of metastatic tumor cell infiltration into surrounding brain suggests the need to target only a narrow depth of the resection cavity margin to minimize normal tissue injury and prevent treatment size-dependent stereotactic radiosurgery complications.« less

Neural networks improve brain cancer detection with Raman spectroscopy in the presence of light artifacts

NASA Astrophysics Data System (ADS)

Jermyn, Michael; Desroches, Joannie; Mercier, Jeanne; St-Arnaud, Karl; Guiot, Marie-Christine; Petrecca, Kevin; Leblond, Frederic

2016-03-01

It is often difficult to identify cancer tissue during brain cancer (glioma) surgery. Gliomas invade into areas of normal brain, and this cancer invasion is frequently not detected using standard preoperative magnetic resonance imaging (MRI). This results in enduring invasive cancer following surgery and leads to recurrence. A hand-held Raman spectroscopy is able to rapidly detect cancer invasion in patients with grade 2-4 gliomas. However, ambient light sources can produce spectral artifacts which inhibit the ability to distinguish between cancer and normal tissue using the spectral information available. To address this issue, we have demonstrated that artificial neural networks (ANN) can accurately classify invasive cancer versus normal brain tissue, even when including measurements with significant spectral artifacts from external light sources. The non-parametric and adaptive model used by ANN makes it suitable for detecting complex non-linear spectral characteristics associated with different tissues and the confounding presence of light artifacts. The use of ANN for brain cancer detection with Raman spectroscopy, in the presence of light artifacts, improves the robustness and clinical translation potential for intraoperative use. Integration with the neurosurgical workflow is facilitated by accounting for the effect of light artifacts which may occur, due to operating room lights, neuronavigation systems, windows, or other light sources. The ability to rapidly detect invasive brain cancer under these conditions may reduce residual cancer remaining after surgery, and thereby improve patient survival.

Multimodality instrument for tissue characterization

NASA Technical Reports Server (NTRS)

Mah, Robert W. (Inventor); Andrews, Russell J. (Inventor)

2004-01-01

A system with multimodality instrument for tissue identification includes a computer-controlled motor driven heuristic probe with a multisensory tip. For neurosurgical applications, the instrument is mounted on a stereotactic frame for the probe to penetrate the brain in a precisely controlled fashion. The resistance of the brain tissue being penetrated is continually monitored by a miniaturized strain gauge attached to the probe tip. Other modality sensors may be mounted near the probe tip to provide real-time tissue characterizations and the ability to detect the proximity of blood vessels, thus eliminating errors normally associated with registration of pre-operative scans, tissue swelling, elastic tissue deformation, human judgement, etc., and rendering surgical procedures safer, more accurate, and efficient. A neural network program adaptively learns the information on resistance and other characteristic features of normal brain tissue during the surgery and provides near real-time modeling. A fuzzy logic interface to the neural network program incorporates expert medical knowledge in the learning process. Identification of abnormal brain tissue is determined by the detection of change and comparison with previously learned models of abnormal brain tissues. The operation of the instrument is controlled through a user friendly graphical interface. Patient data is presented in a 3D stereographics display. Acoustic feedback of selected information may optionally be provided. Upon detection of the close proximity to blood vessels or abnormal brain tissue, the computer-controlled motor immediately stops probe penetration. The use of this system will make surgical procedures safer, more accurate, and more efficient. Other applications of this system include the detection, prognosis and treatment of breast cancer, prostate cancer, spinal diseases, and use in general exploratory surgery.

Effects of high-pressure oxygen therapy on brain tissue water content and AQP4 expression in rabbits with cerebral hemorrhage.

PubMed

Wu, Jing; Chen, Jiong; Guo, Hua; Peng, Fang

2014-12-01

To investigate the effects of different atmosphere absolutes (ATA) of high-pressure oxygen (HPO) on brain tissue water content and Aquaporin-4 (AQP4) expression in rabbits with cerebral hemorrhage. 180 New Zealand white rabbits were selected and randomly divided into normal group (n = 30), control group (n = 30) and cerebral hemorrhage group (n = 120), and cerebral hemorrhage group was divided into group A, B, C and D with 30 rabbits in each group. The groups received 1.0, 1.8, 2.0 and 2.2 ATA of HPO treatments, respectively. Ten rabbits in each group were killed at first, third and fifth day to detect the brain tissue water content and change of AQP4 expression. In cerebral hemorrhage group, brain tissue water content and AQP4 expression after model establishment were first increased, then decreased and reached the maximum on third day (p < 0.05). Brain tissue water content and AQP4 expression in control group and cerebral hemorrhage group were significantly higher than normal group at different time points (p < 0.05). In contrast, brain tissue water content and AQP4 expression in group C were significantly lower than in group A, group B, group D and control group (p < 0.05). In control group, AQP4-positive cells significantly increased after model establishment, which reached maximum on third day, and positive cells in group C were significantly less than in group A, group B and group D. We also found that AQP4 expression were positively correlated with brain tissue water content (r = 0.719, p < 0.05) demonstrated by significantly increased AQP4 expression along with increased brain tissue water content. In conclusion, HPO can decrease AQP4 expression in brain tissue of rabbits with cerebral hemorrhage to suppress the progression of brain edema and promote repairing of injured tissue. 2.0 ATA HPO exerts best effects, which provides an experimental basis for ATA selection of HPO in treating cerebral hemorrhage.

Effects of the Variation in Brain Tissue Mechanical Properties on the Intracranial Response of a 6-Year-Old Child.

PubMed

Cui, Shihai; Li, Haiyan; Li, Xiangnan; Ruan, Jesse

2015-01-01

Brain tissue mechanical properties are of importance to investigate child head injury using finite element (FE) method. However, these properties used in child head FE model normally vary in a large range in published literatures because of the insufficient child cadaver experiments. In this work, a head FE model with detailed anatomical structures is developed from the computed tomography (CT) data of a 6-year-old healthy child head. The effects of brain tissue mechanical properties on traumatic brain response are also analyzed by reconstruction of a head impact on engine hood according to Euro-NCAP testing regulation using FE method. The result showed that the variations of brain tissue mechanical parameters in linear viscoelastic constitutive model had different influences on the intracranial response. Furthermore, the opposite trend was obtained in the predicted shear stress and shear strain of brain tissues caused by the variations of mentioned parameters.

X-ray diffraction evidence for myelin disorder in brain from humans with Alzheimer's disease.

PubMed

Chia, L S; Thompson, J E; Moscarello, M A

1984-09-05

Wide-angle X-ray diffraction studies revealed that the lipid phase transition temperature of myelin from brain tissue of humans with Alzheimer's disease was about 12 degrees C lower than that of normal age-matched controls, indicating differences in the physical organization of the myelin lipid bilayer. Elevated levels of malondialdehyde and conjugated diene were found in brain tissue from humans with Alzheimer's disease, indicating an increased amount of lipid peroxidation over the controls. An increase in myelin disorder and in lipid peroxidation can both be correlated with aging in human brain, but the changes in myelin from humans with Alzheimer's disease are more pronounced than in normal aging. These changes might represent severe or accelerated aging.

Novel strategies of Raman imaging for brain tumor research.

PubMed

Anna, Imiela; Bartosz, Polis; Lech, Polis; Halina, Abramczyk

2017-10-17

Raman diagnostics and imaging have been shown to be an effective tool for the analysis and discrimination of human brain tumors from normal structures. Raman spectroscopic methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n= 5), low-grade astrocytoma (grades I-II WHO) (n =4), ependymoma (n=3) and metastatic brain tumors (n= 1) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma, low grade astrocytoma and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational features and Raman images we provide a real-time feedback method that is label-free to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, proteins, DNA and RNA. Our results indicate marked metabolic differences between low and high grade brain tumors. We discuss molecular mechanisms causing these metabolic changes, particularly lipid alterations in malignant medulloblastoma and low grade gliomas that may shed light on the mechanisms driving tumor recurrence thereby revealing new approaches for the treatment of malignant glioma. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have found that almost all tumors studied in the paper have increased Raman signals of nucleic acids. This increase can be interpreted as increased DNA/RNA turnover in brain tumors. We have shown that the ratio of Raman intensities I 2930 /I 2845 at 2930 and 2845 cm -1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the different lipid and protein contents of cancerous brain tissue compared to the non-tumor tissue. We found that levels of the saturated fatty acids were significantly reduced in the high grade medulloblastoma samples compared with non-tumor brain samples and low grade astrocytoma. Differences were also noted in the n-6/n-3 polyunsaturated fatty acids (PUFA) content between medulloblastoma and non-tumor brain samples. The content of the oleic acid (OA) was significantly smaller in almost all brain high grade brain tumors than that observed in the control samples. It indicates that the fatty acid composition of human brain tumors differs from that found in non-tumor brain tissue. The iodine number N I for the normal brain tissue is 60. For comparison OA has 87, docosahexaenoic acid (DHA) 464, α-linolenic acid (ALA) 274. The high grade tumors have the iodine numbers between that for palmitic acid, stearic acid, arachidic acid (N I =0) and oleic acid (N I =87). Most low grade tumors have N I similar to that of OA. The iodine number for arachidonic acid (AA) (N I =334) is much higher than those observed for all studied samples.

Novel strategies of Raman imaging for brain tumor research

PubMed Central

Anna, Imiela; Bartosz, Polis; Lech, Polis; Halina, Abramczyk

2017-01-01

Raman diagnostics and imaging have been shown to be an effective tool for the analysis and discrimination of human brain tumors from normal structures. Raman spectroscopic methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n= 5), low-grade astrocytoma (grades I-II WHO) (n =4), ependymoma (n=3) and metastatic brain tumors (n= 1) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma, low grade astrocytoma and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational features and Raman images we provide a real–time feedback method that is label-free to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, proteins, DNA and RNA. Our results indicate marked metabolic differences between low and high grade brain tumors. We discuss molecular mechanisms causing these metabolic changes, particularly lipid alterations in malignant medulloblastoma and low grade gliomas that may shed light on the mechanisms driving tumor recurrence thereby revealing new approaches for the treatment of malignant glioma. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have found that almost all tumors studied in the paper have increased Raman signals of nucleic acids. This increase can be interpreted as increased DNA/RNA turnover in brain tumors. We have shown that the ratio of Raman intensities I2930/I2845 at 2930 and 2845 cm-1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the different lipid and protein contents of cancerous brain tissue compared to the non-tumor tissue. We found that levels of the saturated fatty acids were significantly reduced in the high grade medulloblastoma samples compared with non-tumor brain samples and low grade astrocytoma. Differences were also noted in the n-6/n-3 polyunsaturated fatty acids (PUFA) content between medulloblastoma and non-tumor brain samples. The content of the oleic acid (OA) was significantly smaller in almost all brain high grade brain tumors than that observed in the control samples. It indicates that the fatty acid composition of human brain tumors differs from that found in non-tumor brain tissue. The iodine number NI for the normal brain tissue is 60. For comparison OA has 87, docosahexaenoic acid (DHA) 464, α-linolenic acid (ALA) 274. The high grade tumors have the iodine numbers between that for palmitic acid, stearic acid, arachidic acid (NI=0) and oleic acid (NI=87). Most low grade tumors have NI similar to that of OA. The iodine number for arachidonic acid (AA) (NI=334) is much higher than those observed for all studied samples. PMID:29156720

Locally adaptive MR intensity models and MRF-based segmentation of multiple sclerosis lesions

NASA Astrophysics Data System (ADS)

Galimzianova, Alfiia; Lesjak, Žiga; Likar, Boštjan; Pernuš, Franjo; Špiclin, Žiga

2015-03-01

Neuroimaging biomarkers are an important paraclinical tool used to characterize a number of neurological diseases, however, their extraction requires accurate and reliable segmentation of normal and pathological brain structures. For MR images of healthy brains the intensity models of normal-appearing brain tissue (NABT) in combination with Markov random field (MRF) models are known to give reliable and smooth NABT segmentation. However, the presence of pathology, MR intensity bias and natural tissue-dependent intensity variability altogether represent difficult challenges for a reliable estimation of NABT intensity model based on MR images. In this paper, we propose a novel method for segmentation of normal and pathological structures in brain MR images of multiple sclerosis (MS) patients that is based on locally-adaptive NABT model, a robust method for the estimation of model parameters and a MRF-based segmentation framework. Experiments on multi-sequence brain MR images of 27 MS patients show that, compared to whole-brain model and compared to the widely used Expectation-Maximization Segmentation (EMS) method, the locally-adaptive NABT model increases the accuracy of MS lesion segmentation.

Increased IMP dehydrogenase gene expression in solid tumor tissues and tumor cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Collart, F.R.; Chubb, C.B.; Mirkin, B.L.

1992-07-10

IMP dehydrogenase, a regulatory enzyme of guanine nucleotide biosynthesis, may play a role in cell proliferation and malignancy. To assess this possibility, we examined IMP dehydrogenase expression in a series of human solid tumor tissues and tumor cell lines in comparison with their normal counterparts. Increased IMP dehydrogenase gene expression was observed in brain tumors relative to normal brain tissue and in sarcoma cells relative to normal fibroblasts. Similarly, in several B- and T-lymphoid leukemia cell lines, elevated levels of IMP dehydrogenase mRNA and cellular enzyme were observed in comparison with the levels in peripheral blood lymphocytes. These results aremore » consistent with an association between increased IMP dehydrogenase expression and either enhanced cell proliferation or malignant transformation.« less

Bioimaging of metals in brain tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and metallomics.

PubMed

Becker, J Sabine; Matusch, Andreas; Palm, Christoph; Salber, Dagmar; Morton, Kathryn A; Becker, J Susanne

2010-02-01

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been developed and established as an emerging technique in the generation of quantitative images of metal distributions in thin tissue sections of brain samples (such as human, rat and mouse brain), with applications in research related to neurodegenerative disorders. A new analytical protocol is described which includes sample preparation by cryo-cutting of thin tissue sections and matrix-matched laboratory standards, mass spectrometric measurements, data acquisition, and quantitative analysis. Specific examples of the bioimaging of metal distributions in normal rodent brains are provided. Differences to the normal were assessed in a Parkinson's disease and a stroke brain model. Furthermore, changes during normal aging were studied. Powerful analytical techniques are also required for the determination and characterization of metal-containing proteins within a large pool of proteins, e.g., after denaturing or non-denaturing electrophoretic separation of proteins in one-dimensional and two-dimensional gels. LA-ICP-MS can be employed to detect metalloproteins in protein bands or spots separated after gel electrophoresis. MALDI-MS can then be used to identify specific metal-containing proteins in these bands or spots. The combination of these techniques is described in the second section.

Human brain cancer studied by resonance Raman spectroscopy

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-Hui; Sun, Yi; Pu, Yang; Boydston-White, Susie; Liu, Yulong; Alfano, Robert R.

2012-11-01

The resonance Raman (RR) spectra of six types of human brain tissues are examined using a confocal micro-Raman system with 532-nm excitation in vitro. Forty-three RR spectra from seven subjects are investigated. The spectral peaks from malignant meningioma, stage III (cancer), benign meningioma (benign), normal meningeal tissues (normal), glioblastoma multiforme grade IV (cancer), acoustic neuroma (benign), and pituitary adenoma (benign) are analyzed. Using a 532-nm excitation, the resonance-enhanced peak at 1548 cm-1 (amide II) is observed in all of the tissue specimens, but is not observed in the spectra collected using the nonresonance Raman system. An increase in the intensity ratio of 1587 to 1605 cm-1 is observed in the RR spectra collected from meningeal cancer tissue as compared with the spectra collected from the benign and normal meningeal tissue. The peak around 1732 cm-1 attributed to fatty acids (lipids) are diminished in the spectra collected from the meningeal cancer tumors as compared with the spectra from normal and benign tissues. The characteristic band of spectral peaks observed between 2800 and 3100 cm-1 are attributed to the vibrations of methyl (-CH3) and methylene (-CH2-) groups. The ratio of the intensities of the spectral peaks of 2935 to 2880 cm-1 from the meningeal cancer tissues is found to be lower in comparison with that of the spectral peaks from normal, and benign tissues, which may be used as a distinct marker for distinguishing cancerous tissues from normal meningeal tissues. The statistical methods of principal component analysis and the support vector machine are used to analyze the RR spectral data collected from meningeal tissues, yielding a diagnostic sensitivity of 90.9% and specificity of 100% when two principal components are used.

ABERRANT SPLICING OF A BRAIN-ENRICHED ALTERNATIVE EXON ELIMINATES TUMOR SUPPRESSOR FUNCTION AND PROMOTES ONCOGENE FUNCTION DURING BRAIN TUMORIGENESIS

PubMed Central

Bredel, Markus; Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; Elverfeldt, Dominik v.; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.

2014-01-01

BACKGROUND: Tissue-specific alternative splicing is known to be critical to emergence of tissue identity during development, yet its role in malignant transformation is undefined. Tissue-specific splicing involves evolutionary-conserved, alternative exons, which represent only a minority of total alternative exons. Many, however, have functional features that influence activity in signaling pathways to profound biological effect. Given that tissue-specific splicing has a determinative role in brain development and the enrichment of genes containing tissue-specific exons for proteins with roles in signaling and development, it is thus plausible that changes in such exons could rewire normal neurogenesis towards malignant transformation. METHODS: We used integrated molecular genetic and cell biology analyses, computational biology, animal modeling, and clinical patient profiles to characterize the effect of aberrant splicing of a brain-enriched alternative exon in the membrane-binding tumor suppressor Annexin A7 (ANXA7) on oncogene regulation and brain tumorigenesis. RESULTS: We show that aberrant splicing of a tissue-specific cassette exon in ANXA7 diminishes endosomal targeting and consequent termination of the signal of the EGFR oncoprotein during brain tumorigenesis. Splicing of this exon is mediated by the ribonucleoprotein Polypyrimidine Tract-Binding Protein 1 (PTBP1), which is normally repressed during brain development but, we find, is excessively expressed in glioblastomas through either gene amplification or loss of a neuron-specific microRNA, miR-124. Silencing of PTBP1 attenuates both malignancy and angiogenesis in a stem cell-derived glioblastoma animal model characterized by a high native propensity to generate tumor endothelium or vascular pericytes to support tumor growth. We show that EGFR amplification and PTBP1 overexpression portend a similarly poor clinical outcome, further highlighting the importance of PTBP1-mediated activation of EGFR. CONCLUSIONS: Our data illustrate how anomalous splicing of a tissue-regulated exon in a constituent of an oncogenic signaling pathway eliminates its tumor suppressor function and promotes tumorigenesis. This paradigm of malignant glial transformation as a consequence of tissue-specific alternative exon splicing in a tumor suppressor, may have widespread applicability in explaining how changes in critical tissue-specific regulatory mechanisms reprogram normal development to oncogenesis. SECONDARY CATEGORY: n/a.

Optimization of Treatment Geometry to Reduce Normal Brain Dose in Radiosurgery of Multiple Brain Metastases with Single-Isocenter Volumetric Modulated Arc Therapy.

PubMed

Wu, Qixue; Snyder, Karen Chin; Liu, Chang; Huang, Yimei; Zhao, Bo; Chetty, Indrin J; Wen, Ning

2016-09-30

Treatment of patients with multiple brain metastases using a single-isocenter volumetric modulated arc therapy (VMAT) has been shown to decrease treatment time with the tradeoff of larger low dose to the normal brain tissue. We have developed an efficient Projection Summing Optimization Algorithm to optimize the treatment geometry in order to reduce dose to normal brain tissue for radiosurgery of multiple metastases with single-isocenter VMAT. The algorithm: (a) measures coordinates of outer boundary points of each lesion to be treated using the Eclipse Scripting Application Programming Interface, (b) determines the rotations of couch, collimator, and gantry using three matrices about the cardinal axes, (c) projects the outer boundary points of the lesion on to Beam Eye View projection plane, (d) optimizes couch and collimator angles by selecting the least total unblocked area for each specific treatment arc, and (e) generates a treatment plan with the optimized angles. The results showed significant reduction in the mean dose and low dose volume to normal brain, while maintaining the similar treatment plan qualities on the thirteen patients treated previously. The algorithm has the flexibility with regard to the beam arrangements and can be integrated in the treatment planning system for clinical application directly.

Rough Sets and Stomped Normal Distribution for Simultaneous Segmentation and Bias Field Correction in Brain MR Images.

PubMed

Banerjee, Abhirup; Maji, Pradipta

2015-12-01

The segmentation of brain MR images into different tissue classes is an important task for automatic image analysis technique, particularly due to the presence of intensity inhomogeneity artifact in MR images. In this regard, this paper presents a novel approach for simultaneous segmentation and bias field correction in brain MR images. It integrates judiciously the concept of rough sets and the merit of a novel probability distribution, called stomped normal (SN) distribution. The intensity distribution of a tissue class is represented by SN distribution, where each tissue class consists of a crisp lower approximation and a probabilistic boundary region. The intensity distribution of brain MR image is modeled as a mixture of finite number of SN distributions and one uniform distribution. The proposed method incorporates both the expectation-maximization and hidden Markov random field frameworks to provide an accurate and robust segmentation. The performance of the proposed approach, along with a comparison with related methods, is demonstrated on a set of synthetic and real brain MR images for different bias fields and noise levels.

Astrocytes.

ERIC Educational Resources Information Center

Kimelberg, Harold K.; Norenberg, Michael D.

1989-01-01

Describes the astrocytes' function as equal partners with neurons in both the normal and the abnormal brain. Discusses the developmental scaffolds, inert scar tissue, Huntington's disease, psychiatric disorders, and the identification of these brain cells. (RT)

Calculation of Absorbed Dose in Target Tissue and Equivalent Dose in Sensitive Tissues of Patients Treated by BNCT Using MCNP4C

NASA Astrophysics Data System (ADS)

Zamani, M.; Kasesaz, Y.; Khalafi, H.; Pooya, S. M. Hosseini

Boron Neutron Capture Therapy (BNCT) is used for treatment of many diseases, including brain tumors, in many medical centers. In this method, a target area (e.g., head of patient) is irradiated by some optimized and suitable neutron fields such as research nuclear reactors. Aiming at protection of healthy tissues which are located in the vicinity of irradiated tissue, and based on the ALARA principle, it is required to prevent unnecessary exposure of these vital organs. In this study, by using numerical simulation method (MCNP4C Code), the absorbed dose in target tissue and the equiavalent dose in different sensitive tissues of a patiant treated by BNCT, are calculated. For this purpose, we have used the parameters of MIRD Standard Phantom. Equiavelent dose in 11 sensitive organs, located in the vicinity of target, and total equivalent dose in whole body, have been calculated. The results show that the absorbed dose in tumor and normal tissue of brain equal to 30.35 Gy and 0.19 Gy, respectively. Also, total equivalent dose in 11 sensitive organs, other than tumor and normal tissue of brain, is equal to 14 mGy. The maximum equivalent doses in organs, other than brain and tumor, appear to the tissues of lungs and thyroid and are equal to 7.35 mSv and 3.00 mSv, respectively.

Effects of the Variation in Brain Tissue Mechanical Properties on the Intracranial Response of a 6-Year-Old Child

PubMed Central

Cui, Shihai; Li, Haiyan; Li, Xiangnan; Ruan, Jesse

2015-01-01

Brain tissue mechanical properties are of importance to investigate child head injury using finite element (FE) method. However, these properties used in child head FE model normally vary in a large range in published literatures because of the insufficient child cadaver experiments. In this work, a head FE model with detailed anatomical structures is developed from the computed tomography (CT) data of a 6-year-old healthy child head. The effects of brain tissue mechanical properties on traumatic brain response are also analyzed by reconstruction of a head impact on engine hood according to Euro-NCAP testing regulation using FE method. The result showed that the variations of brain tissue mechanical parameters in linear viscoelastic constitutive model had different influences on the intracranial response. Furthermore, the opposite trend was obtained in the predicted shear stress and shear strain of brain tissues caused by the variations of mentioned parameters. PMID:26495031

Evaluation of Raman spectra of human brain tumor tissue using the learning vector quantization neural network

NASA Astrophysics Data System (ADS)

Liu, Tuo; Chen, Changshui; Shi, Xingzhe; Liu, Chengyong

2016-05-01

The Raman spectra of tissue of 20 brain tumor patients was recorded using a confocal microlaser Raman spectroscope with 785 nm excitation in vitro. A total of 133 spectra were investigated. Spectra peaks from normal white matter tissue and tumor tissue were analyzed. Algorithms, such as principal component analysis, linear discriminant analysis, and the support vector machine, are commonly used to analyze spectral data. However, in this study, we employed the learning vector quantization (LVQ) neural network, which is typically used for pattern recognition. By applying the proposed method, a normal diagnosis accuracy of 85.7% and a glioma diagnosis accuracy of 89.5% were achieved. The LVQ neural network is a recent approach to excavating Raman spectra information. Moreover, it is fast and convenient, does not require the spectra peak counterpart, and achieves a relatively high accuracy. It can be used in brain tumor prognostics and in helping to optimize the cutting margins of gliomas.

Computational analysis of transcranial magnetic stimulation in the presence of deep brain stimulation probes

NASA Astrophysics Data System (ADS)

Syeda, F.; Holloway, K.; El-Gendy, A. A.; Hadimani, R. L.

2017-05-01

Transcranial Magnetic Stimulation is an emerging non-invasive treatment for depression, Parkinson's disease, and a variety of other neurological disorders. Many Parkinson's patients receive the treatment known as Deep Brain Stimulation, but often require additional therapy for speech and swallowing impairment. Transcranial Magnetic Stimulation has been explored as a possible treatment by stimulating the mouth motor area of the brain. We have calculated induced electric field, magnetic field, and temperature distributions in the brain using finite element analysis and anatomically realistic heterogeneous head models fitted with Deep Brain Stimulation leads. A Figure of 8 coil, current of 5000 A, and frequency of 2.5 kHz are used as simulation parameters. Results suggest that Deep Brain Stimulation leads cause surrounding tissues to experience slightly increased E-field (Δ Emax =30 V/m), but not exceeding the nominal values induced in brain tissue by Transcranial Magnetic Stimulation without leads (215 V/m). The maximum temperature in the brain tissues surrounding leads did not change significantly from the normal human body temperature of 37 °C. Therefore, we ascertain that Transcranial Magnetic Stimulation in the mouth motor area may stimulate brain tissue surrounding Deep Brain Stimulation leads, but will not cause tissue damage.

Nanoparticle-assisted photothermal ablation of brain tumor in an orthotopic canine model

NASA Astrophysics Data System (ADS)

Schwartz, Jon A.; Shetty, Anil M.; Price, Roger E.; Stafford, R. Jason; Wang, James C.; Uthamanthil, Rajesh K.; Pham, Kevin; McNichols, Roger J.; Coleman, Chris L.; Payne, J. Donald

2009-02-01

We report on a pilot study demonstrating a proof of concept for the passive delivery of nanoshells to an orthotopic tumor where they induce a local, confined therapeutic response distinct from that of normal brain resulting in the photo-thermal ablation of canine Transmissible Venereal Tumor (cTVT) in a canine brain model. cTVT fragments grown in SCID mice were successfully inoculated in the parietal lobe of immuno-suppressed, mixed-breed hound dogs. A single dose of near-infrared absorbing, 150 nm nanoshells was infused intravenously and allowed time to passively accumulate in the intracranial tumors which served as a proxy for an orthotopic brain metastasis. The nanoshells accumulated within the intracranial cTVT suggesting that its neo-vasculature represented an interruption of the normal blood-brain barrier. Tumors were thermally ablated by percutaneous, optical fiber-delivered, near-infrared radiation using a 3.5 W average, 3-minute laser dose at 808 nm that selectively elevated the temperature of tumor tissue to 65.8+/-4.1ºC. Identical laser doses applied to normal white and gray matter on the contralateral side of the brain yielded sub-lethal temperatures of 48.6+/-1.1ºC. The laser dose was designed to minimize thermal damage to normal brain tissue in the absence of nanoshells and compensate for variability in the accumulation of nanoshells in tumor. Post-mortem histopathology of treated brain sections demonstrated the effectiveness and selectivity of the nanoshell-assisted thermal ablation.

[Research of anti-aging mechanism of ginsenoside Rg1 on brain].

PubMed

Li, Cheng-peng; Zhang, Meng-si; Liu, Jun; Geng, Shan; Li, Jing; Zhu, Jia-hong; Zhang, Yan-yan; Jia, Yan-yan; Wang, Lu; Wang, Shun-he; Wang, Ya-ping

2014-11-01

Neurodegenerative disease is common and frequently occurs in elderly patients. Previous studies have shown that ginsenoside Rg1 was able to inhibit senescent of brain, but the mechanism on the brain during the treatment remains elucidated. To study the mechanism of ginsenoside Rg1 in the process of anti-aging of brain, forty male SD rats were randomly divided into normal group, Rg1 normal group, brain aging model group and Rg1 brain aging model group, each group with 10 rats (brain aging model group: subcutaneous injection of D-galactose (120 mg kg(-1)), qd for 42 consecutive days; Rg1 brain aging model group: while copying the same test as that of brain aging model group, begin intraperitoneal injection of ginsenosides Rg1 (20 mg x kg(-1)) qd for 27 d from 16 d. Rg1 normal group: subcutaneous injection of the same amount of saline; begin intraperitoneal injection of ginsenosides Rg1 (20 mg x kg(-1)) qd for 27 d from 16 d. Normal: injected with an equal volume of saline within the same time. Perform the related experiment on the second day after finishing copying the model or the completion of the first two days of drug injections). Learning and memory abilities were measured by Morris water maze. The number of senescent cells was detected by SA-beta-Gal staining while the level of IL-1 and IL-6 proinflammatory cytokines in hippocampus were detected by ELISA. The activities of SOD, contents of GSH in hippo- campus were quantified by chromatometry. The change of telomerase activities and telomerase length were performed by TRAP-PCR and southern blotting assay, respectively. It is pointed that, in brain aging model group, the spatial learning and memory capacities were weaken, SA-beta-Gal positive granules increased in section of brain tissue, the activity of antioxidant enzyme SOD and the contents of GSH decreased in hippocampus, the level of IL-1 and IL-6 increased in hippocampus, while the length of telomere and the activity of telomerase decreased in hippocampus. Rats of Rg1 brain aging group had their spatial learning and memory capacities enhanced, SA-beta-Gal positive granules in section of brain tissue decreased, the activity of antioxidant enzyme SOD and the contents of GSH increased in hippocampus, the level of IL-1 and IL-6 in hippocampus decreased, the length contraction of telomere suppressed while the change of telomerase activity increased in hippocampus. Compared with that of normal group, the spatial learning and memory capacities were enhanced in Rg1 normal group, SA-beta-Gal positive granules in section of brain tissue decreased in Rg1 normal group, the level of IL-1 and IL-6 in hippocampus decreased in Rg1 normal group. The results indicated that improvement of antioxidant ability, regulating the level of proinflammatory cytokines and regulation of telomerase system may be the underlying anti-aging mechanism of Ginsenoside Rg1.

In Silico Neuro-Oncology: Brownian Motion-Based Mathematical Treatment as a Potential Platform for Modeling the Infiltration of Glioma Cells into Normal Brain Tissue.

PubMed

Antonopoulos, Markos; Stamatakos, Georgios

2015-01-01

Intensive glioma tumor infiltration into the surrounding normal brain tissues is one of the most critical causes of glioma treatment failure. To quantitatively understand and mathematically simulate this phenomenon, several diffusion-based mathematical models have appeared in the literature. The majority of them ignore the anisotropic character of diffusion of glioma cells since availability of pertinent truly exploitable tomographic imaging data is limited. Aiming at enriching the anisotropy-enhanced glioma model weaponry so as to increase the potential of exploiting available tomographic imaging data, we propose a Brownian motion-based mathematical analysis that could serve as the basis for a simulation model estimating the infiltration of glioblastoma cells into the surrounding brain tissue. The analysis is based on clinical observations and exploits diffusion tensor imaging (DTI) data. Numerical simulations and suggestions for further elaboration are provided.

Focused Ultrasound Immunotherapy for Central Nervous System Pathologies: Challenges and Opportunities

PubMed Central

Curley, Colleen T.; Sheybani, Natasha D.; Bullock, Timothy N.; Price, Richard J.

2017-01-01

Immunotherapy is rapidly emerging as the cornerstone for the treatment of several forms of metastatic cancer, as well as for a host of other pathologies. Meanwhile, several new high-profile studies have uncovered remarkable linkages between the central nervous and immune systems. With these recent developments, harnessing the immune system for the treatment of brain pathologies is a promising strategy. Here, we contend that MR image-guided focused ultrasound (FUS) represents a noninvasive approach that will allow for favorable therapeutic immunomodulation in the setting of the central nervous system. One obstacle to effective immunotherapeutic drug delivery to the brain is the blood brain barrier (BBB), which refers to the specialized structure of brain capillaries that prevents transport of most therapeutics from the blood into brain tissue. When applied in the presence of circulating microbubbles, FUS can safely and transiently open the BBB to facilitate the delivery of immunotherapeutic agents into the brain parenchyma. Furthermore, it has been demonstrated that physical perturbations of the tissue microenvironment via FUS can modulate immune response in both normal and diseased tissue. In this review article, we provide an overview of FUS energy regimens and corresponding tissue bioeffects, followed by a review of the literature pertaining to FUS for therapeutic antibody delivery in normal brain and preclinical models of brain disease. We provide an overview of studies that demonstrate FUS-mediated immune modulation in both the brain and peripheral settings. Finally, we provide remarks on challenges facing FUS immunotherapy and opportunities for future expansion in this area. PMID:29109764

Fluorescence intensity and bright spot analyses using a confocal microscope for photodynamic diagnosis of brain tumors.

PubMed

Yoneyama, Takeshi; Watanabe, Tetsuyo; Kagawa, Hiroyuki; Hayashi, Yutaka; Nakada, Mitsutoshi

2017-03-01

In photodynamic diagnosis using 5-aminolevulinic acid (5-ALA), discrimination between the tumor and normal tissue is very important for a precise resection. However, it is difficult to distinguish between infiltrating tumor and normal regions in the boundary area. In this study, fluorescent intensity and bright spot analyses using a confocal microscope is proposed for the precise discrimination between infiltrating tumor and normal regions. From the 5-ALA-resected brain tumor tissue, the red fluorescent and marginal regions were sliced for observation under a confocal microscope. Hematoxylin and eosin (H&E) staining were performed on serial slices of the same tissue. According to the pathological inspection of the H&E slides, the tumor and infiltrating and normal regions on confocal microscopy images were investigated. From the fluorescent intensity of the image pixels, a histogram of pixel number with the same fluorescent intensity was obtained. The fluorescent bright spot sizes and total number were compared between the marginal and normal regions. The fluorescence intensity distribution and average intensity in the tumor were different from those in the normal region. The probability of a difference from the dark enhanced the difference between the tumor and the normal region. The bright spot size and number in the infiltrating tumor were different from those in the normal region. Fluorescence intensity analysis is useful to distinguish a tumor region, and a bright spot analysis is useful to distinguish between infiltrating tumor and normal regions. These methods will be important for the precise resection or photodynamic therapy of brain tumors. Copyright © 2016 Elsevier B.V. All rights reserved.

Genetics Home Reference: acrocallosal syndrome

MedlinePlus

... callosum occurs when the tissue that connects the left and right halves of the brain (the corpus callosum ) fails to form normally during the early stages of development before birth. Other brain abnormalities, including the growth ...

VARIATION IN CHOLINESTERASE ACTIVITY IN TISSUES OF RATS AT DIFFERENT TIMES AFTER IRRADIATION (in Russian)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zubkova, S.R.; Chernavskaya, N.M.

1959-06-11

It was found that a single lethal dose (1000 r) changes the cholinesterase activity in the brain, liver, and blood serum. After 5 hr and 45 min the cholinesterase activity in tissues drops from the normal level (15.9% in blood serum, 20.6% in the brain, and 18.4% in the liver). After three days the activity changes in various tissues: in the liver it continues to drop, in the brain it rises but does not reach the standard level, and it increases sharply in the blood serum. (R.V.J.)

Clinical applications of image guided-intensity modulated radiation therapy (IG-IMRT) for conformal avoidance of normal tissue

NASA Astrophysics Data System (ADS)

Gutierrez, Alonso Navar

2007-12-01

Recent improvements in imaging technology and radiation delivery have led to the development of advanced treatment techniques in radiotherapy which have opened the door for novel therapeutic approaches to improve the efficacy of radiation cancer treatments. Among these advances is image-guided, intensity modulated radiation therapy (IG-IMRT), in which imaging is incorporated to aid in inter-/intra-fractional target localization and to ensure accurate delivery of precise and highly conformal dose distributions. In principle, clinical implementation of IG-IMRT should improve normal tissue sparing and permit effective biological dose escalation thus widening the radiation therapeutic window and lead to increases in survival through improved local control of primary neoplastic diseases. Details of the development of three clinical applications made possible solely with IG-IMRT radiation delivery techniques are presented: (1) Laparoscopically implanted tissue expander radiotherapy (LITE-RT) has been developed to enhance conformal avoidance of normal tissue during the treatment of intra-abdominopelvic cancers. LITE-RT functions by geometrically displacing surrounding normal tissue and isolating the target volume through the interfractional inflation of a custom-shaped tissue expander throughout the course of treatment. (2) The unique delivery geometry of helical tomotherapy, a novel form of IG-IMRT, enables the delivery of composite treatment plan m which whole brain radiotherapy (WBRT) with hippocampal avoidance, hypothesized to reduce the risk of memory function decline and improve the patient's quality of life, and simultaneously integrated boost to multiple brain metastases to improve intracranial tumor control is achieved. (3) Escalation of biological dose to targets through integrated, selective subvolume boosts have been shown to efficiently increase tumor dose without significantly increasing normal tissue dose. Helical tomotherapy was used to investigate the feasibility of delivering a simultaneously integrated subvolume boost to canine nasal tumors and was found to dramatically increase estimated 1-year tumor control probability (TCP) without increasing the dose to the eyes, so as to preserve vision, and to the brain, so as to prevent neuropathy.

Brain tissue water content in patients with idiopathic normal pressure hydrocephalus.

PubMed

Aygok, G; Marmarou, A; Fatouros, P; Young, H

2006-01-01

Relatively little is known regarding the water content of brain tissue in idiopathic normal-pressure hydrocephalus (NPH) patients. The objective of our study was to determine absolute water content non-invasively in hydrocephalic patients, particularly in the anterior and posterior ventricular horns and in the periventricular white matter. Ten patients who were diagnosed and treated for idiopathic NPH in our clinic were selected for study. Magnetic resonance imaging (MRI) techniques were used to obtain anatomical image slices for quantitative brain water measurements. Apparent diffusion coefficient measures were also extracted from regions of interest. To our knowledge, this is the first study to confirm that periventricular lucency seen on MRI represents increased water content in the extracellular space that is markedly elevated prior to shunting.

Aberrant rhythmic expression of cryptochrome2 regulates the radiosensitivity of rat gliomas.

PubMed

Fan, Wang; Caiyan, Li; Ling, Zhu; Jiayun, Zhao

2017-09-29

In this study, we investigated the role of the clock regulatory protein cryptochrome 2 (Cry2) in determining the radiosensitivity of C6 glioma cells in a rat model. We observed that Cry2 mRNA and protein levels showed aberrant rhythmic periodicity of 8 h in glioma tissues, compared to 24 h in normal brain tissue. Cry2 mRNA and protein levels did not respond to irradiation in normal tissues, but both were increased at the ZT4 (low Cry2) and ZT8 (high Cry2) time points in gliomas. Immunohistochemical staining of PCNA and TUNEL assays demonstrated that high Cry2 expression in glioma tissues was associated with increased cell proliferation and decreased apoptosis. Western blot analysis showed that glioma cell fate was independent of p53, but was probably dependent on p73, which was more highly expressed at ZT4 (low Cry2) than at ZT8 (high Cry2). Levels of both p53 and p73 were unaffected by irradiation in normal brain tissues. These findings suggest aberrant rhythmic expression of Cry2 influence on radiosensitivity in rat gliomas.

Viral Immunotherapy to Eradicate Subclinical Brain Metastases

DTIC Science & Technology

2014-05-01

host innate and adaptive immune cells in metastases and normal tissues i. Months 6-21 ii. Basse Brain tissue with D2F2/E2 tumors from animals...and viral antigens which could activate memory T- cells in the draining lymphoid organs. Time course studies showed that virus infection produced a 2.6... lymphoid tissues. III. ACTIVATED NK CELLS LOCALIZE EFFICIENTLY AT TUMOR SITES The densities of NK cells found in well-established tumors in most

NI-16INTRA-OPERATIVE USE OF FLUORESCEIN FOR MALIGNANT GLIOMA RESECTION DIFFERENTIATES TUMOR FROM NORMAL BRAIN TISSUE BASED ON HISTOPATHOLOGIC ANALYSIS

PubMed Central

Decker, Matthew; Kresak, Jesse; Yachnis, Anthony; Bova, Frank; Rahman, Maryam

2014-01-01

OBJECTIVES: To determine whether the use of IV fluorescein during surgery for malignant glioma can reliably be used to differentiate between infiltrative tumor and normal brain tissue. BACKGROUND: Fluorescein sodium is a molecular compound with fluorescent capabilities between light wavelengths of 520-530nm, appearing yellow-green (1). Neurosurgical application of fluorescein has been studied primarily for increasing intra-operative visibility of malignant gliomas (1). The mechanism of action has been hypothesized to involve disruption of the blood brain barrier (BBB) (2). Cells in areas with disrupted BBB take up fluorescein with a sensitivity of 94% and specificity of 89% for high-grade gliomas (2). We performed histopathologic analysis on tissue obtained during fluorescein-guided tumor resections to evaluate the differences between fluorescent and non-fluorescent tissue. METHODS: Two adult patients with suspected high-grade gliomas underwent surgical resection. Prior to opening of the dura 3mg/kg of IV fluorescein was given. A Zeiss OPMI Pentero microscope (Carl Zeiss Meditech Inc.) with a yellow 560nm filter was used to visualize the tumor. At the tumor margins, tissue was identified as "bright" and "dark" and sent as separate specimens for histopathological analysis. RESULTS: Histological sections of specimens labeled "bright" contained infiltrating glioma with focal microvascular proliferation. Histological sections of specimens labeled "dark" contained gray matter and focal subcortical white matter with no high-grade glioma identified. Final grading for both patients was WHO Grade IV, glioblastoma. CONCLUSION: Intra-operative use of fluorescein in surgical resection of malignant gliomas can help to distinguish between infiltrating tumor and normal brain tissue based on histopathological analysis. Further evaluation of the utility of flurorescein during high and low-grade glioma surgery is necessary.

In vitro terahertz spectroscopy of gelatin-embedded human brain tumors: a pilot study

NASA Astrophysics Data System (ADS)

Chernomyrdin, N. V.; Gavdush, A. A.; Beshplav, S.-I. T.; Malakhov, K. M.; Kucheryavenko, A. S.; Katyba, G. M.; Dolganova, I. N.; Goryaynov, S. A.; Karasik, V. E.; Spektor, I. E.; Kurlov, V. N.; Yurchenko, S. O.; Komandin, G. A.; Potapov, A. A.; Tuchin, V. V.; Zaytsev, K. I.

2018-04-01

We have performed the in vitro terahertz (THz) spectroscopy of human brain tumors. In order to fix tissues for the THz measurements, we have applied the gelatin embedding. It allows for preserving tissues from hydration/dehydration and sustaining their THz response similar to that of the freshly-excised tissues for a long time after resection. We have assembled an experimental setup for the reflection-mode measurements of human brain tissues based on the THz pulsed spectrometer. We have used this setup to study in vitro the refractive index and the amplitude absorption coefficient of 2 samples of malignant glioma (grade IV), 1 sample of meningioma (grade I), and samples of intact tissues. We have observed significant differences between the THz responses of normal and pathological tissues of the brain. The results of this paper highlight the potential of the THz technology in the intraoperative neurodiagnosis of tumors relying on the endogenous labels of tumorous tissues.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy.

PubMed

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue; Wu, Yuan-Hung

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting.

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy

PubMed Central

Lee, Jia-Cheng; Chuang, Keh-Shih; Chen, Yi-Wei; Hsu, Fang-Yuh; Chou, Fong-In; Yen, Sang-Hue

2017-01-01

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting. PMID:28662135

Brain tissues volume measurements from 2D MRI using parametric approach

NASA Astrophysics Data System (ADS)

L'vov, A. A.; Toropova, O. A.; Litovka, Yu. V.

2018-04-01

The purpose of the paper is to propose a fully automated method of volume assessment of structures within human brain. Our statistical approach uses maximum interdependency principle for decision making process of measurements consistency and unequal observations. Detecting outliers performed using maximum normalized residual test. We propose a statistical model which utilizes knowledge of tissues distribution in human brain and applies partial data restoration for precision improvement. The approach proposes completed computationally efficient and independent from segmentation algorithm used in the application.

Regional muscle tissue saturation is an indicator of global inadequate circulation during cardiopulmonary bypass: a randomized porcine study using muscle, intestinal and brain tissue metabolomics.

PubMed

Thomassen, Sisse Anette; Kjærgaard, Benedict; Sørensen, Preben; Andreasen, Jan Jesper; Larsson, Anders; Rasmussen, Bodil Steen

2017-04-01

Muscle tissue saturation (StO 2 ) measured with near-infrared spectroscopy has generally been considered a measurement of the tissue microcirculatory condition. However, we hypothesized that StO 2 could be more regarded as a fast and reliable measure of global than of regional circulatory adequacy and tested this with muscle, intestinal and brain metabolomics at normal and two levels of low cardiopulmonary bypass blood flow rates in a porcine model. Twelve 80 kg pigs were connected to normothermic cardiopulmonary bypass with a blood flow of 60 mL/kg/min for one hour, reduced randomly to 47.5 mL/kg/min (Group I) or 35 mL/kg/min (Group II) for one hour followed by one hour of 60 mL/kg/min in both groups. Regional StO 2 was measured continuously above the musculus gracilis (non-cannulated leg). Metabolomics were obtained by brain tissue oxygen monitoring system (Licox) measurements of the brain and microdialysis perfusate from the muscle, intestinal mucosa and brain. A non-parametric statistical method was used. The systemic parameters showed profound systemic ischaemia during low CPB blood flow. StO 2 did not change markedly in Group I, but in Group II, StO 2 decreased immediately when blood flow was reduced and, furthermore, was not restored despite blood flow being normalized. Changes in the metabolomics from the muscle, colon and brain followed the changes in StO 2 . We found, in this experimental cardiopulmonary bypass model, that StO 2 reacted rapidly when the systemic circulation became inadequate and, furthermore, reliably indicate insufficient global tissue perfusion even when the systemic circulation was restored after a period of systemic hypoperfusion.

Distribution of the anticancer drugs doxorubicin, mitoxantrone and topotecan in tumors and normal tissues.

PubMed

Patel, Krupa J; Trédan, Olivier; Tannock, Ian F

2013-07-01

Pharmacokinetic analyses estimate the mean concentration of drug within a given tissue as a function of time, but do not give information about the spatial distribution of drugs within that tissue. Here, we compare the time-dependent spatial distribution of three anticancer drugs within tumors, heart, kidney, liver and brain. Mice bearing various xenografts were treated with doxorubicin, mitoxantrone or topotecan. At various times after injection, tumors and samples of heart, kidney, liver and brain were excised. Within solid tumors, the distribution of doxorubicin, mitoxantrone and topotecan was limited to perivascular regions at 10 min after administration and the distance from blood vessels at which drug intensity fell to half was ~25-75 μm. Although drug distribution improved after 3 and 24 h, there remained a significant decrease in drug fluorescence with increasing distance from tumor blood vessels. Drug distribution was relatively uniform in the heart, kidney and liver with substantially greater perivascular drug uptake than in tumors. There was significantly higher total drug fluorescence in the liver than in tumors after 10 min, 3 and 24 h. Little to no drug fluorescence was observed in the brain. There are marked differences in the spatial distributions of three anticancer drugs within tumor tissue and normal tissues over time, with greater exposure to most normal tissues and limited drug distribution to many cells in tumors. Studies of the spatial distribution of drugs are required to complement pharmacokinetic data in order to better understand and predict drug effects and toxicities.

16S rRNA Next Generation Sequencing Analysis Shows Bacteria in Alzheimer’s Post-Mortem Brain

PubMed Central

Emery, David C.; Shoemark, Deborah K.; Batstone, Tom E.; Waterfall, Christy M.; Coghill, Jane A.; Cerajewska, Tanya L.; Davies, Maria; West, Nicola X.; Allen, Shelley J.

2017-01-01

The neurological deterioration associated with Alzheimer’s disease (AD), involving accumulation of amyloid-beta peptides and neurofibrillary tangles, is associated with evident neuroinflammation. This is now seen to be a significant contributor to pathology. Recently the tenet of the privileged status of the brain, regarding microbial compromise, has been questioned, particularly in terms of neurodegenerative diseases. It is now being considered that microbiological incursion into the central nervous system could be either an initiator or significant contributor to these. This is a novel study using 16S ribosomal gene-specific Next generation sequencing (NGS) of extracted brain tissue. A comparison was made of the bacterial species content of both frozen and formaldehyde fixed sections of a small cohort of Alzheimer-affected cases with those of cognitively unimpaired (normal). Our findings suggest an increase in bacterial populations in Alzheimer brain tissue compared with normal. PMID:28676754

Comparison of the behavior of normal factor IX and the factor IX Bm variant Hilo in the prothrombin time test using tissue factors from bovine, human, and rabbit sources.

PubMed

Lefkowitz, J B; Monroe, D M; Kasper, C K; Roberts, H R

1993-07-01

A subset of hemophilia B patients have a prolonged bovine-brain prothrombin time. These CRM+ patients are classified as having hemophilia Bm. The prolongation of the prothrombin time has been reported only with bovine brain (referred to as ox brain in some literature) as the source of thromboplastin; prothrombin times determined with thromboplastin from rabbit brain or human brain are not reported to be prolonged. Factor IX from a hemophilia Bm patient (factor IX Hilo) was isolated. The activity of factor IX Hilo was compared to that of normal factor IX in prothrombin time assays when the thromboplastin source was of bovine, rabbit, or human origin. Factor IX, either normal or Hilo, prolonged a prothrombin time regardless of the tissue factor source. However, unless thromboplastin was from a bovine source, this prolongation required high concentrations of factor IX. Further, factor IX normal was as effective as factor IX Hilo in prolonging the prothrombin time when rabbit or human thromboplastin was used. With bovine thromboplastin, factor IX Hilo was significantly better than factor IX normal at prolonging the prothrombin time. The amount of prolongation was dependent on the amount of factor IX Hilo added. In addition, the prolongation was dependent on the concentration of factor X present in the sample. The prothrombin time changed as much as 20 seconds when the factor X concentration was varied from 50% to 150% to normal (fixed concentration of factor IX Hilo). These results demonstrate the difficulty of classifying the severity of a hemophilia Bm patient based on the bovine brain prothrombin time unless both the factor IX and factor X concentrations are known.

Evidence for the absence of cerebral glucose-6-phosphatase activity in glycogen storage disease type I (Von Gierke's disease)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phelps, M.E.; Mazziotta, J.C.; Hawkins, R.A.

1981-01-01

Glycogen storage disease type I (GSD-I) is characterized by a functional deficit in glucose-6-phosphatase that normally hydrolyzes glucose-6-PO/sub 4/ to glucose. This enzyme is primarily found in liver, kidney, and muscle but it is also present in brain, where it appears to participate in the regulation of cerebral tissue glucose. Since most neurological symptoms in GSD-I patients involve systemic hypoglycemia, previous reports have not examined possible deficiencies in phosphatase activity in the brain. Positron computed tomography, F-18-labeled 2-fluorodeoxyglucose (FDG) and a tracer kinetic model for FDG were used to measure the cortical plasma/tissue forward and reverse transport, phosphorylation and dephosphorylationmore » rate constants, tissue/plasma concentration gradient, tissue concentration turnover rate for this competitive analog of glucose, and the cortical metabolic rates for glucose. Studies were carried out in age-matched normals (N = 13) and a single GSD-I patient. The dephosphorylation rate constant in the GSD-I patient was about one tenth the normal value indicating a low level of cerebral phosphatase activity. The other measured parameters were within normal limits except for the rate of glucose phosphorylation which reflected a cortical glucose metabolic rate one half the normal value. Since glucose transport and tissue glucose concentration was normal, the reduced cortical glucose metabolism probably results from the use of alternative substrates (..beta..-hydroxybutyrate and acetoacetate) which are consistently elevated in the plasma of GSD-I patients.« less

Targeting Phosphatidylserine for Radioimmunotherapy of Breast Cancer Brain Metastasis

DTIC Science & Technology

2015-12-01

response. e. Correlate imaging findings with histological studies of vascular damage, tumor cell and endothelial cell apoptosis or necrosis and vascular ...phosphatidylserine (PS) is exposed exclusively on tumor vascular endothelium of brain metastases in mouse models. A novel PS-targeting antibody, PGN635... vascular endothelial cells in multi-focal brain metastases throughout the whole mouse brain. Vascular endothelium in normal brain tissues is negative

Tissue and organ donation for research in forensic pathology: the MRC Sudden Death Brain and Tissue Bank.

PubMed

Millar, T; Walker, R; Arango, J-C; Ironside, J W; Harrison, D J; MacIntyre, D J; Blackwood, D; Smith, C; Bell, J E

2007-12-01

Novel methodological approaches to the investigation of brain and non-central nervous system disorders have led to increased demand for well-characterized, high quality human tissue samples, particularly from control cases. In the setting of the new Human Tissue legislation, we sought to determine whether relatives who have been suddenly bereaved are willing to grant authorization for research use of post mortem tissue samples and organs in sufficient numbers to support the establishment of a brain and tissue bank based in the forensic service. Research authorization was sought from families on the day prior to forensic post mortem examination followed up by written confirmation. We have to date selected individuals who have died suddenly (age range 1-89 years) and who were likely to have normal brains or who had displayed symptoms of a CNS disorder of interest to researchers, including psychiatric disorders. One hundred and eleven families have been approached during the first 2 years of this project. Research use of tissue samples was authorized by 96% of families and 17% agreed to whole brain donation. Audit of families' experience does not suggest that they are further distressed by being approached. Respondents expressed a clear view that the opportunity for research donation should be open to all bereaved families. Despite the sometimes long post mortem intervals, the quality of tissue samples is good, as assessed by a range of markers including Agilent BioAnalyzer quantification of RNA integrity (mean value 6.4). We conclude that the vast majority of families are willing to support research use of post mortem tissues even in the context of sudden bereavement and despite previous adverse publicity. The potential for acquisition of normal CNS and non-CNS tissues and of various hard-to-get CNS disorders suggests that efforts to access the forensic post mortem service for research material are eminently worthwhile. (c) 2007 Pathological Society of Great Britain and Ireland

Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I.

PubMed

Kakkis, E; McEntee, M; Vogler, C; Le, S; Levy, B; Belichenko, P; Mobley, W; Dickson, P; Hanson, S; Passage, M

2004-01-01

Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood-brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human alpha-L-iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose-response study showed that doses of 0.46-4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of approximately 1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.

Subject-Specific Sparse Dictionary Learning for Atlas-Based Brain MRI Segmentation.

PubMed

Roy, Snehashis; He, Qing; Sweeney, Elizabeth; Carass, Aaron; Reich, Daniel S; Prince, Jerry L; Pham, Dzung L

2015-09-01

Quantitative measurements from segmentations of human brain magnetic resonance (MR) images provide important biomarkers for normal aging and disease progression. In this paper, we propose a patch-based tissue classification method from MR images that uses a sparse dictionary learning approach and atlas priors. Training data for the method consists of an atlas MR image, prior information maps depicting where different tissues are expected to be located, and a hard segmentation. Unlike most atlas-based classification methods that require deformable registration of the atlas priors to the subject, only affine registration is required between the subject and training atlas. A subject-specific patch dictionary is created by learning relevant patches from the atlas. Then the subject patches are modeled as sparse combinations of learned atlas patches leading to tissue memberships at each voxel. The combination of prior information in an example-based framework enables us to distinguish tissues having similar intensities but different spatial locations. We demonstrate the efficacy of the approach on the application of whole-brain tissue segmentation in subjects with healthy anatomy and normal pressure hydrocephalus, as well as lesion segmentation in multiple sclerosis patients. For each application, quantitative comparisons are made against publicly available state-of-the art approaches.

Rectification of pulsatile stress on soft tissues: a mechanism for normal-pressure hydrocephalus

NASA Astrophysics Data System (ADS)

Jalikop, Shreyas; Hilgenfeldt, Sascha

2011-11-01

Hydrocephalus is a pathological condition of the brain that occurs when cerebrospinal fluid (CSF) accumulates excessively in the brain cavities, resulting in compression of the brain parenchyma. Counter-intuitively, normal-pressure hydrocephalus (NPH) does not show elevated pressure differences across the compressed parenchyma. We investigate the effects of nonlinear tissue mechanics and periodic driving in this system. The latter is due to the cardiac cycle, which provides significant intracranial pressure and volume flow rate fluctuations. Nonlinear rectification of the periodic driving within a model of fluid flow in poroelastic material can lead to compression or expansion of the parenchyma, and this effect does not rely on changes in the mean intracranial pressure. The rectification effects can occur gradually over several days, in agreement with clinical studies of NPH.

Quantitative assessment of cerebral glucose metabolic rates after blood-brain barrier disruption induced by focused ultrasound using FDG-MicroPET.

PubMed

Yang, Feng-Yi; Chang, Wen-Yuan; Chen, Jyh-Cheng; Lee, Lin-Chien; Hung, Yi-Shun

2014-04-15

The goal of this study was to evaluate the pharmacokinetics of (18)F-2-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the expression of glucose transporter 1 (GLUT1) protein after blood-brain barrier (BBB) disruption of normal rat brains by focused ultrasound (FUS). After delivery of an intravenous bolus of ~37 MBq (1 mCi) (18)F-FDG, dynamic positron emission tomography scans were performed on rats with normal brains and those whose BBBs had been disrupted by FUS. Arterial blood sampling was collected throughout the scanning procedure. A 2-tissue compartmental model was used to estimate (18)F-FDG kinetic parameters in brain tissues. The rate constants Ki, K1, and k3 were assumed to characterize the uptake, transport, and hexokinase activity, respectively, of (18)F-FDG. The uptake of (18)F-FDG in brains significantly decreased immediately after the blood-brain barrier was disrupted. At the same time, the derived values of Ki, K1, and k3 for the sonicated brains were significantly lower than those for the control brains. In agreement with the reduction in glucose, Western blot analyses confirmed that focused ultrasound exposure significantly reduced the expression of GLUT1 protein in the brains. Furthermore, the effect of focused ultrasound on glucose uptake was transient and reversible 24h after sonication. Our results indicate that focused ultrasound may inhibit GLUT1 expression to decrease the glucose uptake in brain tissue during the period of BBB disruption. Copyright © 2013 Elsevier Inc. All rights reserved.

Diagnostic segregation of human brain tumours using Fourier-transform infrared and/or Raman spectroscopy coupled with discriminant analysis†

PubMed Central

Gajjar, Ketan; Heppenstall, Lara D.; Pang, Weiyi; Ashton, Katherine M.; Trevisan, Júlio; Patel, Imran I.; Llabjani, Valon; Stringfellow, Helen F.; Martin-Hirsch, Pierre L.; Dawson, Timothy; Martin, Francis L.

2013-01-01

The most common initial treatment received by patients with a brain tumour is surgical removal of the growth. Precise histopathological diagnosis of brain tumours is to some extent subjective. Furthermore, currently available diagnostic imaging techniques to delineate the excision border during cytoreductive surgery lack the required spatial precision to aid surgeons. We set out to determine whether infrared (IR) and/or Raman spectroscopy combined with multivariate analysis could be applied to discriminate between normal brain tissue and different tumour types (meningioma, glioma and brain metastasis) based on the unique spectral “fingerprints” of their biochemical composition. Formalin-fixed paraffin-embedded tissue blocks of normal brain and different brain tumours were de-waxed, mounted on low-E slides and desiccated before being analyzed using attenuated total reflection Fourier-transform IR (ATR-FTIR) and Raman spectroscopy. ATR-FTIR spectroscopy showed a clear segregation between normal and different tumour subtypes. Discrimination of tumour classes was also apparent with Raman spectroscopy. Further analysis of spectral data revealed changes in brain biochemical structure associated with different tumours. Decreased tentatively-assigned lipid-to-protein ratio was associated with increased tumour progression. Alteration in cholesterol esters-to-phenylalanine ratio was evident in grade IV glioma and metastatic tumours. The current study indicates that IR and/or Raman spectroscopy have the potential to provide a novel diagnostic approach in the accurate diagnosis of brain tumours and have potential for application in intra-operative diagnosis. PMID:24098310

Wavelet-domain de-noising of OCT images of human brain malignant glioma

NASA Astrophysics Data System (ADS)

Dolganova, I. N.; Aleksandrova, P. V.; Beshplav, S.-I. T.; Chernomyrdin, N. V.; Dubyanskaya, E. N.; Goryaynov, S. A.; Kurlov, V. N.; Reshetov, I. V.; Potapov, A. A.; Tuchin, V. V.; Zaytsev, K. I.

2018-04-01

We have proposed a wavelet-domain de-noising technique for imaging of human brain malignant glioma by optical coherence tomography (OCT). It implies OCT image decomposition using the direct fast wavelet transform, thresholding of the obtained wavelet spectrum and further inverse fast wavelet transform for image reconstruction. By selecting both wavelet basis and thresholding procedure, we have found an optimal wavelet filter, which application improves differentiation of the considered brain tissue classes - i.e. malignant glioma and normal/intact tissue. Namely, it allows reducing the scattering noise in the OCT images and retaining signal decrement for each tissue class. Therefore, the observed results reveals the wavelet-domain de-noising as a prospective tool for improved characterization of biological tissue using the OCT.

Neural Stability, Sparing, and Behavioral Recovery Following Brain Damage

ERIC Educational Resources Information Center

LeVere, T. E.

1975-01-01

The present article discusses the possibility that behavioral recovery following brain damage is not dependent on the functional reorganization of neural tissue but is rather the result of the continued normal operation of spared neural mechanisms. (Editor)

Supervised novelty detection in brain tissue classification with an application to white matter hyperintensities

NASA Astrophysics Data System (ADS)

Kuijf, Hugo J.; Moeskops, Pim; de Vos, Bob D.; Bouvy, Willem H.; de Bresser, Jeroen; Biessels, Geert Jan; Viergever, Max A.; Vincken, Koen L.

2016-03-01

Novelty detection is concerned with identifying test data that differs from the training data of a classifier. In the case of brain MR images, pathology or imaging artefacts are examples of untrained data. In this proof-of-principle study, we measure the behaviour of a classifier during the classification of trained labels (i.e. normal brain tissue). Next, we devise a measure that distinguishes normal classifier behaviour from abnormal behavior that occurs in the case of a novelty. This will be evaluated by training a kNN classifier on normal brain tissue, applying it to images with an untrained pathology (white matter hyperintensities (WMH)), and determine if our measure is able to identify abnormal classifier behaviour at WMH locations. For our kNN classifier, behaviour is modelled as the mean, median, or q1 distance to the k nearest points. Healthy tissue was trained on 15 images; classifier behaviour was trained/tested on 5 images with leave-one-out cross-validation. For each trained class, we measure the distribution of mean/median/q1 distances to the k nearest point. Next, for each test voxel, we compute its Z-score with respect to the measured distribution of its predicted label. We consider a Z-score >=4 abnormal behaviour of the classifier, having a probability due to chance of 0.000032. Our measure identified >90% of WMH volume and also highlighted other non-trained findings. The latter being predominantly vessels, cerebral falx, brain mask errors, choroid plexus. This measure is generalizable to other classifiers and might help in detecting unexpected findings or novelties by measuring classifier behaviour.

Markers for human brain pericytes and smooth muscle cells.

PubMed

Smyth, Leon C D; Rustenhoven, Justin; Scotter, Emma L; Schweder, Patrick; Faull, Richard L M; Park, Thomas I H; Dragunow, Mike

2018-06-07

Brain pericytes and vascular smooth muscle cells (vSMCs) are a critical component of the neurovascular unit and are important in regulating cerebral blood flow and blood-brain barrier integrity. Identification of subtypes of mural cells in tissue and in vitro is important to any study of their function, therefore we identified distinct mural cell morphologies in neurologically normal post-mortem human brain. Further, the distribution of mural cell markers platelet-derived growth factor receptor-β (PDGFRβ), α-smooth muscle actin (αSMA), CD13, neural/glial antigen-2 (NG2), CD146 and desmin was examined. We determined that PDGFRβ, NG2, CD13, and CD146 were expressed in capillary-associated pericytes. NG2, and CD13 were also present on vSMCs in large vessels, however abundant CD146 and desmin staining was also detected in vSMCs on large vessels, co-labelling with αSMA. To determine whether cultures recapitulated observations from tissue, primary human brain pericytes derived from neurologically normal autopsies were analysed for the presence of pericyte markers by immunocytochemistry, western blotting and qPCR. The proteins observed in brain pericytes in tissue (PDGFRβ, αSMA, desmin, CD146, CD13, and NG2) were present in vitro, validating a panel of proteins that can be used to label brain pericytes and vSMCs in tissue and in vitro. Finally, we showed that the proteins CD146 and desmin that are expressed on large vessels in situ, are also selective markers of a smooth muscle cell phenotype in vitro. Copyright © 2018 Elsevier B.V. All rights reserved.

Lineage-specific splicing of a brain-enriched alternative exon promotes glioblastoma progression

PubMed Central

Ferrarese, Roberto; Harsh, Griffith R.; Yadav, Ajay K.; Bug, Eva; Maticzka, Daniel; Reichardt, Wilfried; Dombrowski, Stephen M.; Miller, Tyler E.; Masilamani, Anie P.; Dai, Fangping; Kim, Hyunsoo; Hadler, Michael; Scholtens, Denise M.; Yu, Irene L.Y.; Beck, Jürgen; Srinivasasainagendra, Vinodh; Costa, Fabrizio; Baxan, Nicoleta; Pfeifer, Dietmar; von Elverfeldt, Dominik; Backofen, Rolf; Weyerbrock, Astrid; Duarte, Christine W.; He, Xiaolin; Prinz, Marco; Chandler, James P.; Vogel, Hannes; Chakravarti, Arnab; Rich, Jeremy N.; Carro, Maria S.; Bredel, Markus

2014-01-01

Tissue-specific alternative splicing is critical for the emergence of tissue identity during development, yet the role of this process in malignant transformation is undefined. Tissue-specific splicing involves evolutionarily conserved, alternative exons that represent only a minority of the total alternative exons identified. Many of these conserved exons have functional features that influence signaling pathways to profound biological effect. Here, we determined that lineage-specific splicing of a brain-enriched cassette exon in the membrane-binding tumor suppressor annexin A7 (ANXA7) diminishes endosomal targeting of the EGFR oncoprotein, consequently enhancing EGFR signaling during brain tumor progression. ANXA7 exon splicing was mediated by the ribonucleoprotein PTBP1, which is normally repressed during neuronal development. PTBP1 was highly expressed in glioblastomas due to loss of a brain-enriched microRNA (miR-124) and to PTBP1 amplification. The alternative ANXA7 splicing trait was present in precursor cells, suggesting that glioblastoma cells inherit the trait from a potential tumor-initiating ancestor and that these cells exploit this trait through accumulation of mutations that enhance EGFR signaling. Our data illustrate that lineage-specific splicing of a tissue-regulated alternative exon in a constituent of an oncogenic pathway eliminates tumor suppressor functions and promotes glioblastoma progression. This paradigm may offer a general model as to how tissue-specific regulatory mechanisms can reprogram normal developmental processes into oncogenic ones. PMID:24865424

Selection of internal reference genes for normalization of quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis in the canine brain and other organs.

PubMed

Park, Sang-Je; Huh, Jae-Won; Kim, Young-Hyun; Lee, Sang-Rae; Kim, Sang-Hyun; Kim, Sun-Uk; Kim, Heui-Soo; Kim, Min Kyu; Chang, Kyu-Tae

2013-05-01

Quantitative reverse transcription polymerase chain reaction (qRT-PCR) is a specific and sensitive technique for quantifying gene expression. To analyze qRT-PCR data accurately, suitable reference genes that show consistent expression patterns across different tissues and experimental conditions should be selected. The objective of this study was to obtain the most stable reference genes in dogs, using samples from 13 different brain tissues and 10 other organs. 16 well-known candidate reference genes were analyzed by the geNorm, NormFinder, and BestKeeper programs. Brain tissues were derived from several different anatomical regions, including the forebrain, cerebrum, diencephalon, hindbrain, and metencephalon, and grouped accordingly. Combination of the three different analyses clearly indicated that the ideal reference genes are ribosomal protien S5 (RPS5) in whole brain, RPL8 and RPS5 in whole body tissues, RPS5 and RPS19 in the forebrain and cerebrum, RPL32 and RPS19 in the diencephalon, GAPDH and RPS19 in the hindbrain, and MRPS7 and RPL13A in the metencephalon. These genes were identified as ideal for the normalization of qRT-PCR results in the respective tissues. These findings indicate more suitable and stable reference genes for future studies of canine gene expression.

Neurocognitive sparing of desktop microbeam irradiation.

PubMed

Bazyar, Soha; Inscoe, Christina R; Benefield, Thad; Zhang, Lei; Lu, Jianping; Zhou, Otto; Lee, Yueh Z

2017-08-11

Normal tissue toxicity is the dose-limiting side effect of radiotherapy. Spatial fractionation irradiation techniques, like microbeam radiotherapy (MRT), have shown promising results in sparing the normal brain tissue. Most MRT studies have been conducted at synchrotron facilities. With the aim to make this promising treatment more available, we have built the first desktop image-guided MRT device based on carbon nanotube x-ray technology. In the current study, our purpose was to evaluate the effects of MRT on the rodent normal brain tissue using our device and compare it with the effect of the integrated equivalent homogenous dose. Twenty-four, 8-week-old male C57BL/6 J mice were randomly assigned to three groups: MRT, broad-beam (BB) and sham. The hippocampal region was irradiated with two parallel microbeams in the MRT group (beam width = 300 μm, center-to-center = 900 μm, 160 kVp). The BB group received the equivalent integral dose in the same area of their brain. Rotarod, marble burying and open-field activity tests were done pre- and every month post-irradiation up until 8 months to evaluate the cognitive changes and potential irradiation side effects on normal brain tissue. The open-field activity test was substituted by Barnes maze test at 8th month. A multilevel model, random coefficients approach was used to evaluate the longitudinal and temporal differences among treatment groups. We found significant differences between BB group as compared to the microbeam-treated and sham mice in the number of buried marble and duration of the locomotion around the open-field arena than shams. Barnes maze revealed that BB mice had a lower capacity for spatial learning than MRT and shams. Mice in the BB group tend to gain weight at the slower pace than shams. No meaningful differences were found between MRT and sham up until 8-month follow-up using our measurements. Applying MRT with our newly developed prototype compact CNT-based image-guided MRT system utilizing the current irradiation protocol can better preserve the integrity of normal brain tissue. Consequently, it enables applying higher irradiation dose that promises better tumor control. Further studies are required to evaluate the full extent effects of this novel modality.

Intraoperative detection of glioma invasion beyond MRI enhancement with Raman spectroscopy in humans

NASA Astrophysics Data System (ADS)

Jermyn, Michael; Mok, Kelvin; Mercier, Jeanne; Desroches, Joannie; Pichette, Julien; Saint-Arnaud, Karl; Guiot, Marie-Christine; Petrecca, Kevin; Leblond, Frédéric

2015-03-01

Cancer tissue is frequently impossible to distinguish from normal brain during surgery. Gliomas are a class of brain cancer which invade into the normal brain. If left unresected, these invasive cancer cells are the source of glioma recurrence. Moreover, these invasion areas do not show up on standard-of-care pre-operative Magnetic Resonance Imaging (MRI). This inability to fully visualize invasive brain cancers results in subtotal surgical resections, negatively impacting patient survival. To address this issue, we have demonstrated the efficacy of single-point in vivo Raman spectroscopy using a contact hand-held fiber optic probe for rapid detection of cancer invasion in 8 patients with low and high grade gliomas. Using a supervised machine learning algorithm to analyze the Raman spectra obtained in vivo, we were able to distinguish normal brain from the presence of cancer cells with sensitivity and specificity greater than 90%. Moreover, by correlating these results with pre-operative MRI we demonstrate the ability to detect low density cancer invasion up to 1.5cm beyond the cancer extent visible using MRI. This represents the potential for significant improvements in progression-free and overall patient survival, by identifying previously undetectable residual cancer cell populations and preventing the resection of normal brain tissue. While the importance of maximizing the volume of tumor resection is important for all grades of gliomas, the impact for low grade gliomas can be dramatic because surgery can even be curative. This convenient technology can rapidly classify cancer invasion in real-time, making it ideal for intraoperative use in brain tumor resection.

Equivalence in Dose Fall-Off for Isocentric and Nonisocentric Intracranial Treatment Modalities and Its Impact on Dose Fractionation Schemes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma Lijun, E-mail: lijunma@radonc.ucsf.ed; Sahgal, Arjun; Descovich, Martina

2010-03-01

Purpose: To investigate whether dose fall-off characteristics would be significantly different among intracranial radiosurgery modalities and the influence of these characteristics on fractionation schemes in terms of normal tissue sparing. Methods and Materials: An analytic model was developed to measure dose fall-off characteristics near the target independent of treatment modalities. Variations in the peripheral dose fall-off characteristics were then examined and compared for intracranial tumors treated with Gamma Knife, Cyberknife, or Novalis LINAC-based system. Equivalent uniform biologic effective dose (EUBED) for the normal brain tissue was calculated. Functional dependence of the normal brain EUBED on varying numbers of fractions (1more » to 30) was studied for the three modalities. Results: The derived model fitted remarkably well for all the cases (R{sup 2} > 0.99). No statistically significant differences in the dose fall-off relationships were found between the three modalities. Based on the extent of variations in the dose fall-off curves, normal brain EUBED was found to decrease with increasing number of fractions for the targets, with alpha/beta ranging from 10 to 20. This decrease was most pronounced for hypofractionated treatments with fewer than 10 fractions. Additionally, EUBED was found to increase slightly with increasing number of fractions for targets with alpha/beta ranging from 2 to 5. Conclusion: Nearly identical dose fall-off characteristics were found for the Gamma Knife, Cyberknife, and Novalis systems. Based on EUBED calculations, normal brain sparing was found to favor hypofractionated treatments for fast-growing tumors with alpha/beta ranging from 10 to 20 and single fraction treatment for abnormal tissues with low alpha/beta values such as alpha/beta = 2.« less

Analysis of Electronic Densities and Integrated Doses in Multiform Glioblastomas Stereotactic Radiotherapy

NASA Astrophysics Data System (ADS)

Barón-Aznar, C.; Moreno-Jiménez, S.; Celis, M. A.; Lárraga-Gutiérrez, J. M.; Ballesteros-Zebadúa, P.

2008-08-01

Integrated dose is the total energy delivered in a radiotherapy target. This physical parameter could be a predictor for complications such as brain edema and radionecrosis after stereotactic radiotherapy treatments for brain tumors. Integrated Dose depends on the tissue density and volume. Using CT patients images from the National Institute of Neurology and Neurosurgery and BrainScansoftware, this work presents the mean density of 21 multiform glioblastomas, comparative results for normal tissue and estimated integrated dose for each case. The relationship between integrated dose and the probability of complications is discussed.

Dynamic contrast-enhanced x-ray CT measurement of cerebral blood volume in a rabbit tumor model

NASA Astrophysics Data System (ADS)

Cenic, Aleksa; Lee, Ting-Yim; Craen, Rosemary A.; Gelb, Adrian W.

1998-07-01

Cerebral blood volume (CBV) is a major determinant of intracranial pressure (ICP). Hyperventilation is commonly employed to reduce raised ICP (e.g. in brain tumour patients) presumably through its effect on CBV. With the advent of slip- ring CT scanners, dynamic contrast-enhanced imaging allows for the measurement of CBV with high spatial resolution. Using a two-compartment model to characterize the distribution of X- ray contrast agent in the brain, we have developed a non- equilibrium CT method to measure CBV in normal and pathological regions. We used our method to investigate the effect of hyperventilation on CBV during propofol anaesthesia in rabbits with implanted brain tumours. Eight New Zealand White rabbits with implanted VX2 carcinoma brain tumours were studied. For each rabbit, regional CBV measurements were initially made at normocapnia (PaCO2 40 mmHg) and then at hyperventilation (PaCO2 25 mmHg) during propofol anaesthesia. The head was positioned such that a coronal image through the brain incorporated a significant cross-section of the brain tumour as well as a radial artery in a forelimb. Images at the rate of 1 per second were acquired for 2 minutes as Omnipaque 300 (1.5 ml/kg rabbit weight) was injected via a peripheral vein. In these CT images, regions of interest in the brain tissue (e.g. tumour, contra-lateral normal, and peri-tumoural) and the radial artery were drawn. For each region, the mean CT number in pre-contrast images was subtracted from the mean CT number in post-contrast images to produce either the tissue contrast concentration curve, or the arterial contrast concentration curve. Using our non- equilibrium analysis method based on a two-compartment model, regional CBV values were determined from the measured contrast concentration curves. From our study, the mean CBV values [+/- SD] in the tumour, peri-tumoural, and contra-lateral normal regions during normocapnia were: 5.47 plus or minus 1.97, 3.28 plus or minus 1.01, and 1.86 plus or minus 0.54 ml/100 g, respectively. Following hyperventilation, we found a significant decrease (p less than 0.025) of 10.4% in CBV in the peri-tumoural region, and no statistically significant change in CBV in the tumour or contra-lateral normal regions. We have developed a convenient method for measuring CBV in normal and pathological tissue using a slip-ring CT scanner. In a brain tumour model, we found that CBV was markedly increased in tumour and peri-tumoural regions compared to normal regions. Our results suggest that the reduction of raised ICP following hyperventilation during propofol anaesthesia may be mainly due to a reduction in CBV in the peri-tumoural tissue rather than in the bulk of the tumour or normal regions. Our method has the potential to provide further knowledge on the cerebral hemodynamics of space- occupying lesions during different anaesthetic interventions or treatment regiments.

Localized delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat brain using focused ultrasound.

PubMed

Mulik, Rohit S; Bing, Chenchen; Ladouceur-Wodzak, Michelle; Munaweera, Imalka; Chopra, Rajiv; Corbin, Ian R

2016-03-01

Focused ultrasound exposures in the presence of microbubbles can achieve transient, non-invasive, and localized blood-brain barrier (BBB) opening, offering a method for targeted delivery of therapeutic agents into the brain. Low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) could have significant therapeutic value in the brain, since DHA is known to be neuroprotective. BBB opening was achieved using pulsed ultrasound exposures in a localized brain region in normal rats, after which LDL nanoparticles containing the fluorescent probe DiR (1,1'-Dioctadecyl-3,3,3',3'-Tetramethylindotricarbocyanine Iodide) or DHA were administered intravenously. Fluorescent imaging of brain tissue from rats administered LDL-DiR demonstrated strong localization of fluorescence signal in the exposed hemisphere. LDL-DHA administration produced 2 × more DHA in the exposed region of the brain, with a corresponding increase in Resolvin D1 levels, indicating DHA was incorporated into cells and metabolized. Histological evaluation did not indicate any evidence of increased tissue damage in exposed brain regions compared to normal brain. This work demonstrates that localized delivery of DHA to the brain is possible using systemically-administered LDL nanoparticles combined with pulsed focused ultrasound exposures in the brain. This technology could be used in regions of acute brain injury or as a means to target infiltrating tumor cells in the brain. Copyright © 2016 Elsevier Ltd. All rights reserved.

Localized Delivery of Low-Density Lipoprotein Docosahexaenoic Acid Nanoparticles to the Rat Brain using Focused Ultrasound

PubMed Central

Mulik, Rohit S.; Bing, Chenchen; Ladouceur-Wodzak, Michelle; Munaweera, Imalka; Chopra, Rajiv; Corbin, Ian R.

2016-01-01

Focused ultrasound exposures in the presence of microbubbles can achieve transient, non-invasive, and localized blood-brain barrier (BBB) opening, offering a method for targeted delivery of therapeutic agents into the brain. Low-density lipoprotein (LDL) nanoparticles reconstituted with docosahexaenoic acid (DHA) could have significant therapeutic value in the brain, since DHA is known to be neuroprotective. BBB opening was achieved using pulsed ultrasound exposures in a localized brain region in normal rats, after which LDL nanoparticles containing the fluorescent probe DiR (1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine Iodide) or DHA were administered intravenously. Fluorescent imaging of brain tissue from rats administered LDL-DiR demonstrated strong localization of fluorescence signal in the exposed hemisphere. LDL-DHA administration produced 2× more DHA in the exposed region of the brain, with a corresponding increase in Resolvin D1 levels, indicating DHA was incorporated into cells and metabolized. Histological evaluation did not indicate any evidence of increased tissue damage in exposed brain regions compared to normal brain. This work demonstrates that localized delivery of DHA to the brain is possible using systemically-administered LDL nanoparticles combined with pulsed focused ultrasound exposures in the brain. This technology could be used in regions of acute brain injury or as a means to target infiltrating tumor cells in the brain. PMID:26790145

Modeling Early Postnatal Brain Growth and Development with CT: Changes in the Brain Radiodensity Histogram from Birth to 2 Years.

PubMed

Cauley, K A; Hu, Y; Och, J; Yorks, P J; Fielden, S W

2018-04-01

The majority of brain growth and development occur in the first 2 years of life. This study investigated these changes by analysis of the brain radiodensity histogram of head CT scans from the clinical population, 0-2 years of age. One hundred twenty consecutive head CTs with normal findings meeting the inclusion criteria from children from birth to 2 years were retrospectively identified from 3 different CT scan platforms. Histogram analysis was performed on brain-extracted images, and histogram mean, mode, full width at half maximum, skewness, kurtosis, and SD were correlated with subject age. The effects of scan platform were investigated. Normative curves were fitted by polynomial regression analysis. Average total brain volume was 360 cm 3 at birth, 948 cm 3 at 1 year, and 1072 cm 3 at 2 years. Total brain tissue density showed an 11% increase in mean density at 1 year and 19% at 2 years. Brain radiodensity histogram skewness was positive at birth, declining logarithmically in the first 200 days of life. The histogram kurtosis also decreased in the first 200 days to approach a normal distribution. Direct segmentation of CT images showed that changes in brain radiodensity histogram skewness correlated with, and can be explained by, a relative increase in gray matter volume and an increase in gray and white matter tissue density that occurs during this period of brain maturation. Normative metrics of the brain radiodensity histogram derived from routine clinical head CT images can be used to develop a model of normal brain development. © 2018 by American Journal of Neuroradiology.

Regionally distinct responses of microglia and glial progenitor cells to whole brain irradiation in adult and aging rats.

PubMed

Hua, Kun; Schindler, Matthew K; McQuail, Joseph A; Forbes, M Elizabeth; Riddle, David R

2012-01-01

Radiation therapy has proven efficacy for treating brain tumors and metastases. Higher doses and larger treatment fields increase the probability of eliminating neoplasms and preventing reoccurrence, but dose and field are limited by damage to normal tissues. Normal tissue injury is greatest during development and in populations of proliferating cells but also occurs in adults and older individuals and in non-proliferative cell populations. To better understand radiation-induced normal tissue injury and how it may be affected by aging, we exposed young adult, middle-aged, and old rats to 10 Gy of whole brain irradiation and assessed in gray- and white matter the responses of microglia, the primary cellular mediators of radiation-induced neuroinflammation, and oligodendrocyte precursor cells, the largest population of proliferating cells in the adult brain. We found that aging and/or irradiation caused only a few microglia to transition to the classically "activated" phenotype, e.g., enlarged cell body, few processes, and markers of phagocytosis, that is seen following more damaging neural insults. Microglial changes in response to aging and irradiation were relatively modest and three markers of reactivity - morphology, proliferation, and expression of the lysosomal marker CD68- were regulated largely independently within individual cells. Proliferation of oligodendrocyte precursors did not appear to be altered during normal aging but increased following irradiation. The impacts of irradiation and aging on both microglia and oligodendrocyte precursors were heterogeneous between white- and gray matter and among regions of gray matter, indicating that there are regional regulators of the neural response to brain irradiation. By several measures, the CA3 region of the hippocampus appeared to be differentially sensitive to effects of aging and irradiation. The changes assessed here likely contribute to injury following inflammatory challenges like brain irradiation and represent important end-points for analysis in studies of therapeutic strategies to protect patients from neural dysfunction.

L-Phenylalanine preloading reduces the (10)B(n, α)(7)Li dose to the normal brain by inhibiting the uptake of boronophenylalanine in boron neutron capture therapy for brain tumours.

PubMed

Watanabe, Tsubasa; Tanaka, Hiroki; Fukutani, Satoshi; Suzuki, Minoru; Hiraoka, Masahiro; Ono, Koji

2016-01-01

Boron neutron capture therapy (BNCT) is a cellular-level particle radiation therapy that combines the selective delivery of boron compounds to tumour tissue with neutron irradiation. Previously, high doses of one of the boron compounds used for BNCT, L-BPA, were found to reduce the boron-derived irradiation dose to the central nervous system. However, injection with a high dose of L-BPA is not feasible in clinical settings. We aimed to find an alternative method to improve the therapeutic efficacy of this therapy. We examined the effects of oral preloading with various analogues of L-BPA in a xenograft tumour model and found that high-dose L-phenylalanine reduced the accumulation of L-BPA in the normal brain relative to tumour tissue. As a result, the maximum irradiation dose in the normal brain was 19.2% lower in the L-phenylalanine group relative to the control group. This study provides a simple strategy to improve the therapeutic efficacy of conventional boron compounds for BNCT for brain tumours and the possibility to widen the indication of BNCT to various kinds of other tumours. Copyright © 2015. Published by Elsevier Ireland Ltd.

Quantification of brain lipids by FTIR spectroscopy and partial least squares regression

NASA Astrophysics Data System (ADS)

Dreissig, Isabell; Machill, Susanne; Salzer, Reiner; Krafft, Christoph

2009-01-01

Brain tissue is characterized by high lipid content. Its content decreases and the lipid composition changes during transformation from normal brain tissue to tumors. Therefore, the analysis of brain lipids might complement the existing diagnostic tools to determine the tumor type and tumor grade. Objective of this work is to extract lipids from gray matter and white matter of porcine brain tissue, record infrared (IR) spectra of these extracts and develop a quantification model for the main lipids based on partial least squares (PLS) regression. IR spectra of the pure lipids cholesterol, cholesterol ester, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, galactocerebroside and sulfatide were used as references. Two lipid mixtures were prepared for training and validation of the quantification model. The composition of lipid extracts that were predicted by the PLS regression of IR spectra was compared with lipid quantification by thin layer chromatography.

Differences in Relative Levels of 88 microRNAs in Various Regions of the Normal Adult Human Brain.

PubMed

Filatova, Elena V; Alieva, Anelya; Shadrina, Maria I; Slominsky, Petr A

2017-08-16

Since the discovery of microRNAs (miRNAs) in the 1990s, our knowledge about their biology has grown considerably. The increasing number of studies addressing the role of miRNAs in development and in various diseases emphasizes the need for a comprehensive catalogue of accurate sequence, expression and conservation information regarding the large number of miRNAs proposed recently in all organs and tissues. The objective of this study was to provide data on the levels of miRNA expression in 15 tissues of the normal human brain. We conducted an analysis of the relative levels of 88 of the most abundantly expressed and best characterized miRNA derived postmortem from well-characterized samples of various regions of the brains from five normal individuals. The cluster analysis revealed some differences in the relative levels of these miRNAs among the brain regions studied. Such diversity can be explained by different functioning of these brain regions. We hope that the data from the current study are a resource that will be useful to our colleagues in this exciting field, as more hypotheses will be generated and tested with regard to small noncoding RNA in the human brain in healthy and disease states. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A proposed role for efflux transporters in the pathogenesis of hydrocephalus

PubMed Central

Krishnamurthy, Satish; Tichenor, Michael D.; Satish, Akhila G.; Lehmann, David B.

2014-01-01

Hydrocephalus is a common brain disorder that is treated only with surgery. The basis for surgical treatment rests on the circulation theory. However, clinical and experimental data to substantiate circulation theory have remained inconclusive. In brain tissue and in the ventricles, we see that osmotic gradients drive water diffusion in water-permeable tissue. As the osmolarity of ventricular CSF increases within the cerebral ventricles, water movement into the ventricles increases and causes hydrocephalus. Macromolecular clearance from the ventricles is a mechanism to establish the normal CSF osmolarity, and therefore ventricular volume. Efflux transporters, (p-glycoprotein), are located along the blood brain barrier and play an important role in the clearance of macromolecules (endobiotics and xenobiotics) from the brain to the blood. There is clinical and experimental data to show that macromolecules are cleared out of the brain in normal and hydrocephalic brains. This article summarizes the existing evidence to support the role of efflux transporters in the pathogenesis of hydrocephalus. The location of p-gp along the pathways of macromolecular clearance and the broad substrate specificity of this abundant transporter to a variety of different macromolecules are reviewed. Involvement of p-gp in the transport of amyloid beta in Alzheimer disease and its relation to normal pressure hydrocephalus is reviewed. Finally, individual variability of p-gp expression might explain the variability in the development of hydrocephalus following intraventricular hemorrhage. PMID:25165050

3D variational brain tumor segmentation on a clustered feature set

NASA Astrophysics Data System (ADS)

Popuri, Karteek; Cobzas, Dana; Jagersand, Martin; Shah, Sirish L.; Murtha, Albert

2009-02-01

Tumor segmentation from MRI data is a particularly challenging and time consuming task. Tumors have a large diversity in shape and appearance with intensities overlapping the normal brain tissues. In addition, an expanding tumor can also deflect and deform nearby tissue. Our work addresses these last two difficult problems. We use the available MRI modalities (T1, T1c, T2) and their texture characteristics to construct a multi-dimensional feature set. Further, we extract clusters which provide a compact representation of the essential information in these features. The main idea in this paper is to incorporate these clustered features into the 3D variational segmentation framework. In contrast to the previous variational approaches, we propose a segmentation method that evolves the contour in a supervised fashion. The segmentation boundary is driven by the learned inside and outside region voxel probabilities in the cluster space. We incorporate prior knowledge about the normal brain tissue appearance, during the estimation of these region statistics. In particular, we use a Dirichlet prior that discourages the clusters in the ventricles to be in the tumor and hence better disambiguate the tumor from brain tissue. We show the performance of our method on real MRI scans. The experimental dataset includes MRI scans, from patients with difficult instances, with tumors that are inhomogeneous in appearance, small in size and in proximity to the major structures in the brain. Our method shows good results on these test cases.

Theoretical Benefits of Dynamic Collimation in Pencil Beam Scanning Proton Therapy for Brain Tumors: Dosimetric and Radiobiological Metrics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moignier, Alexandra, E-mail: alexandra-moignier@uiowa.edu; Gelover, Edgar; Wang, Dongxu

Purpose: To quantify the dosimetric benefit of using a dynamic collimation system (DCS) for penumbra reduction during the treatment of brain tumors by pencil beam scanning proton therapy (PBS PT). Methods and Materials: Collimated and uncollimated brain treatment plans were created for 5 patients previously treated with PBS PT and retrospectively enrolled in an institutional review board–approved study. The in-house treatment planning system, RDX, was used to generate the plans because it is capable of modeling both collimated and uncollimated beamlets. The clinically delivered plans were reproduced with uncollimated plans in terms of target coverage and organ at risk (OAR) sparingmore » to ensure a clinically relevant starting point, and collimated plans were generated to improve the OAR sparing while maintaining target coverage. Physical and biological comparison metrics, such as dose distribution conformity, mean and maximum doses, normal tissue complication probability, and risk of secondary brain cancer, were used to evaluate the plans. Results: The DCS systematically improved the dose distribution conformity while preserving the target coverage. The average reduction of the mean dose to the 10-mm ring surrounding the target and the healthy brain were 13.7% (95% confidence interval [CI] 11.6%-15.7%; P<.0001) and 25.1% (95% CI 16.8%-33.4%; P<.001), respectively. This yielded an average reduction of 24.8% (95% CI 0.8%-48.8%; P<.05) for the brain necrosis normal tissue complication probability using the Flickinger model, and 25.1% (95% CI 16.8%-33.4%; P<.001) for the risk of secondary brain cancer. A general improvement of the OAR sparing was also observed. Conclusion: The lateral penumbra reduction afforded by the DCS increases the normal tissue sparing capabilities of PBS PT for brain cancer treatment while preserving target coverage.« less

Raman molecular imaging of brain frozen tissue sections.

PubMed

Kast, Rachel E; Auner, Gregory W; Rosenblum, Mark L; Mikkelsen, Tom; Yurgelevic, Sally M; Raghunathan, Aditya; Poisson, Laila M; Kalkanis, Steven N

2014-10-01

Raman spectroscopy provides a molecular signature of the region being studied. It is ideal for neurosurgical applications because it is non-destructive, label-free, not impacted by water concentration, and can map an entire region of tissue. The objective of this paper is to demonstrate the meaningful spatial molecular information provided by Raman spectroscopy for identification of regions of normal brain, necrosis, diffusely infiltrating glioma and solid glioblastoma (GBM). Five frozen section tissues (1 normal, 1 necrotic, 1 GBM, and 2 infiltrating glioma) were mapped in their entirety using a 300-µm-square step size. Smaller regions of interest were also mapped using a 25-µm step size. The relative concentrations of relevant biomolecules were mapped across all tissues and compared with adjacent hematoxylin and eosin-stained sections, allowing identification of normal, GBM, and necrotic regions. Raman peaks and peak ratios mapped included 1003, 1313, 1431, 1585, and 1659 cm(-1). Tissue maps identified boundaries of grey and white matter, necrosis, GBM, and infiltrating tumor. Complementary information, including relative concentration of lipids, protein, nucleic acid, and hemoglobin, was presented in a manner which can be easily adapted for in vivo tissue mapping. Raman spectroscopy can successfully provide label-free imaging of tissue characteristics with high accuracy. It can be translated to a surgical or laboratory tool for rapid, non-destructive imaging of tumor margins.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated networkmore » (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.« less

Anti-EGFRvIII Chimeric Antigen Receptor-Modified T Cells for Adoptive Cell Therapy of Glioblastoma

PubMed Central

Ren, Pei-pei; Li, Ming; Li, Tian-fang; Han, Shuang-yin

2017-01-01

Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues. Immunotherapy is a promising approach due to its capability to suppress the growth of various tumors in preclinical model and clinical trials. Adoptive cell therapy (ACT) using T cells engineered with chimeric antigen receptor (CAR) targeting an ideal molecular marker in GBM, e.g. epidermal growth factor receptor type III (EGFRvIII) has demonstrated a satisfactory efficacy in treating malignant brain tumors. Here we summarize the recent progresses in immunotherapeutic strategy using CAR-modified T cells oriented to EGFRvIII against GBM. PMID:28302023

2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in a nude rat glioma model: implications for photodynamic therapy.

PubMed

Lobel, J; MacDonald, I J; Ciesielski, M J; Barone, T; Potter, W R; Pollina, J; Plunkett, R J; Fenstermaker, R A; Dougherty, T J

2001-01-01

In this study, we evaluated 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha (HPPH or Photochlor) as a photosensitizer for the treatment of malignant gliomas by photodynamic therapy (PDT). We performed in vivo reflection spectroscopy in athymic rats to measure the attenuation of light in normal brain tissue. We also studied HPPH pharmacokinetics and PDT effects in nude rats with brain tumors derived from stereotactically implanted U87 human glioma cells. Rats implanted with tumors were sacrificed at designated time points to determine the pharmacokinetics of HPPH in serum, tumor, normal brain, and brain adjacent to tumor (BAT). HPPH concentrations in normal brain, BAT and tumor were determined using fluorescence spectroscopy. Twenty-four hours after intravenous injection of HPPH, we administered interstitial PDT treatment at a wavelength of 665 nm. Light was given in doses of 3.5, 7.5 or 15 J/cm at the tumor site and at a rate of 50 mW/cm. In vivo spectroscopy of normal brain tissue showed that the attenuation depth of 665 nm light is approximately 30% greater than that of 630 nm light used to activate Photofrin, which is currently being evaluated for PDT as an adjuvant to surgery for malignant gliomas. The t1/2 of disappearance of drug from serum and tumor was 25 and 30 hours, respectively. Twenty-four hours after injection of 0.5 mg/kg HPPH, tumor-to-brain drug ratios ranged from 5:1 to 15:1. Enhanced survival was observed in each of the HPPH/PDT-treated animal groups. These data suggest that HPPH may be a useful adjuvant for the treatment of malignant gliomas.

Increased brain edema following 5-aminolevulinic acid mediated photodynamic in normal and tumor bearing rats

NASA Astrophysics Data System (ADS)

Hirschberg, Henry; Angell-Petersen, Even; Spetalen, Signe; Mathews, Marlon; Madsen, Steen J.

2007-02-01

Introduction: Failure of treatment for high grade gliomas is usually due to local recurrence at the site of surgical resection indicating that a more aggressive form of local therapy, such as PDT, could be of benefit. PDT causes damage to both tumor cells as well as cerebral blood vessels leading to degradation of the blood brain barrier with subsequent increase of brain edema. The increase in brain edema following ALA-PDT was evaluated in terms of animal survival, histopatological changes in normal brain and tumor tissue and MRI scanning. The effect of steroid treatment, to reduce post-treatment PDT induced edema, was also examined. Methods:Tumors were established in the brains of inbred BD-IX and Fisher rats. At various times following tumor induction the animals were injected with ALA ip. and four hours later light treatment at escalating fluences and fluence rates were given. Nontumor bearing control animals were also exposed to ALA-PDT in a similar manner to evaluate damage to normal brain and degree of blood brain barrier (BBB) disruption. Results: Despite a very low level of PpIX production in normal brain, with a 200:1 tumor to normal tissue selectivity ratio measured at a distance of 2 mm from the tumor border, many animals succumbed shortly after treatment. A total radiant energy of 54 J to non-tumor bearing animals resulted in 50% mortality within 5 days of treatment. Treatment of tumor bearing animals with moderate fluence levels produced similar brain edema compared to higher fluence levels. ALA PDT in nontumor bearing animals produced edema that was light dose dependent. PDT appeared to open the BBB for a period of 24-48 hrs after which it was restored. The addition of post operative steroid treatment reduced the incident of post treatment morbidity and mortality. Conclusions: T2 and contrast enhanced T1 MRI scanning proved to be a highly effective and non-evasive modality in following the development of the edema reaction and the degree and time course of BBB dysfunction thus allowing the use of fewer animals.

Responses of the Human Brain to Mild Dehydration and Rehydration Explored In Vivo by 1H-MR Imaging and Spectroscopy.

PubMed

Biller, A; Reuter, M; Patenaude, B; Homola, G A; Breuer, F; Bendszus, M; Bartsch, A J

2015-12-01

As yet, there are no in vivo data on tissue water changes and associated morphometric changes involved in the osmo-adaptation of normal brains. Our aim was to evaluate osmoadaptive responses of the healthy human brain to osmotic challenges of de- and rehydration by serial measurements of brain volume, tissue fluid, and metabolites. Serial T1-weighted and (1)H-MR spectroscopy data were acquired in 15 healthy individuals at normohydration, on 12 hours of dehydration, and during 1 hour of oral rehydration. Osmotic challenges were monitored by serum measures, including osmolality and hematocrit. MR imaging data were analyzed by using FreeSurfer and LCModel. On dehydration, serum osmolality increased by 0.67% and brain tissue fluid decreased by 1.63%, on average. MR imaging morphometry demonstrated corresponding decreases of cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus. These changes reversed during rehydration. Continuous fluid ingestion of 1 L of water for 1 hour within the scanner lowered serum osmolality by 0.96% and increased brain tissue fluid by 0.43%, on average. Concomitantly, cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus increased. Changes in brain tissue fluid were related to volume changes of the whole brain, the white matter, and hypothalamus/thalamus. Only volume changes of the hypothalamus/thalamus significantly correlated with serum osmolality. This is the first study simultaneously evaluating changes in brain tissue fluid, metabolites, volume, and cortical thickness. Our results reflect cellular volume regulatory mechanisms at a macroscopic level and emphasize that it is essential to control for hydration levels in studies on brain morphometry and metabolism in order to avoid confounding the findings. © 2015 by American Journal of Neuroradiology.

DRAG REDUCING POLYMER ENCHANCES MICROVASCULAR PERFUSION IN THE TRAUMATIZED BRAIN WITH INTRACRANIAL HYPERTENSION

PubMed Central

Bragin, Denis E.; Thomson, Susan; Bragina, Olga; Statom, Gloria; Kameneva, Marina V.; Nemoto, Edwin M.

2016-01-01

SUMMARY Current treatments for traumatic brain injury (TBI) have not focused on improving microvascular perfusion. Drag-reducing polymers (DRP), linear, long-chain, blood soluble non-toxic macromolecules, may offer a new approach to improving cerebral perfusion by primary alteration of the fluid dynamic properties of blood. Nanomolar concentrations of DRP have been shown to improve hemodynamics in animal models of ischemic myocardium and limb, but have not yet been studied in the brain. Recently, we demonstrated that that DRP improved microvascular perfusion and tissue oxygenation in a normal rat brain. We hypothesized that DRP could restore microvascular perfusion in hypertensive brain after TBI. Using the in-vivo 2-photon laser scanning microscopy we examined the effect of DRP on microvascular blood flow and tissue oxygenation in hypertensive rat brains with and without TBI. DRP enhanced and restored capillary flow, decreased microvascular shunt flow and, as a result, reduced tissue hypoxia in both un-traumatized and traumatized rat brains at high ICP. Our study suggests that DRP could be an effective treatment for improving microvascular flow in brain ischemia caused by high ICP after TBI. PMID:27165871

Analysis of Electronic Densities and Integrated Doses in Multiform Glioblastomas Stereotactic Radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Baron-Aznar, C.; Moreno-Jimenez, S.; Celis, M. A.

2008-08-11

Integrated dose is the total energy delivered in a radiotherapy target. This physical parameter could be a predictor for complications such as brain edema and radionecrosis after stereotactic radiotherapy treatments for brain tumors. Integrated Dose depends on the tissue density and volume. Using CT patients images from the National Institute of Neurology and Neurosurgery and BrainScan(c) software, this work presents the mean density of 21 multiform glioblastomas, comparative results for normal tissue and estimated integrated dose for each case. The relationship between integrated dose and the probability of complications is discussed.

Fetal magnetic resonance imaging (MRI): a tool for a better understanding of normal and abnormal brain development.

PubMed

Saleem, Sahar N

2013-07-01

Knowledge of the anatomy of the developing fetal brain is essential to detect abnormalities and understand their pathogenesis. Capability of magnetic resonance imaging (MRI) to visualize the brain in utero and to differentiate between its various tissues makes fetal MRI a potential diagnostic and research tool for the developing brain. This article provides an approach to understand the normal and abnormal brain development through schematic interpretation of fetal brain MR images. MRI is a potential screening tool in the second trimester of pregnancies in fetuses at risk for brain anomalies and helps in describing new brain syndromes with in utero presentation. Accurate interpretation of fetal MRI can provide valuable information that helps genetic counseling, facilitates management decisions, and guides therapy. Fetal MRI can help in better understanding the pathogenesis of fetal brain malformations and can support research that could lead to disease-specific interventions.

Prohormone convertase 7 is necessary for the normal processing of cholecystokinin in mouse brain.

PubMed

Anyetei-Anum, Emmanuel N; Blum, Alissa; Seidah, Nabil G; Beinfeld, Margery C

2017-01-22

Endoproteases in the secretory pathway process pro-cholecystokinin (CCK) into the biologically active forms found in the tissues that express CCK mRNA. Thus far, the endoproteases involved in CCK processing include cathepsin L and the prohormone convertases (PC) 1, 2, and 5. This study finds that PC7 is also critical for normal production of CCK in specific areas of the brain. Loss of PC7 results in decreased levels of CCK in more brain regions than any other endoprotease studied to date. Substantial decreases in brain levels of CCK are found in the prefrontal, frontal, parietal-insular-pyriform, and temporal cortex, caudate-putamen, basal forebrain, thalamus, hippocampus, septum, and medulla of PC7 knock-out (KO) mice. A tissue-specific sexual dimorphism of PC7 activity was also identified. This is the first report that loss of PC7 alters levels of a neuropeptide in the brain. This loss of PC7 and CCK may independently contribute to the decrease in Brain Derived Neurotrophic Factor production and be partially responsible for the learning and memory defects observed in mice that lack PC7. Copyright © 2016 Elsevier Inc. All rights reserved.

Gadolinium Deposition in Human Brain Tissues after Contrast-enhanced MR Imaging in Adult Patients without Intracranial Abnormalities.

PubMed

McDonald, Robert J; McDonald, Jennifer S; Kallmes, David F; Jentoft, Mark E; Paolini, Michael A; Murray, David L; Williamson, Eric E; Eckel, Laurence J

2017-11-01

Purpose To determine whether gadolinium deposits in neural tissues of patients with intracranial abnormalities following intravenous gadolinium-based contrast agent (GBCA) exposure might be related to blood-brain barrier integrity by studying adult patients with normal brain pathologic characteristics. Materials and Methods After obtaining antemortem consent and institutional review board approval, the authors compared postmortem neuronal tissue samples from five patients who had undergone four to 18 gadolinium-enhanced magnetic resonance (MR) examinations between 2005 and 2014 (contrast group) with samples from 10 gadolinium-naive patients who had undergone at least one MR examination during their lifetime (control group). All patients in the contrast group had received gadodiamide. Neuronal tissues from the dentate nuclei, pons, globus pallidus, and thalamus were harvested and analyzed with inductively coupled plasma mass spectrometry (ICP-MS), transmission electron microscopy with energy-dispersive x-ray spectroscopy, and light microscopy to quantify, localize, and assess the effects of gadolinium deposition. Results Tissues from the four neuroanatomic regions of gadodiamide-exposed patients contained 0.1-19.4 μg of gadolinium per gram of tissue in a statistically significant dose-dependent relationship (globus pallidus: ρ = 0.90, P = .04). In contradistinction, patients in the control group had undetectable levels of gadolinium with ICP-MS. All patients had normal brain pathologic characteristics at autopsy. Three patients in the contrast group had borderline renal function (estimated glomerular filtration rate <45 mL/min/1.73 m 2 ) and hepatobiliary dysfunction at MR examination. Gadolinium deposition in the contrast group was localized to the capillary endothelium and neuronal interstitium and, in two cases, within the nucleus of the cell. Conclusion Gadolinium deposition in neural tissues after GBCA administration occurs in the absence of intracranial abnormalities that might affect the permeability of the blood-brain barrier. These findings challenge current understanding of the biodistribution of these contrast agents and their safety. © RSNA, 2017.

Is NAA reduction in normal contralateral cerebral tissue in stroke patients dependent on underlying risk factors?

PubMed

Walker, P M; Ben Salem, D; Giroud, M; Brunotte, F

2006-05-01

This retrospective study investigated the dependence of N-acetyl aspartate (NAA) ratios on risk factors for cerebral vasculopathy such as sex, age, hypertension, diabetes mellitus, carotid stenosis, and dyslipidaemia, which may have affected brain vessels and induced metabolic brain abnormalities prior to stroke. We hypothesise that in stroke patients metabolic alterations in the apparently normal contralateral brain are dependent on the presence or not of such risk factors. Fifty nine patients (31 male, 28 female: 58.8+/-16.1 years old) with cortical middle cerebral artery (MCA) territory infarction were included. Long echo time chemical shift imaging spectroscopy was carried out on a Siemens 1.5 T Magnetom Vision scanner using a multi-voxel PRESS technique. Metabolite ratios (NAA/choline, NAA/creatine, lactate/choline, etc) were studied using uni- and multivariate analyses with respect to common risk factors. The influence of age, stroke lesion size, and time since stroke was studied using a linear regression approach. Age, sex, and hypertension all appeared to individually influence metabolite ratios, although only hypertension was significant after multivariate analysis. In both basal ganglia and periventricular white matter regions in apparently normal contralateral brain, the NAA/choline ratio was significantly lower in hypertensive (1.37+/-0.16 and 1.50+/-0.19, respectively) than in normotensive patients (1.72+/-0.19 and 1.85+/-0.15, respectively). Regarding MCA infarction, contralateral tissue remote from the lesion behaves abnormally in the presence of hypertension, the NAA ratios in hypertensive patients being significantly lower. These data suggest that hypertension may compromise the use of contralateral tissue data as a reference for comparison with ischaemic tissue.

Intra-operative probe for brain cancer: feasibility study

NASA Astrophysics Data System (ADS)

Vu Thi, M. H.; Charon, Y.; Duval, M. A.; Lefebvre, F.; Menard, L.; Pitre, S.; Pinot, L.; Siebert, R.

2007-07-01

The present work aims a new medical probe for surgeons devoted to brain cancers, in particular glioblastoma multiforme. Within the last years, our group has started the development of a new intra-operative beta imaging probe. More recently, we took an alternative approach for the same application: a fluorescence probe. In both cases the purpose is to differentiate normal from tumor brain tissue. In a first step, we developed set-ups capable to measure autofluorescence. They are based on a dedicated epi-fluorescence design and on specific fiber optic probes. Relative signal amplitude, spectral shape and fluorescence lifetime measurements are foreseen to distinguish normal and cancer tissue by analyzing fluorophores like NADH, lipopigments and porphyrines. The autofluorescence spectra are recorded in the 460-640 nm range with a low resolution spectrometer. For lifetime measurements a fast detector (APD) is used together with a TCSPC-carte. Intrinsic wavelength- and time-resolutions are a few nm and 200 ps, respectively. Different samples have been analyzed to validate our new detection system and to allow a first configuration of our medical fluorescence probe. First results from the tissue measurements are shown.

Maternal transfer of methimazole and effects on thyroid hormone availability in embryonic tissues.

PubMed

Van Herck, Stijn L J; Geysens, Stijn; Bald, Edward; Chwatko, Grazyna; Delezie, Evelyne; Dianati, Elham; Ahmed, R G; Darras, Veerle M

2013-07-01

Methimazole (MMI) is an anti-thyroid drug used in the treatment of chronic hyperthyroidism. There is, however, some debate about its use during pregnancy as MMI is known to cross the mammalian placenta and reach the developing foetus. A similar problem occurs in birds, where MMI is deposited in the egg and taken up by the developing embryo. To investigate whether maternally derived MMI can have detrimental effects on embryonic development, we treated laying hens with MMI (0.03% in drinking water) and measured total and reduced MMI contents in the tissues of hens and embryos at different stages of development. In hens, MMI was selectively increased in the thyroid gland, while its levels in the liver and especially brain remained relatively low. Long-term MMI treatment induced a pronounced goitre with a decrease in thyroxine (T₄) content but an increase in thyroidal 3,5,3'-triiodothyronine (T₃) content. This resulted in normal T₃ levels in tissues except in the brain. In chicken embryos, MMI levels were similar in the liver and brain. They gradually decreased during development but always remained above those in the corresponding maternal tissues. Contrary to the situation in hens, T₄ availability was only moderately affected in embryos. Peripheral T₃ levels were reduced in 14-day-old embryos but normal in 18-day-old embryos, while brain T₃ content was decreased at all embryonic stages tested. We conclude that all embryonic tissues are exposed to relatively high doses of MMI and its oxidised metabolites. The effect of maternal MMI treatment on embryonic thyroid hormone availability is most pronounced for brain T₃ content, which is reduced throughout the embryonic development period.

Effects of tissue optical properties on time-resolved fluorescence measurements from brain tumors: an experimental and computational study

NASA Astrophysics Data System (ADS)

Butte, Pramod V.; Vishwanath, Karthik; Pikul, Brian K.; Mycek, Mary-Ann; Marcu, Laura

2003-07-01

Time-Resolved Laser-Induced Fluorescence Spectroscopy (tr-LIFS) offers the potential for intra-operative diagnosis of primary brain tumors. However, both the intrinsic properties of endogenous fluorophores and the optical properties of brain tissue could affect the fluorescence measurements from brain. Scattering has been demonstrated to increase, for instance, detected lifetimes by 10-20% in media less scattering than the brain. The overall goal of this study is to investigate experimentally and computationally how optical properties of distinct types of brain tissue (normal porcine white and gray matter) affect the propagation of the excitation pulse and fluorescent transients and the detected fluorescence lifetime. A time-domain tr-LIFS apparatus (fast digitizer and gated detection) was employed to measure the propagation of ultra-short pulsed light through brain specimens (1-2.5-mm source-detector separation; 0.100-mm increment). A Monte Carlo model for semi-infinite turbid media was used to simulate time-resolved light propagation for arbitrary source-detector fiber geometries and optical fiber specifications; and to record spatially- and temporally resolved information. We determined a good correlation between experimental and computational results. Our findings provide means for quantification of time-resolved fluorescence spectra from healthy and diseased brain tissue.

In vivo detection of microstructural correlates of brain pathology in preclinical and early Alzheimer Disease with magnetic resonance imaging.

PubMed

Zhao, Yue; Raichle, Marcus E; Wen, Jie; Benzinger, Tammie L; Fagan, Anne M; Hassenstab, Jason; Vlassenko, Andrei G; Luo, Jie; Cairns, Nigel J; Christensen, Jon J; Morris, John C; Yablonskiy, Dmitriy A

2017-03-01

Alzheimer disease (AD) affects at least 5 million individuals in the USA alone stimulating an intense search for disease prevention and treatment therapies as well as for diagnostic techniques allowing early identification of AD during a long pre-symptomatic period that can be used for the initiation of prevention trials of disease-modifying therapies in asymptomatic individuals. Our approach to developing such techniques is based on the Gradient Echo Plural Contrast Imaging (GEPCI) technique that provides quantitative in vivo measurements of several brain-tissue-specific characteristics of the gradient echo MRI signal (GEPCI metrics) that depend on the integrity of brain tissue cellular structure. Preliminary data were obtained from 34 participants selected from the studies of aging and dementia at the Knight Alzheimer's Disease Research Center at Washington University in St. Louis. Cognitive status was operationalized with the Clinical Dementia Rating (CDR) scale. The participants, assessed as cognitively normal (CDR=0; n=23) or with mild AD dementia (CDR=0.5 or 1; n=11) underwent GEPCI MRI, a collection of cognitive performance tests and CSF amyloid (Aβ) biomarker Aβ 42 . A subset of 19 participants also underwent PET PiB studies to assess their brain Aβ burden. According to the Aβ status, cognitively normal participants were divided into normal (Aβ negative; n=13) and preclinical (Aβ positive; n=10) groups. GEPCI quantitative measurements demonstrated significant differences between all the groups: normal and preclinical, normal and mild AD, and preclinical and mild AD. GEPCI quantitative metrics characterizing tissue cellular integrity in the hippocampus demonstrated much stronger correlations with psychometric tests than the hippocampal atrophy. Importantly, GEPCI-determined changes in the hippocampal tissue cellular integrity were detected even in the hippocampal areas not affected by the atrophy. Our studies also uncovered strong correlations between GEPCI brain tissue metrics and beta-amyloid (Aβ) burden defined by positron emission tomography (PET) - the current in vivo gold standard for detection of cortical Aβ, thus supporting GEPCI as a potential surrogate marker for Aβ imaging - a known biomarker of early AD. Remarkably, the data show significant correlations not only in the areas of high Aβ accumulation (e.g. precuneus) but also in some areas of medial temporal lobe (e.g. parahippocampal cortex), where Aβ accumulation is relatively low. We have demonstrated that GEPCI provides a new approach for the in vivo evaluation of AD-related tissue pathology in the preclinical and early symptomatic stages of AD. Since MRI is a widely available technology, the GEPCI surrogate markers of AD pathology have a potential for improving the quality of AD diagnostic, and the evaluation of new disease-modifying therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

Dimethyl sulfoxide (DMSO) as a potential contrast agent for brain tumors.

PubMed

Delgado-Goñi, T; Martín-Sitjar, J; Simões, R V; Acosta, M; Lope-Piedrafita, S; Arús, C

2013-02-01

Dimethyl sulfoxide (DMSO) is commonly used in preclinical studies of animal models of high-grade glioma as a solvent for chemotherapeutic agents. A strong DMSO signal was detected by single-voxel MRS in the brain of three C57BL/6 control mice during a pilot study of DMSO tolerance after intragastric administration. This led us to investigate the accumulation and wash-out kinetics of DMSO in both normal brain parenchyma (n=3 control mice) by single-voxel MRS, and in 12 GL261 glioblastomas (GBMs) by single-voxel MRS (n=3) and MRSI (n=9). DMSO accumulated differently in each tissue type, reaching its highest concentration in tumors: 6.18 ± 0.85 µmol/g water, 1.5-fold higher than in control mouse brain (p<0.05). A faster wash-out was detected in normal brain parenchyma with respect to GBM tissue: half-lives of 2.06 ± 0.58 and 4.57 ± 1.15 h, respectively. MRSI maps of time-course DMSO changes revealed clear hotspots of differential spatial accumulation in GL261 tumors. Additional MRSI studies with four mice bearing oligodendrogliomas (ODs) revealed similar results as in GBM tumors. The lack of T(1) contrast enhancement post-gadolinium (gadopentetate dimeglumine, Gd-DTPA) in control mouse brain and mice with ODs suggested that DMSO was fully able to cross the intact blood-brain barrier in both normal brain parenchyma and in low-grade tumors. Our results indicate a potential role for DMSO as a contrast agent for brain tumor detection, even in those tumors 'invisible' to standard gadolinium-enhanced MRI, and possibly for monitoring heterogeneities associated with progression or with therapeutic response. Copyright © 2012 John Wiley & Sons, Ltd.

Creating an anthropomorphic digital MR phantom—an extensible tool for comparing and evaluating quantitative imaging algorithms

NASA Astrophysics Data System (ADS)

Bosca, Ryan J.; Jackson, Edward F.

2016-01-01

Assessing and mitigating the various sources of bias and variance associated with image quantification algorithms is essential to the use of such algorithms in clinical research and practice. Assessment is usually accomplished with grid-based digital reference objects (DRO) or, more recently, digital anthropomorphic phantoms based on normal human anatomy. Publicly available digital anthropomorphic phantoms can provide a basis for generating realistic model-based DROs that incorporate the heterogeneity commonly found in pathology. Using a publicly available vascular input function (VIF) and digital anthropomorphic phantom of a normal human brain, a methodology was developed to generate a DRO based on the general kinetic model (GKM) that represented realistic and heterogeneously enhancing pathology. GKM parameters were estimated from a deidentified clinical dynamic contrast-enhanced (DCE) MRI exam. This clinical imaging volume was co-registered with a discrete tissue model, and model parameters estimated from clinical images were used to synthesize a DCE-MRI exam that consisted of normal brain tissues and a heterogeneously enhancing brain tumor. An example application of spatial smoothing was used to illustrate potential applications in assessing quantitative imaging algorithms. A voxel-wise Bland-Altman analysis demonstrated negligible differences between the parameters estimated with and without spatial smoothing (using a small radius Gaussian kernel). In this work, we reported an extensible methodology for generating model-based anthropomorphic DROs containing normal and pathological tissue that can be used to assess quantitative imaging algorithms.

Determination of fluence rate and temperature distributions in the rat brain; implications for photodynamic therapy.

PubMed

Angell-Petersen, Even; Hirschberg, Henry; Madsen, Steen J

2007-01-01

Light and heat distributions are measured in a rat glioma model used in photodynamic therapy. A fiber delivering 632-nm light is fixed in the brain of anesthetized BDIX rats. Fluence rates are measured using calibrated isotropic probes that are positioned stereotactically. Mathematical models are then used to derive tissue optical properties, enabling calculation of fluence rate distributions for general tumor and light application geometries. The fluence rates in tumor-free brains agree well with the models based on diffusion theory and Monte Carlo simulation. In both cases, the best fit is found for absorption and reduced scattering coefficients of 0.57 and 28 cm(-1), respectively. In brains with implanted BT(4)C tumors, a discrepancy between diffusion and Monte Carlo-derived two-layer models is noted. Both models suggest that tumor tissue has higher absorption and less scattering than normal brain. Temperatures are measured by inserting thermocouples directly into tumor-free brains. A model based on diffusion theory and the bioheat equation is found to be in good agreement with the experimental data and predict a thermal penetration depth of 0.60 cm in normal rat brain. The predicted parameters can be used to estimate the fluences, fluence rates, and temperatures achieved during photodynamic therapy.

AUTOSENSITIZATION REACTION IN VITRO

PubMed Central

Koprowski, Hilary; Fernandes, Mario V.

1962-01-01

Lymph node cells were obtained from an inbred strain of Lewis rats injected with guinea pig cord tissue in Freund's adjuvant. These cells, when added to tissue culture monolayers of puppy brain, aggregated on or around the glial elements. This reaction, called contactual agglutination, was followed by the specific destruction of glial cells, leaving cultures consisting only of fibroblasts. No such reaction was noted when lymph node cells obtained either from normal rats or those injected with adjuvant alone were used. Absorption of serum obtained from rats injected with guinea pig cord tissue by non-sensitized lymph node cells made them reactive in brain tissue culture. The contactual agglutination test seems to provide an opportunity for investigation of sensitization reaction in tissue culture systems. PMID:14034719

Apparent diffusion coefficient of the normal human brain for various experimental conditions

NASA Astrophysics Data System (ADS)

Moraru, Luminita; Dimitrievici, Lucian

2017-01-01

Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) is being increasingly used to assess both brain tissues and cerebrospinal fluid integrity. In this paper we study inter-site reproducibility of the apparent diffusion coefficient values for the main cerebral tissues such as gray matter, white matter and into cerebrospinal fluid and for three different stacks of slices that were spaced at L = 79.8, 84.9 and 90 mm. We assessed the impact of the attenuation factor and diffusion gradient on the results reproducibility.

Use of EPO as an adjuvant in PDT of brain tumors to reduce damage to normal brain

NASA Astrophysics Data System (ADS)

Rendon, Cesar A.; Lilge, Lothar

2004-10-01

In order to reduce damage to surrounding normal brain in the treatment of brain tumors with photodynamic therapy (PDT), we have investigated the use of the cytokine erythropoietin (EPO) to exploit its well-established role as a neuroprotective agent. In vitro experiments demonstrated that EPO does not confer protection from PDT to rat glioma cells. In vivo testing of the possibility of EPO protecting normal brain tissue was carried out. The normal brains of Lewis rats were treated with Photofrin mediated PDT (6.25 mg/Kg B.W. 22 hours pre irradiation) and the outcome of the treatment compared between animals that received EPO (5000 U/Kg B.W. 22 hours pre irradiation) and controls. This comparison was made based on the volume of necrosis, as measured with the viability stain 2,3,5- Triphenyl tetrazoium chloride (TTC), and incidence of apoptosis, as measured with in situ end labeling assay (ISEL). Western blotting showed that EPO reaches the normal brain and activates the anti-apoptotic protein PKB/AKT1 within the brain cortex. The comparison based on volume of necrosis showed no statistical significance between the two groups. No clear difference was observed in the ISEL staining between the groups. A possible lack of responsivity in the assays that give rise to these results is discussed and future corrections are described.

Resonance Raman Spectroscopy of human brain metastasis of lung cancer analyzed by blind source separation

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-Hui; Pu, Yang; Cheng, Gangge; Yu, Xinguang; Zhou, Lixin; Lin, Dongmei; Zhu, Ke; Alfano, Robert R.

2017-02-01

Resonance Raman (RR) spectroscopy offers a novel Optical Biopsy method in cancer discrimination by a means of enhancement in Raman scattering. It is widely acknowledged that the RR spectrum of tissue is a superposition of spectra of various key building block molecules. In this study, the Resonance Raman (RR) spectra of human metastasis of lung cancerous and normal brain tissues excited by a visible selected wavelength at 532 nm are used to explore spectral changes caused by the tumor evolution. The potential application of RR spectra human brain metastasis of lung cancer was investigated by Blind Source Separation such as Principal Component Analysis (PCA). PCA is a statistical procedure that uses an orthogonal transformation to convert a set of observations of possibly correlated variables into a set of values of linearly uncorrelated variables called principal components (PCs). The results show significant RR spectra difference between human metastasis of lung cancerous and normal brain tissues analyzed by PCA. To evaluate the efficacy of for cancer detection, a linear discriminant analysis (LDA) classifier is utilized to calculate the sensitivity, and specificity and the receiver operating characteristic (ROC) curves are used to evaluate the performance of this criterion. Excellent sensitivity of 0.97, specificity (close to 1.00) and the Area Under ROC Curve (AUC) of 0.99 values are achieved under best optimal circumstance. This research demonstrates that RR spectroscopy is effective for detecting changes of tissues due to the development of brain metastasis of lung cancer. RR spectroscopy analyzed by blind source separation may have potential to be a new armamentarium.

Ascorbic acid, cognitive function, and Alzheimer’s disease: a current review and future direction

PubMed Central

Bowman, Gene L.

2013-01-01

This narrative review appraises the human and animal studies implicating ascorbic acid (AA) in normal cognitive function and Alzheimer’s disease. A research framework for how nutrition affects brain aging is proposed with emphasis on AA intake, status, metabolism, and transport into brain tissue. A final synopsis highlights areas for future research regarding AA nourishment and healthy brain aging. PMID:22419527

Proton MRS of the peritumoral brain.

PubMed

Chernov, Mikhail F; Kubo, Osami; Hayashi, Motohiro; Izawa, Masahiro; Maruyama, Takashi; Usukura, Masao; Ono, Yuko; Hori, Tomokatsu; Takakura, Kintomo

2005-02-15

Long-echo (TR: 2000 ms, TE: 136 ms) proton MRS of the cerebral tissue in the vicinity to intracranial lesion was done in 15 patients, mainly with parenchymal brain tumors. Significant decrease of N-acetylaspartate (NAA) (P<0.001) and more frequent presence of lactate (P<0.01) comparing with distant normal white matter were found in the perilesional brain tissue. The level of NAA in the perilesional brain tissue had negative associations with presence of lactate in the lesion (P<0.05), excess of lactate in the lesion compared to perilesional brain (P<0.01), grade of the perilesional edema (P<0.01) and patient's age (P<0.05). Multivariate analysis disclosed that identification of lactate in the lesion is associated with lower relative NAA content in the perilesional brain tissue, independently on the presence or absence of any other factor, including brain edema (P<0.001). In patients with lobar lesions who had at least one epileptic seizure during course of their disease the relative NAA content in the perilesional brain was significantly lower, comparing with those who were seizure-free (P<0.05). Therefore, lactate diffused from the tumor, or other metabolites secreted by lactate-producing neoplasm, should be considered as important contributors to the neuronal dysfunction in the surrounding brain. Decrease of NAA in the vicinity to intracranial lesions may reflect neuronal alteration responsible for associated epilepsy.

Brain tissue volumes in the general elderly population. The Rotterdam Scan Study.

PubMed

Ikram, M Arfan; Vrooman, Henri A; Vernooij, Meike W; van der Lijn, Fedde; Hofman, Albert; van der Lugt, Aad; Niessen, Wiro J; Breteler, Monique M B

2008-06-01

We investigated how volumes of cerebrospinal fluid (CSF), grey matter (GM) and white matter (WM) varied with age, sex, small vessel disease and cardiovascular risk factors in the Rotterdam Scan Study. Participants (n=490; 60-90 years) were non-demented and 51.0% had hypertension, 4.9% had diabetes mellitus, 17.8% were current smoker and 54.0% were former smoker. We segmented brain MR-images into GM, normal WM, white matter lesion (WML) and CSF. Brain infarcts were rated visually. Volumes were expressed as percentage of intra-cranial volume. With increasing age, volumes of total brain, normal WM and total WM decreased; that of GM remained unchanged; and that of WML increased, in both men and women. Excluding persons with infarcts did not alter these results. Persons with larger load of small vessel disease had smaller brain volume, especially normal WM volume. Diastolic blood pressure, diabetes mellitus and current smoking were also related to smaller brain volume. In the elderly, higher age, small vessel disease and cardiovascular risk factors are associated with smaller brain volume, especially WM volume.

Histogram-based normalization technique on human brain magnetic resonance images from different acquisitions.

PubMed

Sun, Xiaofei; Shi, Lin; Luo, Yishan; Yang, Wei; Li, Hongpeng; Liang, Peipeng; Li, Kuncheng; Mok, Vincent C T; Chu, Winnie C W; Wang, Defeng

2015-07-28

Intensity normalization is an important preprocessing step in brain magnetic resonance image (MRI) analysis. During MR image acquisition, different scanners or parameters would be used for scanning different subjects or the same subject at a different time, which may result in large intensity variations. This intensity variation will greatly undermine the performance of subsequent MRI processing and population analysis, such as image registration, segmentation, and tissue volume measurement. In this work, we proposed a new histogram normalization method to reduce the intensity variation between MRIs obtained from different acquisitions. In our experiment, we scanned each subject twice on two different scanners using different imaging parameters. With noise estimation, the image with lower noise level was determined and treated as the high-quality reference image. Then the histogram of the low-quality image was normalized to the histogram of the high-quality image. The normalization algorithm includes two main steps: (1) intensity scaling (IS), where, for the high-quality reference image, the intensities of the image are first rescaled to a range between the low intensity region (LIR) value and the high intensity region (HIR) value; and (2) histogram normalization (HN),where the histogram of low-quality image as input image is stretched to match the histogram of the reference image, so that the intensity range in the normalized image will also lie between LIR and HIR. We performed three sets of experiments to evaluate the proposed method, i.e., image registration, segmentation, and tissue volume measurement, and compared this with the existing intensity normalization method. It is then possible to validate that our histogram normalization framework can achieve better results in all the experiments. It is also demonstrated that the brain template with normalization preprocessing is of higher quality than the template with no normalization processing. We have proposed a histogram-based MRI intensity normalization method. The method can normalize scans which were acquired on different MRI units. We have validated that the method can greatly improve the image analysis performance. Furthermore, it is demonstrated that with the help of our normalization method, we can create a higher quality Chinese brain template.

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

PubMed

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J

2009-01-01

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

Time-dependent diffuse reflectance spectroscopy for in vivo characterization of pediatric epileptogenic brain lesions

NASA Astrophysics Data System (ADS)

Oh, Sanghoon; Ragheb, John; Bhatia, Sanjiv; Sandberg, David; Johnson, Mahlon; Fernald, Bradley; Lin, Wei-Chiang

2008-02-01

Optical spectroscopy for in vivo tissue diagnosis is performed traditionally in a static manner; a snap shot of the tissue biochemical and morphological characteristics is captured through the interaction between light and the tissue. This approach does not capture the dynamic nature of a living organ, which is critical to the studies of brain disorders such as epilepsy. Therefore, a time-dependent diffuse reflectance spectroscopy system with a fiber-optic probe was designed and developed. The system was designed to acquire broadband diffuse reflectance spectra (240 ~ 932 nm) at an acquisition rate of 33 Hz. The broadband spectral acquisition feature allows simultaneous monitoring of various physiological characteristics of tissues. The utility of such a system in guiding pediatric epilepsy surgery was tested in a pilot clinical study including 13 epilepsy patients and seven brain tumor patients. The control patients were children undergoing suregery for brain tumors in which measurements were taken from normal brain exposed during the surgery. Diffuse reflectance spectra were acquired for 12 seconds from various parts of the brain of the patients during surgery. Recorded spectra were processed and analyzed in both spectral and time domains to gain insights into the dynamic changes in, for example, hemodynamics of the investigated brain tissue. One finding from this pilot study is that unsynchronized alterations in local blood oxygenation and local blood volume were observed in epileptogenic cortex. These study results suggest the advantage of using a time-dependent diffuse reflectance spectroscopy system to study epileptogenic brain in vivo.

In situ FTIR microspectroscopy of extravasated blood-damaged brain tissue

NASA Astrophysics Data System (ADS)

Wetzel, David L.; Le Vine, Steven M.

1994-01-01

Fourier transform infrared (FT-IR) microspectroscopy enables the collection of infrared spectra from microscopic regions of tissue sections. The objectives of this study were to utilize FT-IR microspectroscopy to analyze the spatial distribution of chemical changes that result from the extravasation of blood into the brain and to determine if products of free radical damage are associated with the damaged areas. An animal model that involves the injection of blood into the white matter of rat brains was used. Maps depicting the relative concentrations of chemical functional groups of lesioned sites and surrounding areas were made. Significant decreases were observed for CH2, C equals O, P equals O, and HO-C-H functional groups at the lesioned site and penumbra regions compared to the neighboring normal tissue areas.

NASA Robotic Neurosurgery Testbed

NASA Technical Reports Server (NTRS)

Mah, Robert

1997-01-01

The detection of tissue interface (e.g., normal tissue, cancer, tumor) has been limited clinically to tactile feedback, temperature monitoring, and the use of a miniature ultrasound probe for tissue differentiation during surgical operations, In neurosurgery, the needle used in the standard stereotactic CT or MRI guided brain biopsy provides no information about the tissue being sampled. The tissue sampled depends entirely upon the accuracy with which the localization provided by the preoperative CT or MRI scan is translated to the intracranial biopsy site. In addition, no information about the tissue being traversed by the needle (e.g., a blood vessel) is provided. Hemorrhage due to the biopsy needle tearing a blood vessel within the brain is the most devastating complication of stereotactic CT/MRI guided brain biopsy. A robotic neurosurgery testbed has been developed at NASA Ames Research Center as a spin-off of technologies from space, aeronautics and medical programs. The invention entitled "Robotic Neurosurgery Leading to Multimodality Devices for Tissue Identification" is nearing a state ready for commercialization. The devices will: 1) improve diagnostic accuracy and precision of general surgery, with near term emphasis on stereotactic brain biopsy, 2) automate tissue identification, with near term emphasis on stereotactic brain biopsy, to permit remote control of the procedure, and 3) reduce morbidity for stereotactic brain biopsy. The commercial impact from this work is the potential development of a whole new generation of smart surgical tools to increase the safety, accuracy and efficiency of surgical procedures. Other potential markets include smart surgical tools for tumor ablation in neurosurgery, general exploratory surgery, prostate cancer surgery, and breast cancer surgery.

NASA Robotic Neurosurgery Testbed

NASA Technical Reports Server (NTRS)

Mah, Robert

1997-01-01

The detection of tissue interface (e.g., normal tissue, cancer, tumor) has been limited clinically to tactile feedback, temperature monitoring, and the use of a miniature ultrasound probe for tissue differentiation during surgical operations. In neurosurgery, the needle used in the standard stereotactic CT (Computational Tomography) or MRI (Magnetic Resonance Imaging) guided brain biopsy provides no information about the tissue being sampled. The tissue sampled depends entirely upon the accuracy with which the localization provided by the preoperative CT or MRI scan is translated to the intracranial biopsy site. In addition, no information about the tissue being traversed by the needle (e.g., a blood vessel) is provided. Hemorrhage due to the biopsy needle tearing a blood vessel within the brain is the most devastating complication of stereotactic CT/MRI guided brain biopsy. A robotic neurosurgery testbed has been developed at NASA Ames Research Center as a spin-off of technologies from space, aeronautics and medical programs. The invention entitled 'Robotic Neurosurgery Leading to Multimodality Devices for Tissue Identification' is nearing a state ready for commercialization. The devices will: 1) improve diagnostic accuracy and precision of general surgery, with near term emphasis on stereotactic brain biopsy, 2) automate tissue identification, with near term emphasis on stereotactic brain biopsy, to permit remote control of the procedure, and 3) reduce morbidity for stereotactic brain biopsy. The commercial impact from this work is the potential development of a whole new generation of smart surgical tools to increase the safety, accuracy and efficiency of surgical procedures. Other potential markets include smart surgical tools for tumor ablation in neurosurgery, general exploratory surgery, prostate cancer surgery, and breast cancer surgery.

Skull Base Tumors

NASA Astrophysics Data System (ADS)

Schulz-Ertner, Daniela

In skull base tumors associated with a low radiosensitivity for conventional radiotherapy (RT), irradiation with proton or carbon ion beams facilitates a safe and accurate application of high tumor doses due to the favorable beam localization properties of these particle beams. Cranial nerves, the brain stem and normal brain tissue can at the same time be optimally spared.

Anti-EGFRvIII Chimeric Antigen Receptor-Modified T Cells for Adoptive Cell Therapy of Glioblastoma.

PubMed

Ren, Pei-Pei; Li, Ming; Li, Tian-Fang; Han, Shuang-Yin

2017-01-01

Glioblastoma (GBM) is one of the most devastating brain tumors with poor prognosis and high mortality. Although radical surgical treatment with subsequent radiation and chemotherapy can improve the survival, the efficacy of such regimens is insufficient because the GBM cells can spread and destroy normal brain structures. Moreover, these non-specific treatments may damage adjacent healthy brain tissue. It is thus imperative to develop novel therapies to precisely target invasive tumor cells without damaging normal tissues. Immunotherapy is a promising approach due to its capability to suppress the growth of various tumors in preclinical model and clinical trials. Adoptive cell therapy (ACT) using T cells engineered with chimeric antigen receptor (CAR) targeting an ideal molecular marker in GBM, e.g. epidermal growth factor receptor type III (EGFRvIII) has demonstrated a satisfactory efficacy in treating malignant brain tumors. Here we summarize the recent progresses in immunotherapeutic strategy using CAR-modified T cells oriented to EGFRvIII against GBM. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Fluorescence lifetime spectroscopy for guided therapy of brain tumors.

PubMed

Butte, Pramod V; Mamelak, Adam N; Nuno, Miriam; Bannykh, Serguei I; Black, Keith L; Marcu, Laura

2011-01-01

This study evaluates the potential of time-resolved laser induced fluorescence spectroscopy (TR-LIFS) as intra-operative tool for the delineation of brain tumor from normal brain. Forty two patients undergoing glioma (WHO grade I-IV) surgery were enrolled in this study. A TR-LIFS prototype apparatus (gated detection, fast digitizer) was used to induce in-vivo fluorescence using a pulsed N2 laser (337 nm excitation, 0.7 ns pulse width) and to record the time-resolved spectrum (360-550 nm range, 10 nm interval). The sites of TR-LIFS measurement were validated by conventional histopathology (H&E staining). Parameters derived from the TR-LIFS data including intensity values and time-resolved intensity decay features (average fluorescence lifetime and Laguerre coefficients values) were used for tissue characterization and classification. 71 areas of tumor and normal brain were analyzed. Several parameters allowed for the differentiation of distinct tissue types. For example, normal cortex (N=35) and normal white matter (N=12) exhibit a longer-lasting fluorescence emission at 390 nm (τ390=2.12±0.10 ns) when compared with 460 nm (τ460=1.16±0.08 ns). High grade glioma (grades III and IV) samples (N=17) demonstrate emission peaks at 460 nm, with large variation at 390 nm while low grade glioma (I and II) samples (N=7) demonstrated a peak fluorescence emission at 460 nm. A linear discriminant algorithm allowed for the classification of low-grade gliomas with 100% sensitivity and 98% specificity. High-grade glioma demonstrated a high degree of heterogeneity thus reducing the discrimination accuracy of these tumors to 47% sensitivity and 94% specificity. Current findings demonstrate that TR-LIFS holds the potential to diagnose brain tumors intra-operatively and to provide a valuable tool for aiding the neurosurgeon-neuropathologist team in to rapidly distinguish between tumor and normal brain during surgery. Copyright © 2010 Elsevier Inc. All rights reserved.

Manifold Learning in MR spectroscopy using nonlinear dimensionality reduction and unsupervised clustering.

PubMed

Yang, Guang; Raschke, Felix; Barrick, Thomas R; Howe, Franklyn A

2015-09-01

To investigate whether nonlinear dimensionality reduction improves unsupervised classification of (1) H MRS brain tumor data compared with a linear method. In vivo single-voxel (1) H magnetic resonance spectroscopy (55 patients) and (1) H magnetic resonance spectroscopy imaging (MRSI) (29 patients) data were acquired from histopathologically diagnosed gliomas. Data reduction using Laplacian eigenmaps (LE) or independent component analysis (ICA) was followed by k-means clustering or agglomerative hierarchical clustering (AHC) for unsupervised learning to assess tumor grade and for tissue type segmentation of MRSI data. An accuracy of 93% in classification of glioma grade II and grade IV, with 100% accuracy in distinguishing tumor and normal spectra, was obtained by LE with unsupervised clustering, but not with the combination of k-means and ICA. With (1) H MRSI data, LE provided a more linear distribution of data for cluster analysis and better cluster stability than ICA. LE combined with k-means or AHC provided 91% accuracy for classifying tumor grade and 100% accuracy for identifying normal tissue voxels. Color-coded visualization of normal brain, tumor core, and infiltration regions was achieved with LE combined with AHC. The LE method is promising for unsupervised clustering to separate brain and tumor tissue with automated color-coding for visualization of (1) H MRSI data after cluster analysis. © 2014 Wiley Periodicals, Inc.

SU-E-T-568: Improving Normal Brain Sparing with Increasing Number of Arc Beams for Volume Modulated Arc Beam Radiosurgery of Multiple Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hossain, S; Hildebrand, K; Ahmad, S

Purpose: Intensity modulated arc beams have been newly reported for treating multiple brain metastases. The purpose of this study was to determine the variations in the normal brain doses with increasing number of arc beams for multiple brain metastases treatments via the TrueBeam Rapidarc system (Varian Oncology, Palo Alto, CA). Methods: A patient case with 12 metastatic brain lesions previously treated on the Leksell Gamma Knife Perfexion (GK) was used for the study. All lesions and organs at risk were contoured by a senior radiation oncologist and treatment plans for a subset of 3, 6, 9 and all 12 targetsmore » were developed for the TrueBeam Rapidarc system via 3 to 7 intensity modulated arc-beams with each target covered by at least 99% of the prescribed dose of 20 Gy. The peripheral normal brain isodose volumes as well as the total beam-on time were analyzed with increasing number of arc beams for these targets. Results: All intensisty modulated arc-beam plans produced efficient treatment delivery with the beam-on time averaging 0.6–1.5 min per lesion at an output of 1200 MU/min. With increasing number of arc beams, the peripheral normal brain isodose volumes such as the 12-Gy isodose line enclosed normal brain tissue volumes were on average decreased by 6%, 11%, 18%, and 28% for the 3-, 6-, 9-, 12-target treatment plans respectively. The lowest normal brain isodose volumes were consistently found for the 7-arc treatment plans for all the cases. Conclusion: With nearly identical beam-on times, the peripheral normal brain dose was notably decreased when the total number of intensity modulated arc beams was increased when treating multiple brain metastases. Dr Sahgal and Dr Ma are currently serving on the board of international society of stereotactic radiosurgery.« less

Synchrotron X-ray microtransections: a non invasive approach for epileptic seizures arising from eloquent cortical areas

PubMed Central

Pouyatos, B.; Nemoz, C.; Chabrol, T.; Potez, M.; Bräuer, E.; Renaud, L.; Pernet-Gallay, K.; Estève, F.; David, O.; Kahane, P.; Laissue, J. A.; Depaulis, A.; Serduc, R.

2016-01-01

Synchrotron-generated X-ray (SRX) microbeams deposit high radiation doses to submillimetric targets whilst minimizing irradiation of neighboring healthy tissue. We developed a new radiosurgical method which demonstrably transects cortical brain tissue without affecting adjacent regions. We made such image-guided SRX microtransections in the left somatosensory cortex in a rat model of generalized epilepsy using high radiation doses (820 Gy) in thin (200 μm) parallel slices of tissue. This procedure, targeting the brain volume from which seizures arose, altered the abnormal neuronal activities for at least 9 weeks, as evidenced by a decrease of seizure power and coherence between tissue slices in comparison to the contralateral cortex. The brain tissue located between transections stayed histologically normal, while the irradiated micro-slices remained devoid of myelin and neurons two months after irradiation. This pre-clinical proof of concept highlights the translational potential of non-invasive SRX transections for treating epilepsies that are not eligible for resective surgery. PMID:27264273

Synchrotron X-ray microtransections: a non invasive approach for epileptic seizures arising from eloquent cortical areas

NASA Astrophysics Data System (ADS)

Pouyatos, B.; Nemoz, C.; Chabrol, T.; Potez, M.; Bräuer, E.; Renaud, L.; Pernet-Gallay, K.; Estève, F.; David, O.; Kahane, P.; Laissue, J. A.; Depaulis, A.; Serduc, R.

2016-06-01

Synchrotron-generated X-ray (SRX) microbeams deposit high radiation doses to submillimetric targets whilst minimizing irradiation of neighboring healthy tissue. We developed a new radiosurgical method which demonstrably transects cortical brain tissue without affecting adjacent regions. We made such image-guided SRX microtransections in the left somatosensory cortex in a rat model of generalized epilepsy using high radiation doses (820 Gy) in thin (200 μm) parallel slices of tissue. This procedure, targeting the brain volume from which seizures arose, altered the abnormal neuronal activities for at least 9 weeks, as evidenced by a decrease of seizure power and coherence between tissue slices in comparison to the contralateral cortex. The brain tissue located between transections stayed histologically normal, while the irradiated micro-slices remained devoid of myelin and neurons two months after irradiation. This pre-clinical proof of concept highlights the translational potential of non-invasive SRX transections for treating epilepsies that are not eligible for resective surgery.

Poster — Thur Eve — 64: Preliminary investigation of arc configurations for optimal sparing of normal tissue in hypofractionated stereotactic radiotherapy (HF-SRT) of multiple brain metastases using a 5mm interdigitating micro-multileaf collimator

DOE Office of Scientific and Technical Information (OSTI.GOV)

Leavens, C; Wronski, M; Lee, YK

2014-08-15

Purpose: To evaluate normal tissue sparing in intra-cranial HF-SRT, comparing various arc configurations with the Synergy Beam Modulator (SynBM) and Agility linacs, the latter incorporating leaf interdigitation and backup jaws. Methods: Five patients with multiple brain metastases (BMs), (5 BMs (n=2), 3 BMs (n=3)) treated with HF-SRT using 25 Gy (n=2) or 30 Gy (n=3) in 5 fractions, were investigated. Clinical treatment plans used the SynBM. Each patient was retrospectively re-planned on Agility, employing three planning strategies: (A) one isocenter and dedicated arc for each BM; (B) a single isocenter, centrally placed with respect to BMs; (C) the isocenter andmore » arc configuration used in the SynBM plan, where closely spaced (<5cm) BMs used a dedicated isocenter and arcs. Agility plans were normalized for PTV coverage and heterogeneity. Results and Conclusion: Strategy A obtained the greatest improvements over the SynBM plan, where the maximum OAR dose, and mean dose to normal brain (averaged for all patients) were reduced by 55cGy and 25cGy, respectively. Strategy B was limited by having a single isocenter, hence less jaw shielding and increased MLC leakage. The maximum OAR dose was reduced by 13cGy, however mean dose to normal brain increased by 84cGy. Strategy C reduced the maximum OAR dose and mean dose to normal brain by 32cGy and 9cGy, respectively. The results from this study indicate that, for intra-cranial HF-SRT of multiple BMs, Agility plans are equal or better than SynBM plans. Further planning is needed to investigate dose sparing using Strategy A and the SynBM.« less

SU-E-T-21: A D-D Based Neutron Generator System for Boron Neutron Capture Therapy: A Feasibility Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsieh, M; Liu, Y; Nie, L

2015-06-15

Purpose: To investigate the feasibility of a deuterium-deuterium (DD) neutron generator for application in boron neutron capture therapy (BNCT) of brain cancer Methods: MCNP simulations were performed using a head phantom and a monoenergetic neutron source, which resembles the point source in a DD generator that emits 2.45-MeV neutrons. Source energies ranging from 5eV to 2.45MeV were simulated to determine the optimal treatment energy. The phantom consisted of soft tissue, brain tissue, skull, skin layer, and a brain tumor of 5 cm in diameter. Tumor depth was varied from 5–10 cm. Boron-10 concentrations of 10 ppm, 15 ppm, and 30more » ppm were used in the soft/brain tissues, skin, and tumor, respectively. The neutron flux required to deliver 60 Gy to the tumor as well as the normal tissue doses were determined. Results: Beam energies between 5eV and 10keV obtained doses with the highest dose ratios (3.3–25.9) between the tumor and the brain at various depths. The dose ratio with 2.45-MeV neutrons ranged from 0.8–6.6. To achieve the desired tumor dose in 40 minutes, the required neutron flux for a DD generator was between 8.8E10 and 5.2E11 n/s and the resulting brain dose was between 2.3 and 18 Gy, depending on the tumor depth. The skin and soft tissue doses were within acceptable tolerances. The boron-neutron interaction accounted for 54–58% of the total dose. Conclusion: This study shows that the DD neutron generator can be a feasible neutron source for BNCT. The required neutron flux for treatment is achievable with the current DD neutron technology. With a well-designed beam shaping assembly and treatment geometry, the neutron flux can be further improved and a 60-Gy prescription can be accurately delivered to the target while maintaining tolerable normal tissue doses. Further experimental studies will be developed and conducted to validate the simulation results.« less

Expression of metalloprotease insulin-degrading enzyme insulysin in normal and malignant human tissues.

PubMed

Yfanti, Christina; Mengele, Karin; Gkazepis, Apostolos; Weirich, Gregor; Giersig, Cecylia; Kuo, Wen-Liang; Tang, Wei-Jen; Rosner, Marsha; Schmitt, Manfred

2008-10-01

Insulin-degrading enzyme (IDE, insulysin, insulinase; EC 3.4.22.11), a thiol metalloendopeptidase, is involved in intracellular degradation of insulin, thereby inhibiting its translocation and accumulation to the nucleus. Recently, protein expression of IDE has been demonstrated in the epithelial ducts of normal breast and breast cancer tissue. Utilizing four different antibodies generated against different epitopes of the IDE molecule, we performed Western blot analysis and immunohistochemical staining on several normal human tissues, on a plethora of tumor cell lines of different tissue origin, and on malignant breast and ovarian tissue. Applying the four IDE-directed antibodies, we demonstrated IDE expression at the protein level, by means of immunoblotting and immunocytochemistry, in each of the tumor cell lines analyzed. Insulin-degrading enzyme protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. Immunohistochemical visualization of IDE indicated cytoplasmic localization of IDE in each of the cell lines and tissues assessed. In conclusion, we performed for the first time a wide-ranging survey on IDE protein expression in normal and malignant tissues and cells thus extending our knowledge on the cellular and tissue distribution of IDE, an enzyme which to date has mainly been studied in connection with Alzheimer's disease and diabetes but not in cancer.

Effects of fasting, temperature, and photoperiod on preproghrelin mRNA expression in Chinese perch.

PubMed

Song, Yi; Zhao, Cheng; Liang, Xu-Fang; He, Shan; Tian, Changxu; Cheng, Xiaoyan; Yuan, Xiaochen; Lv, Liyuan; Guo, Wenjie; Xue, Min; Tao, Ya-Xiong

2017-06-01

Preproghrelin, a gut/brain peptide, plays an important role in the regulation of food intake and energy homeostasis in teleost and mammals. In the present study, we obtained the full-length preproghrelin cDNA in Chinese perch. The preproghrelin messenger RNA (mRNA) tissue expression showed that level was much higher in stomach and pituitary than in other tissues. The fasting study showed, after gastric emptying (3-6 h), short-term fasting (6-12 h) increased preproghrelin expression in the stomach. While in the pituitary, fasting reduced preproghrelin expression at 1, 3, 12, and 48 h, presenting state fluctuation of self-adjustment. The temperature study showed that the mRNA expression of preproghrelin was the highest in the brain at 26 °C and highest in the stomach at 32 °C, respectively, with different optimum temperature in these two tissues, reflecting spatiotemporal differences of regulation by central nervous system and peripheral organs. The photoperiod study showed that normal light (11 h of lightness and 13 h of darkness) led to highest preproghrelin expression, both in the brain and in the stomach, than continuous light or continuous dark, proving food intake is adapted to natural photoperiod or normal light in this study. These results all indicated that tissue-specific preproghrelin expression of Chinese perch could be significantly affected by environmental factors. Short-term fasting of 6 h after gastric emptying, 26 °C, and normal light led to higher preproghrelin expression, which indicated potential appetite increase in Chinese perch.

Tissue distribution and depuration kinetics of waterborne 14C-labeled light PAHs in mummichog (Fundulus heteroclitus).

PubMed

Valdez Domingos, F X; Oliveira Ribeiro, C A; Pelletier, É; Rouleau, C

2011-04-01

Light polycyclic aromatic hydrocarbons (PAHs) of petrogenic origin are commonly found in estuaries and coastal areas. Though they are known to be toxic to fish, little is known about their uptake and tissue distribution. This paper reports on the results of a study on uptake, elimination, and tissue distribution of three waterborne 14C-labeled PAHs in the mummichog, Fundulus heteroclitus, using whole-body autoradiography. After a 24 h exposure to 1 μCi·L(-1) of 14C-naphthalene, 14C-1-naphthol, and 14C-phenanthrene, fish were transferred to clean water and tissue distribution examined after 0, 1, 3, 7, 14, and 21 days of depuration. All compounds were readily accumulated by fish and were also rapidly eliminated (t0.5 range=1.1 to 3.0 days). Most of the radioactivity in naphthalene- and phenanthrene-treated fish was found in gall bladder≫liver>intestinal lumen. In naphthol-exposed fish, an important labeling of some brain areas was observed. Brain of naphthalene-exposed fish was also labeled after 24 h depuration, indicating that exposure to naphthalene may result in metabolite accumulation in the brain. This is the first study showing that naphthalene, naphthol, and/or unidentified metabolite(s) can accumulate in brain tissues, which may impair normal brain function.

Multiplex coherent anti-Stokes Raman scattering microspectroscopy of brain tissue with higher ranking data classification for biomedical imaging

NASA Astrophysics Data System (ADS)

Pohling, Christoph; Bocklitz, Thomas; Duarte, Alex S.; Emmanuello, Cinzia; Ishikawa, Mariana S.; Dietzeck, Benjamin; Buckup, Tiago; Uckermann, Ortrud; Schackert, Gabriele; Kirsch, Matthias; Schmitt, Michael; Popp, Jürgen; Motzkus, Marcus

2017-06-01

Multiplex coherent anti-Stokes Raman scattering (MCARS) microscopy was carried out to map a solid tumor in mouse brain tissue. The border between normal and tumor tissue was visualized using support vector machines (SVM) as a higher ranking type of data classification. Training data were collected separately in both tissue types, and the image contrast is based on class affiliation of the single spectra. Color coding in the image generated by SVM is then related to pathological information instead of single spectral intensities or spectral differences within the data set. The results show good agreement with the H&E stained reference and spontaneous Raman microscopy, proving the validity of the MCARS approach in combination with SVM.

Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII

PubMed Central

Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter; Zhu, Yanqing; Yu, Hongwei; Wang, Ping; Bagel, Jessica; Vite, Charles H; Sikora, Tracey; Hinderer, Christian; Calcedo, Roberto; Yox, Alexander D; Steet, Richard A; Ruane, Therese; O'Donnell, Patricia; Gao, Guangping; Wilson, James M; Casal, Margret; Ponder, Katherine P; Haskins, Mark E

2016-01-01

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII. PMID:26447927

Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII.

PubMed

Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter; Zhu, Yanqing; Yu, Hongwei; Wang, Ping; Bagel, Jessica; Vite, Charles H; Sikora, Tracey; Hinderer, Christian; Calcedo, Roberto; Yox, Alexander D; Steet, Richard A; Ruane, Therese; O'Donnell, Patricia; Gao, Guangping; Wilson, James M; Casal, Margret; Ponder, Katherine P; Haskins, Mark E

2016-02-01

Mucopolysaccharidosis VII (MPS VII) is a lysosomal storage disease arising from mutations in β-d-glucuronidase (GUSB), which results in glycosaminoglycan (GAG) accumulation and a variety of clinical manifestations including neurological disease. Herein, MPS VII dogs were injected intravenously (i.v.) and/or intrathecally (i.t.) via the cisterna magna with AAV9 or AAVrh10 vectors carrying the canine GUSB cDNA. Although i.v. injection alone at 3 days of age resulted in normal cerebrospinal fluid (CSF) GUSB activity, brain tissue homogenates had only ~1 to 6% normal GUSB activity and continued to have elevated GAG storage. In contrast, i.t. injection at 3 weeks of age resulted in CSF GUSB activity 44-fold normal while brain tissue homogenates had >100% normal GUSB activity and reduced GAGs compared with untreated dogs. Markers for secondary storage and inflammation were eliminated in i.t.-treated dogs and reduced in i.v.-treated dogs compared with untreated dogs. Given that i.t.-treated dogs expressed higher levels of GUSB in the CNS tissues compared to those treated i.v., we conclude that i.t. injection of AAV9 or AAVrh10 vectors is more effective than i.v. injection alone in the large animal model of MPS VII.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lupo, Janine M., E-mail: janine.lupo@ucsf.edu; Chuang, Cynthia F.; Chang, Susan M.

Purpose: To evaluate the intermediate- and long-term imaging manifestations of radiotherapy on normal-appearing brain tissue in patients with treated gliomas using 7T susceptibility-weighted imaging (SWI). Methods and Materials: SWI was performed on 25 patients with stable gliomas on a 7 Tesla magnet. Microbleeds were identified as discrete foci of susceptibility that did not correspond to vessels. The number of microbleeds was counted within and outside of the T2-hyperintense lesion. For 3 patients, radiation dosimetry maps were reconstructed and fused with the 7T SWI data. Results: Multiple foci of susceptibility consistent with microhemorrhages were observed in patients 2 years after chemoradiation.more » These lesions were not present in patients who were not irradiated. The prevalence of microhemorrhages increased with the time since completion of radiotherapy, and these lesions often extended outside the boundaries of the initial high-dose volume and into the contralateral hemisphere. Conclusions: High-field SWI has potential for visualizing the appearance of microbleeds associated with long-term effects of radiotherapy on brain tissue. The ability to visualize these lesions in normal-appearing brain tissue may be important in further understanding the utility of this treatment in patients with longer survival.« less

Ectopic High Expression of E2-EPF Ubiquitin Carrier Protein Indicates a More Unfavorable Prognosis in Brain Glioma.

PubMed

Zhang, Xiaohui; Zhao, Fangbo; Zhang, Shujun; Song, Yichun

2017-04-01

Ubiquitination of proteins meant for elimination is a primary method of eukaryotic cellular protein degradation. The ubiquitin carrier protein E2-EPF is a key degradation enzyme that is highly expressed in many tumors. However, its expression and prognostic significance in brain glioma are still unclear. The aim of this study was to reveal how the level of E2-EPF relates to prognosis in brain glioma. Thirty low-grade and 30 high-grade brain glioma samples were divided into two tissue microarrays each. Levels of E2-EPF protein were examined by immunohistochemistry and immunofluorescence. Quantitative real-time polymerase chain reaction was used to analyze the level of E2-EPF in 60 glioma and 3 normal brain tissue samples. The relationship between E2-EPF levels and prognosis was analyzed by Kaplan-Meier survival curves. E2-EPF levels were low in normal brain tissue samples but high in glioma nuclei. E2-EPF levels gradually increased as glioma grade increased (p < 0.05). Ectopic E2-EPF levels in high-grade glioma were significantly higher than in low-grade glioma (p < 0.01). The 5-year survival rate of glioma patients with high E2-EPF levels was shorter than in patients with low expression (p < 0.05). Furthermore, the 5-year survival rate of patients with ectopic E2-EPF was significantly shorter than patients with only nuclear E2-EPF (p < 0.01). These results suggest that higher E2-EPF levels, especially ectopic, are associated with higher grade glioma and shorter survival. E2-EPF levels may play a key role in predicting the prognosis for patients with brain glioma.

Quantitative measurements of regional glucose utilization and rate of valine incorporation into proteins by double-tracer autoradiography in the rat brain tumor model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kirikae, M.; Diksic, M.; Yamamoto, Y.L.

1989-02-01

We examined the rate of glucose utilization and the rate of valine incorporation into proteins using 2-(/sup 18/F)fluoro-2-deoxyglucose and L-(1-14C)-valine in a rat brain tumor model by quantitative double-tracer autoradiography. We found that in the implanted tumor the rate of valine incorporation into proteins was about 22 times and the rate of glucose utilization was about 1.5 times that in the contralateral cortex. (In the ipsilateral cortex, the tumor had a profound effect on glucose utilization but no effect on the rate of valine incorporation into proteins.) Our findings suggest that it is more useful to measure protein synthesis thanmore » glucose utilization to assess the effectiveness of antitumor agents and their toxicity to normal brain tissue. We compared two methods to estimate the rate of valine incorporation: kinetic (quantitation done using an operational equation and the average brain rate coefficients) and washed slices (unbound labeled valine removed by washing brain slices in 10% trichloroacetic acid). The results were the same using either method. It would seem that the kinetic method can thus be used for quantitative measurement of protein synthesis in brain tumors and normal brain tissue using (/sup 11/C)-valine with positron emission tomography.« less

Non-destructive optical clearing technique enhances optical coherence tomography (OCT) for real-time, 3D histomorphometry of brain tissue (Conference Presentation)

NASA Astrophysics Data System (ADS)

Paul, Akshay; Chang, Theodore H.; Chou, Li-Dek; Ramalingam, Tirunelveli S.

2016-03-01

Evaluation of neurodegenerative disease often requires examination of brain morphology. Volumetric analysis of brain regions and structures can be used to track developmental changes, progression of disease, and the presence of transgenic phenotypes. Current standards for microscopic investigation of brain morphology are limited to detection of superficial structures at a maximum depth of 300μm. While histological techniques can provide detailed cross-sections of brain structures, they require complicated tissue preparation and the ultimate destruction of the sample. A non-invasive, label-free imaging modality known as Optical Coherence Tomography (OCT) can produce 3-dimensional reconstructions through high-speed, cross-sectional scans of biological tissue. Although OCT allows for the preservation of intact samples, the highly scattering and absorbing properties of biological tissue limit imaging depth to 1-2mm. Optical clearing agents have been utilized to increase imaging depth by index matching and lipid digestion, however, these contemporary techniques are expensive and harsh on tissues, often irreversibly denaturing proteins. Here we present an ideal optical clearing agent that offers ease-of-use and reversibility. Similar to how SeeDB has been effective for microscopy, our fructose-based, reversible optical clearing technique provides improved OCT imaging and functional immunohistochemical mapping of disease. Fructose is a natural, non-toxic sugar with excellent water solubility, capable of increasing tissue transparency and reducing light scattering. We will demonstrate the improved depth-resolving performance of OCT for enhanced whole-brain imaging of normal and diseased murine brains following a fructose clearing treatment. This technique potentially enables rapid, 3-dimensional evaluation of biological tissues at axial and lateral resolutions comparable to histopathology.

Magnetization Transfer Ratio Relates to Cognitive Impairment in Normal Elderly

PubMed Central

Seiler, Stephan; Pirpamer, Lukas; Hofer, Edith; Duering, Marco; Jouvent, Eric; Fazekas, Franz; Mangin, Jean-Francois; Chabriat, Hugues; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

2014-01-01

Magnetization transfer imaging (MTI) can detect microstructural brain tissue changes and may be helpful in determining age-related cerebral damage. We investigated the association between the magnetization transfer ratio (MTR) in gray and white matter (WM) and cognitive functioning in 355 participants of the Austrian stroke prevention family study (ASPS-Fam) aged 38–86 years. MTR maps were generated for the neocortex, deep gray matter structures, WM hyperintensities, and normal appearing WM (NAWM). Adjusted mixed models determined whole brain and lobar cortical MTR to be directly and significantly related to performance on tests of memory, executive function, and motor skills. There existed an almost linear dose-effect relationship. MTR of deep gray matter structures and NAWM correlated to executive functioning. All associations were independent of demographics, vascular risk factors, focal brain lesions, and cortex volume. Further research is needed to understand the basis of this association at the tissue level, and to determine the role of MTR in predicting cognitive decline and dementia. PMID:25309438

MR elastography of hydrocephalus

NASA Astrophysics Data System (ADS)

Pattison, Adam J.; Lollis, S. Scott; Perrinez, Phillip R.; Weaver, John B.; Paulsen, Keith D.

2009-02-01

Hydrocephalus occurs due to a blockage in the transmission of cerebrospinal fluid (CSF) in either the ventricles or subarachnoid space. Characteristics of this condition include increased intracranial pressure, which can result in neurologic deterioration [1]. Magnetic resonance elastography (MRE) is an imaging technique that estimates the mechanical properties of tissue in vivo. While some investigations of brain tissue have been performed using MRE [2,3,4,5], the effects due to changes in interstitial pressure and fluid content on the mechanical properties of the brain remain unknown. The purpose of this work is to assess the potential of MRE to differentiate between the reconstructed properties of normal and hydrocephalic brains. MRE data was acquired in 18 female feline subjects, 12 of which received kaolin injections resulting in an acute form of hydrocephalus. In each animal, four MRE scans were performed during the process including one pre-injection and three post-injection scans. The elastic parameters were obtained using a subzone-based reconstruction algorithm that solves Navier's equations for linearly elastic materials [6]. The remaining cats were used as controls, injected with saline instead of kaolin. To determine the state of hydrocephalus, ventricular volume was estimated from segmenting anatomical images. The mean ventricular volume of hydrocephalic cats significantly increased (P <~ 0.0001) between the first and second scans. The mean volume was not observed to increase (P >~ 0.5) for the control cats. Also, there was an observable increase in the recorded elastic shear modulus of brain tissue in the normal and hydrocephalic acquisitions. Results suggest that MRE is able to detect changes in the mechanical properties of brain tissue resulting from kaolin-induced hydrocephalus, indicating the need for further study.

Porcine transcriptome analysis based on 97 non-normalized cDNA libraries and assembly of 1,021,891 expressed sequence tags

PubMed Central

Gorodkin, Jan; Cirera, Susanna; Hedegaard, Jakob; Gilchrist, Michael J; Panitz, Frank; Jørgensen, Claus; Scheibye-Knudsen, Karsten; Arvin, Troels; Lumholdt, Steen; Sawera, Milena; Green, Trine; Nielsen, Bente J; Havgaard, Jakob H; Rosenkilde, Carina; Wang, Jun; Li, Heng; Li, Ruiqiang; Liu, Bin; Hu, Songnian; Dong, Wei; Li, Wei; Yu, Jun; Wang, Jian; Stærfeldt, Hans-Henrik; Wernersson, Rasmus; Madsen, Lone B; Thomsen, Bo; Hornshøj, Henrik; Bujie, Zhan; Wang, Xuegang; Wang, Xuefei; Bolund, Lars; Brunak, Søren; Yang, Huanming; Bendixen, Christian; Fredholm, Merete

2007-01-01

Background Knowledge of the structure of gene expression is essential for mammalian transcriptomics research. We analyzed a collection of more than one million porcine expressed sequence tags (ESTs), of which two-thirds were generated in the Sino-Danish Pig Genome Project and one-third are from public databases. The Sino-Danish ESTs were generated from one normalized and 97 non-normalized cDNA libraries representing 35 different tissues and three developmental stages. Results Using the Distiller package, the ESTs were assembled to roughly 48,000 contigs and 73,000 singletons, of which approximately 25% have a high confidence match to UniProt. Approximately 6,000 new porcine gene clusters were identified. Expression analysis based on the non-normalized libraries resulted in the following findings. The distribution of cluster sizes is scaling invariant. Brain and testes are among the tissues with the greatest number of different expressed genes, whereas tissues with more specialized function, such as developing liver, have fewer expressed genes. There are at least 65 high confidence housekeeping gene candidates and 876 cDNA library-specific gene candidates. We identified differential expression of genes between different tissues, in particular brain/spinal cord, and found patterns of correlation between genes that share expression in pairs of libraries. Finally, there was remarkable agreement in expression between specialized tissues according to Gene Ontology categories. Conclusion This EST collection, the largest to date in pig, represents an essential resource for annotation, comparative genomics, assembly of the pig genome sequence, and further porcine transcription studies. PMID:17407547

State of the art survey on MRI brain tumor segmentation.

PubMed

Gordillo, Nelly; Montseny, Eduard; Sobrevilla, Pilar

2013-10-01

Brain tumor segmentation consists of separating the different tumor tissues (solid or active tumor, edema, and necrosis) from normal brain tissues: gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF). In brain tumor studies, the existence of abnormal tissues may be easily detectable most of the time. However, accurate and reproducible segmentation and characterization of abnormalities are not straightforward. In the past, many researchers in the field of medical imaging and soft computing have made significant survey in the field of brain tumor segmentation. Both semiautomatic and fully automatic methods have been proposed. Clinical acceptance of segmentation techniques has depended on the simplicity of the segmentation, and the degree of user supervision. Interactive or semiautomatic methods are likely to remain dominant in practice for some time, especially in these applications where erroneous interpretations are unacceptable. This article presents an overview of the most relevant brain tumor segmentation methods, conducted after the acquisition of the image. Given the advantages of magnetic resonance imaging over other diagnostic imaging, this survey is focused on MRI brain tumor segmentation. Semiautomatic and fully automatic techniques are emphasized. Copyright © 2013 Elsevier Inc. All rights reserved.

Pathological changes in Alzheimer"s brain evaluated with fluorescence emission analysis (FEA)

NASA Astrophysics Data System (ADS)

Christov, Alexander; Ottman, Todd; Grammas, Paula

2004-07-01

Development of AD is associated with cerebrovascular deposition of amyloid beta (Aβ) as well as a progressive increase in vasular collagen content. Both AΒ and collagen are naturally fluorescent compounds when exposed to UV light. We analyzed autofluorescence emitted from brain tissue samples and isolated brain resistance vessels harvested postmortem from patients with Alzheimer's disease (AD) and age-matched controls. Fluorescence emission, excited at 355 nm with an Nd:YAG laser, was measured using a fiber-optic based fluorescence spectroscopic system for tissue analysis. Significantly higher values of fluorescence emission intensity (P<0.001) in the spectral region from 465 to 490 nm were detected in brain resistance vessel samples from AD patients compared to the normal individuals. Results from western blot analysis showed elevated levels of type I and type III collagen, and reduced levels of type IV collagen in resistance vessels from AD patients, compared to control samples. In addition, using direct scanning of the cortical suface for fluoresxcence emission by the laser-induced fluorescence spectroscopy system we detected a significantly (P<0.05) higher level of apoptosis in AD brain tissue compared to age-matched controls. Fluorescence emission analysis (FEA) appears to be a sensitive technique for detecting structural changes in AD brain tissue.

SU-D-BRB-04: Plan Quality Comparison of Intracranial Stereotactic Radiosurgery (SRS) for Gamma Knife and VMAT Treatments

DOE Office of Scientific and Technical Information (OSTI.GOV)

Keeling, V; Algan, O; Ahmad, S

2015-06-15

Purpose: To compare treatment plan quality of intracranial stereotactic radiosurgery (SRS) for VMAT (RapidArc) and Gamma Knife (GK) systems. Methods: Ten patients with 24 tumors (seven with 1–2 and three with 4–6 lesions), previously treated with GK 4C (prescription doses ranging from 14–23 Gy) were re-planned for RapidArc. Identical contour sets were kept on MRI images for both plans with tissues assigned a CT number of zero. RapidArc plans were performed using 6 MV flattening-filter-free (FFF) beams with dose rate of 1400 MU/minute using two to eight arcs with the following combinations: 2 full coplanar arcs and the rest non-coplanarmore » half arcs. Beam selection was based on target depth. Areas that penetrated more than 10 cm of tissue were avoided by creating smaller arcs or using avoidance sectors in optimization. Plans were optimized with jaw tracking and a high weighting to the normal-brain-tissue and Normal-Tissue-Objective without compromising PTV coverage. Plans were calculated on a 1 mm grid size using AAA algorithm and then normalized so that 99% of each target volume received the prescription dose. Plan quality was assessed by target coverage using Paddick Conformity Index (PCI), sparing of normal-brain-tissue through analysis of V4, V8, and V12 Gy, and integral dose. Results: In all cases critical structure dose criteria were met. RapidArc had a higher PCI than GK plans for 23 out of 24 lesions. The average PCI was 0.76±0.21 for RapidArc and 0.46±0.20 for GK plans (p≤0.001), respectively. Integral dose and normal-brain-tissue doses for all criteria were lower for RapidArc in nearly all patients. The average ratio of GK to RapidArc plans was 1.28±0.27 (p=0.018), 1.31±0.25 (p=0.017), 1.81±0.43 (p=0.005), and 1.50±0.61 (p=0.006) for V4, V8, and V12 Gy, and integral dose, respectively. Conclusion: VMAT was capable of producing higher quality treatment plans than GK when using optimal beam geometries and proper optimization techniques.« less

Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma.

PubMed

Tang, Jiaze; Huang, Ning; Zhang, Xiang; Zhou, Tao; Tan, Ying; Pi, Jiangli; Pi, Li; Cheng, Si; Zheng, Huzhi; Cheng, Yuan

2017-01-01

The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood-brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor-targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma.

Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma

PubMed Central

Tang, Jiaze; Huang, Ning; Zhang, Xiang; Zhou, Tao; Tan, Ying; Pi, Jiangli; Pi, Li; Cheng, Si; Zheng, Huzhi; Cheng, Yuan

2017-01-01

The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood–brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor-targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma. PMID:28579776

ON THE BENEFITS AND RISKS OF PROTON THERAPY IN PEDIATRIC CRANIOPHARYNGIOMA

PubMed Central

Beltran, Chris; Roca, Monica; Merchant, Thomas E.

2013-01-01

Purpose Craniopharyngioma is a pediatric brain tumor whose volume is prone to change during radiation therapy. We compared photon- and proton-based irradiation methods to determine the effect of tumor volume change on target coverage and normal tissue irradiation in these patients. Methods and Materials For this retrospective study, we acquired imaging and treatment-planning data from 14 children with craniopharyngioma (mean age, 5.1 years) irradiated with photons (54 Gy) and monitored by weekly magnetic resonance imaging (MRI) examinations during radiation therapy. Photon intensity-modulated radiation therapy (IMRT), double-scatter proton (DSP) therapy, and intensity-modulated proton therapy (IMPT) plans were created for each patient based on his or her pre-irradiation MRI. Target volumes were contoured on each weekly MRI scan for adaptive modeling. The measured differences in conformity index (CI) and normal tissue doses, including functional sub-volumes of the brain, were compared across the planning methods, as was target coverage based on changes in target volumes during treatment. Results CI and normal tissue dose values of IMPT plans were significantly better than those of the IMRT and DSP plans (p < 0.01). Although IMRT plans had a higher CI and lower optic nerve doses (p < 0.01) than did DSP plans, DSP plans had lower cochlear, optic chiasm, brain, and scanned body doses (p < 0.01). The mean planning target volume (PTV) at baseline was 54.8 cm3, and the mean increase in PTV was 11.3% over the course of treatment. The dose to 95% of the PTV was correlated with a change in the PTV; the R2 values for all models, 0.73 (IMRT), 0.38 (DSP), and 0.62 (IMPT), were significant (p < 0.01). Conclusions Compared with photon IMRT, proton therapy has the potential to significantly reduce whole-brain and -body irradiation in pediatric patients with craniopharyngioma. IMPT is the most conformal method and spares the most normal tissue; however, it is highly sensitive to target volume changes, whereas the DSP method is not. PMID:21570209

Constructing and assessing brain templates from Chinese pediatric MRI data using SPM

NASA Astrophysics Data System (ADS)

Yin, Qingjie; Ye, Qing; Yao, Li; Chen, Kewei; Jin, Zhen; Liu, Gang; Wu, Xingchun; Wang, Tingting

2005-04-01

Spatial normalization is a very important step in the processing of magnetic resonance imaging (MRI) data. So the quality of brain templates is crucial for the accuracy of MRI analysis. In this paper, using the classical protocol and the optimized protocol plus nonlinear deformation, we constructed the T1 whole brain templates and apriori brain tissue data from 69 Chinese pediatric MRI data (age 7-16 years). Then we proposed a new assessment method to evaluate our templates. 10 pediatric subjects were chosen to do the assessment as the following steps. First, the cerebellum region, the region of interest (ROI), was located on both the pediatric volume and the template volume by an experienced neuroanatomist. Second, the pediatric whole brain was mapped to the template with affine and nonlinear deformation. Third, the parameter, derived from the second step, was used to only normalize the ROI of the child to the ROI of the template. Last, the overlapping ratio, which described the overlapping rate between the ROI of the template and the normalized ROI of the child, was calculated. The mean of overlapping ratio normalized to the classical template was 0.9687, and the mean normalized to the optimized template was 0.9713. The results show that the two Chinese pediatric brain templates are comparable and their accuracy is adequate to our studies.

High-Throughput Analysis of Age-Dependent Protein Changes in Layer II/III of the Human Orbitofrontal Cortex

NASA Astrophysics Data System (ADS)

Kapadia, Fenika

Studies on the orbitofrontal cortex (OFC) during normal aging have shown a decline in cognitive functions, a loss of spines/synapses in layer III and gene expression changes related to neural communication. Biological changes during the course of normal aging are summarized into 9 hallmarks based on aging in peripheral tissue. Whether these hallmarks apply to non-dividing brain tissue is not known. Therefore, we opted to perform large-scale proteomic profiling of the OFC layer II/III during normal aging from 15 young and 18 old male subjects. MaxQuant was utilized for label-free quantification and statistical analysis by the Random Intercept Model (RIM) identified 118 differentially expressed (DE) age-related proteins. Altered neural communication was the most represented hallmark of aging (54% of DE proteins), highlighting the importance of communication in the brain. Functional analysis showed enrichment in GABA/glutamate signaling and pro-inflammatory responses. The former may contribute to alterations in excitation/inhibition, leading to cognitive decline during aging.

SyMRI of the Brain

PubMed Central

Hagiwara, Akifumi; Warntjes, Marcel; Hori, Masaaki; Andica, Christina; Nakazawa, Misaki; Kumamaru, Kanako Kunishima; Abe, Osamu; Aoki, Shigeki

2017-01-01

Abstract Conventional magnetic resonance images are usually evaluated using the image signal contrast between tissues and not based on their absolute signal intensities. Quantification of tissue parameters, such as relaxation rates and proton density, would provide an absolute scale; however, these methods have mainly been performed in a research setting. The development of rapid quantification, with scan times in the order of 6 minutes for full head coverage, has provided the prerequisites for clinical use. The aim of this review article was to introduce a specific quantification method and synthesis of contrast-weighted images based on the acquired absolute values, and to present automatic segmentation of brain tissues and measurement of myelin based on the quantitative values, along with application of these techniques to various brain diseases. The entire technique is referred to as “SyMRI” in this review. SyMRI has shown promising results in previous studies when used for multiple sclerosis, brain metastases, Sturge-Weber syndrome, idiopathic normal pressure hydrocephalus, meningitis, and postmortem imaging. PMID:28257339

Diffusion MRI at 25: Exploring brain tissue structure and function

PubMed Central

Bihan, Denis Le; Johansen-Berg, Heidi

2013-01-01

Diffusion MRI (or dMRI) came into existence in the mid-1980s. During the last 25 years, diffusion MRI has been extraordinarily successful (with more than 300,000 entries on Google Scholar for diffusion MRI). Its main clinical domain of application has been neurological disorders, especially for the management of patients with acute stroke. It is also rapidly becoming a standard for white matter disorders, as diffusion tensor imaging (DTI) can reveal abnormalities in white matter fiber structure and provide outstanding maps of brain connectivity. The ability to visualize anatomical connections between different parts of the brain, non-invasively and on an individual basis, has emerged as a major breakthrough for neurosciences. The driving force of dMRI is to monitor microscopic, natural displacements of water molecules that occur in brain tissues as part of the physical diffusion process. Water molecules are thus used as a probe that can reveal microscopic details about tissue architecture, either normal or in a diseased state. PMID:22120012

Regional Fluid-Attenuated Inversion Recovery (FLAIR) at 7 Tesla correlates with amyloid beta in hippocampus and brainstem of cognitively normal elderly subjects

PubMed Central

Schreiner, Simon J.; Liu, Xinyang; Gietl, Anton F.; Wyss, Michael; Steininger, Stefanie C.; Gruber, Esmeralda; Treyer, Valerie; Meier, Irene B.; Kälin, Andrea M.; Leh, Sandra E.; Buck, Alfred; Nitsch, Roger M.; Pruessmann, Klaas P.; Hock, Christoph; Unschuld, Paul G.

2014-01-01

Background: Accumulation of amyloid beta (Aβ) may occur during healthy aging and is a risk factor for Alzheimer Disease (AD). While individual Aβ-accumulation can be measured non-invasively using Pittsburgh Compund-B positron emission tomography (PiB-PET), Fluid-attenuated inversion recovery (FLAIR) is a Magnetic Resonance Imaging (MRI) sequence, capable of indicating heterogeneous age-related brain pathologies associated with tissue-edema. In the current study cognitively normal elderly subjects were investigated for regional correlation of PiB- and FLAIR intensity. Methods: Fourteen healthy elderly subjects without known history of cognitive impairment received 11C-PiB-PET for estimation of regional Aβ-load. In addition, whole brain T1-MPRAGE and FLAIR-MRI sequences were acquired at high field strength of 7 Tesla (7T). Volume-normalized intensities of brain regions were assessed by applying an automated subcortical segmentation algorithm for spatial definition of brain structures. Statistical dependence between FLAIR- and PiB-PET intensities was tested using Spearman's rank correlation coefficient (rho), followed by Holm–Bonferroni correction for multiple testing. Results: Neuropsychological testing revealed normal cognitive performance levels in all participants. Mean regional PiB-PET and FLAIR intensities were normally distributed and independent. Significant correlation between volume-normalized PiB-PET signals and FLAIR intensities resulted for Hippocampus (right: rho = 0.86; left: rho = 0.84), Brainstem (rho = 0.85) and left Basal Ganglia vessel region (rho = 0.82). Conclusions: Our finding of a significant relationship between PiB- and FLAIR intensity mainly observable in the Hippocampus and Brainstem, indicates regional Aβ associated tissue-edema in cognitively normal elderly subjects. Further studies including clinical populations are necessary to clarify the relevance of our findings for estimating individual risk for age-related neurodegenerative processes such as AD. PMID:25249977

[Effects of N-butylphthalide on the expressions of ZO-1 and claudin-5 in blood-brain barrier of rats with acute carbon monoxide poisoning].

PubMed

Wang, Li; Ding, Xiaoyu; Bi, Mingjun; Wang, Jinglin; Zou, Yong; Tang, Jiyou; Li, Qin

2018-05-01

To explore the effects of N-butylphthalide on the expressions of ZO-1 and claudin-5 in blood-brain barrier (BBB) in rats with acute carbon monoxide (CO) poisoning. A total of 144 adult healthy male Sprague-Dawley (SD) rats were randomly divided into normal control group, CO poisoning group, and NBP treatment group, with 48 rats in each group. The acute CO poisoning model was reproduced in hyperbaric oxygen chamber, and all model rats were given hyperbaric oxygen therapy once daily. The rats in the normal control group were free to breathe fresh air. The rats in NBP treatment group were administered orally NBP 60 mg/kg twice a day at 2 hours after poisoning until death. The rats in normal control group and CO poisoning group were treated with equal amount of pure olive oil. Four rats were sacrificed from each group at 1, 3, 7, 14 days after model reproducing, respectively. The changes in ultrastructure of BBB were observed under transmission electron microscope. The expressions of ZO-1 and claudin-5 proteins were determined by immunofluorescence staining and Western Blot. The localization of the two target proteins was observed by immunofluorescence double staining. The correlation between the two proteins was analyzed by linear regression. The ultrastructure of BBB was normal in normal control group, some ZO-1 and a large number of claudin-5 positive cells were observed. The ultrastructure of BBB was seriously injured, ZO-1 and claudin-5 positive cells in brain tissue were significantly decreased, and the expressions of ZO-1 and claudin-5 proteins in brain tissue at 1 day after poisoning in CO poisoning group were significantly lower than those of normal control group (ZO-1 protein: 3.38±0.30 vs. 24.50±5.62, claudin-5 protein: 11.38±0.93 vs. 46.35±6.88, both P < 0.05), and although gradually restored, they were maintained at relatively lower levels until 14 days as compared with those in normal control group (ZO-1 protein: 10.35±0.80 vs. 24.63±3.57, claudin-5 protein: 32.35±3.11 vs. 46.43±7.20, both P < 0.05). NBP treatment could significantly alleviate the ultrastructure injury of BBB induced by acute CO poisoning, the amount of ZO-1 and claudin-5 positive cells in brain tissue were significantly increased, as well as the expressions of ZO-1 and claudin-5 proteins were significantly increased, which were significantly higher than those of CO poisoning group from 1 day and 3 days on, respectively (1-day ZO-1 protein: 7.57±0.69 vs. 3.38±0.30, 3-day claudin-5 protein: 20.46±1.42 vs. 11.43±0.86, both P < 0.05), and which showed an increase tendency with time prolongation. The results of immunofluorescence double staining showed that ZO-1 and claudin-5 proteins could not only coexist in the same cell, but also could be expressed separately in different cells. Linear regression analysis showed the positive correlation between the expressions of ZO-1 and claudin-5 proteins in brain tissue of rats with acute CO poisoning (R 2 = 0.917, P = 0.022). NBP could markedly improve the ultrastructure and functional integrity of BBB through up-regulating the expressions of ZO-1 and claudin-5 proteins, and then reduce brain damage caused by CO poisoning.

Expression of metalloprotease insulin-degrading enzyme (insulysin) in normal and malignant human tissues

PubMed Central

Yfanti, Christina; Mengele, Karin; Gkazepis, Apostolos; Weirich, Gregor; Giersig, Cecylia; Kuo, Wen-Liang; Tang, Wei-Jen; Rosner, Marsha; Schmitt, Manfred

2013-01-01

Background Insulin-degrading enzyme (IDE, insulysin, insulinase; EC 3.4.22.11), a thiol metalloendopeptidase, is involved in intracellular degradation of insulin, thereby inhibiting its translocation and accumulation to the nucleus. Recently, protein expression of IDE has been demonstrated in the epithelial ducts of normal breast and in breast cancer tissue (Radulescu et al., Int J Oncol 30:73; 2007). Materials and Methods Utilizing four different antibodies generated against different epitopes of the IDE molecule, we performed western blot analysis and immunohistochemical staining on several normal human tissues, on a plethora of tumor cell lines of different tissue origin, and on malignant breast and ovarian tissue. Results Applying the four IDE-directed antibodies, we demonstrate IDE expression at the protein level, both by means of immunoblotting and immunocytochemistry, in all of the tumor cell lines analyzed. Besides, IDE protein expression was found in normal tissues of the kidney, liver, lung, brain, breast and skeletal muscle, as well as in breast and ovarian cancer tissues. Immunohistochemical visualization of IDE indicated cytoplasmic localization of IDE in all of the cell lines and tissues assessed. Conclusions We performed for the first time a wide-ranging survey on IDE protein expression in normal and malignant tissues and cells and thus extend knowledge about cellular and tissue distribution of IDE, an enzyme which so far has mainly been studied in connection with Alzheimer’s disease and diabetes but not in cancer. PMID:18813847

Demeclocycline as a contrast agent for detecting brain neoplasms using confocal microscopy

NASA Astrophysics Data System (ADS)

Wirth, Dennis; Smith, Thomas W.; Moser, Richard; Yaroslavsky, Anna N.

2015-04-01

Complete resection of brain tumors improves life expectancy and quality. Thus, there is a strong need for high-resolution detection and microscopically controlled removal of brain neoplasms. The goal of this study was to test demeclocycline as a contrast enhancer for the intraoperative detection of brain tumors. We have imaged benign and cancerous brain tumors using multimodal confocal microscopy. The tumors investigated included pituitary adenoma, meningiomas, glioblastomas, and metastatic brain cancers. Freshly excised brain tissues were stained in 0.75 mg ml-1 aqueous solution of demeclocyline. Reflectance images were acquired at 402 nm. Fluorescence signals were excited at 402 nm and registered between 500 and 540 nm. After imaging, histological sections were processed from the imaged specimens and compared to the optical images. Fluorescence images highlighted normal and cancerous brain cells, while reflectance images emphasized the morphology of connective tissue. The optical and histological images were in accordance with each other for all types of tumors investigated. Demeclocyline shows promise as a contrast agent for intraoperative detection of brain tumors.

Proteomics analyses for the global proteins in the brain tissues of different human prion diseases.

PubMed

Shi, Qi; Chen, Li-Na; Zhang, Bao-Yun; Xiao, Kang; Zhou, Wei; Chen, Cao; Zhang, Xiao-Mei; Tian, Chan; Gao, Chen; Wang, Jing; Han, Jun; Dong, Xiao-Ping

2015-04-01

Proteomics changes of brain tissues have been described in different neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the brain proteomics of human prion disease remains less understood. In the study, the proteomics patterns of cortex and cerebellum of brain tissues of sporadic Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD were analyzed with isobaric tags for relative and absolute quantitation combined with multidimensional liquid chromatography and MS analysis, with the brains from three normal individuals as controls. Global protein profiling, significant pathway, and functional categories were analyzed. In total, 2287 proteins were identified with quantitative information both in cortex and cerebellum regions. Cerebellum tissues appeared to contain more up- and down-regulated proteins (727 proteins) than cortex regions (312 proteins) of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD. Viral myocarditis, Parkinson's disease, Alzheimer's disease, lysosome, oxidative phosphorylation, protein export, and drug metabolism-cytochrome P450 were the most commonly affected pathways of the three kinds of diseases. Almost coincident biological functions were identified in the brain tissues of the three diseases. In all, data here demonstrate that the brain tissues of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD have obvious proteomics changes at their terminal stages, which show the similarities not only among human prion diseases but also with other neurodegeneration diseases. This is the first study to provide a reference proteome map for human prion diseases and will be helpful for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Comprehensive analysis of a microRNA expression profile in pediatric medulloblastoma.

PubMed

Dai, Junqiang; Li, Qiao; Bing, Zhitong; Zhang, Yinian; Niu, Liang; Yin, Hang; Yuan, Guoqiang; Pan, Yawen

2017-06-01

Medulloblastoma is the most common malignant brain tumor of the central nervous system among children. Medulloblastoma is an embryonal tumor, of which little is known about the pathogenesis. Several efforts have been made to understand the molecular aspects of its tumorigenic pathways; however, these are poorly understood. microRNA (miRNA), a type of non‑coding short RNA, has been proven to be associated with a number of physiological processes and pathological processes of serious diseases, including brain tumors. Differentially expressed miRNAs serve an important role in numerous types of malignancy. The present study aims to define a differentially expressed set of miRNAs in medulloblastoma tumor tissue, compared with normal samples, to improve the understanding of the tumorigenesis. It was identified that 22 miRNAs were upregulated and 26 miRNAs were downregulated in the tumor tissue compared with the normal group. However, when the medulloblastoma tissue was compared with normal cerebellum tissue, 9 miRNAs were identified to be up or downregulated in the tumor samples. The differentially expressed miRNAs in the tumor tissue were identified in order to clarify the networks and pathways of tumorigenesis using Ingenuity Pathway Analysis. Subsequently, key regulatory genes associated with the development of medulloblastoma were identified, including tumor protein p53, insulin like growth factor 1 receptor, argonaute 2, mitogen‑activated protein kinases 1 and 3, sirtuin 1 and Y box binding protein 1.

Clindamycin in a murine model of toxoplasmic encephalitis.

PubMed Central

Hofflin, J M; Remington, J S

1987-01-01

We investigated the efficacy of clindamycin in a murine model of toxoplasmic encephalitis using direct intracerebral inoculation. Clindamycin reduced mortality from 40% in normal mice and 100% in cortisone-treated mice to 0% in both groups. Although we were unable to document appreciable levels of clindamycin in the brains of infected mice, the histological features of cerebral infection were markedly altered. The formation of large numbers of cysts and the intense inflammatory response seen in the brains of normal mice and the unchecked infection and tissue necrosis in the brains of cortisone-treated mice were absent in the brains of clindamycin-treated mice. Enumeration of cysts in the brains of mice 10 weeks after infection revealed a significantly lower number in the clindamycin-treated mice. Spread of infection to other organs was also decreased during clindamycin administration. These observations suggest that clindamycin may have a role in the therapy of toxoplasmic encephalitis. Images PMID:3606059

Organ distribution of 13N following intravenous injection of [13N]ammonia into portacaval-shunted rats

PubMed Central

Cruz, Nancy F.; Dienel, Gerald A.; Patrick, Tricia A.; Cooper, Arthur J. L.

2016-01-01

Ammonia is neurotoxic, and chronic hyperammonemia is thought to be a major contributing factor to hepatic encephalopathy in patients with liver disease. Portacaval shunting of rats is used as an animal model to study the detrimental metabolic effects of elevated ammonia levels on body tissues, particularly brain and testes that are deleteriously targeted by high blood ammonia. In normal adult rats, the initial uptake of label (expressed as relative concentration) in these organs was relatively low following a bolus intravenous injection of [13N]ammonia compared with lungs, kidneys, liver, and some other organs. The objective of the present study was to determine the distribution of label following intravenous administration of [13N]ammonia among 14 organs in portacaval-shunted rats at 12 weeks after shunt construction. At an early time point (12 sec) following administration of [13N]ammonia the relative concentration of label was highest in lung with lower, but still appreciable relative concentrations in kidney and heart. Clearance of 13N from blood and kidney tended to be slower in portacaval-shunted rats versus normal rats during the 2–10 min interval after the injection. At later times post injection, brain and testes tended to have higher-than-normal 13N levels, whereas many other tissues had similar levels in both groups. Thus, reduced removal of ammonia from circulating blood by the liver diverts more ammonia to extrahepatic tissues, including brain and testes, and alters the nitrogen homeostasis in these tissues. These results emphasize the importance of treatment paradigms designed to reduce blood ammonia levels in patients with liver disease. PMID:27822667

Organ Distribution of 13N Following Intravenous Injection of [13N]Ammonia into Portacaval-Shunted Rats.

PubMed

Cruz, Nancy F; Dienel, Gerald A; Patrick, Patricia A; Cooper, Arthur J L

2017-06-01

Ammonia is neurotoxic, and chronic hyperammonemia is thought to be a major contributing factor to hepatic encephalopathy in patients with liver disease. Portacaval shunting of rats is used as an animal model to study the detrimental metabolic effects of elevated ammonia levels on body tissues, particularly brain and testes that are deleteriously targeted by high blood ammonia. In normal adult rats, the initial uptake of label (expressed as relative concentration) in these organs was relatively low following a bolus intravenous injection of [ 13 N]ammonia compared with lungs, kidneys, liver, and some other organs. The objective of the present study was to determine the distribution of label following intravenous administration of [ 13 N]ammonia among 14 organs in portacaval-shunted rats at 12 weeks after shunt construction. At an early time point (12 s) following administration of [ 13 N]ammonia the relative concentration of label was highest in lung with lower, but still appreciable relative concentrations in kidney and heart. Clearance of 13 N from blood and kidney tended to be slower in portacaval-shunted rats versus normal rats during the 2-10 min interval after the injection. At later times post injection, brain and testes tended to have higher-than-normal 13 N levels, whereas many other tissues had similar levels in both groups. Thus, reduced removal of ammonia from circulating blood by the liver diverts more ammonia to extrahepatic tissues, including brain and testes, and alters the nitrogen homeostasis in these tissues. These results emphasize the importance of treatment paradigms designed to reduce blood ammonia levels in patients with liver disease.

12/15-Lipoxygenase Inhibition or Knockout Reduces Warfarin-Associated Hemorrhagic Transformation After Experimental Stroke.

PubMed

Liu, Yu; Zheng, Yi; Karatas, Hulya; Wang, Xiaoying; Foerch, Christian; Lo, Eng H; van Leyen, Klaus

2017-02-01

For stroke prevention, patients with atrial fibrillation typically receive oral anticoagulation. The commonly used anticoagulant warfarin increases the risk of hemorrhagic transformation (HT) when a stroke occurs; tissue-type plasminogen activator treatment is therefore restricted in these patients. This study was designed to test the hypothesis that 12/15-lipoxygenase (12/15-LOX) inhibition would reduce HT in warfarin-treated mice subjected to experimental stroke. Warfarin was dosed orally in drinking water, and international normalized ratio values were determined using a Coaguchek device. C57BL6J mice or 12/15-LOX knockout mice were subjected to transient middle cerebral artery occlusion with 3 hours severe ischemia (model A) or 2 hours ischemia and tissue-type plasminogen activator infusion (model B), with or without the 12/15-LOX inhibitor ML351. Hemoglobin was determined in brain homogenates, and hemorrhage areas on the brain surface and in brain sections were measured. 12/15-LOX expression was detected by immunohistochemistry. Warfarin treatment resulted in reproducible increased international normalized ratio values and significant HT in both models. 12/15-LOX knockout mice suffered less HT after severe ischemia, and ML351 reduced HT in wild-type mice. When normalized to infarct size, ML351 still independently reduced hemorrhage. HT after tissue-type plasminogen activator was similarly reduced by ML351. In addition to its benefits in infarct size reduction, 12/15-LOX inhibition also may independently reduce HT in warfarin-treated mice. ML351 should be further evaluated as stroke treatment in anticoagulated patients suffering a stroke, either alone or in conjunction with tissue-type plasminogen activator. © 2017 American Heart Association, Inc.

[Alterations of glial fibrillary acidic protein in rat brain after gamma knife irradiation].

PubMed

Ma, Z M; Jiang, B; Ma, J R

2001-08-28

To study glial fibrillary acidic protein (GFAP) immunoreactivity in different time and water content of the rat brain treated with gamma knife radiotherapy and to understand the alteration course of the brain lesion after a single high dose radiosurgical treatment. In the brains of the normal rats were irradiated by gamma knife with 160 Gy-high dose. The irradiated rats were then killed on the 1st day, 7th day, 14th day, and 28th day after radiotherapy, respectively. The positive cells of GFAP in brain tissue were detected by immunostaining; the water content of the brain tissue was measured by microgravimetry. The histological study of the irradiated brain tissue was performed with H.E. and examined under light microscope. The numbers of GFAP-positive astrocytes began to increase on the 1st day after gamma knife irradiation. It was enlarged markedly in the number and size of GFAP-stained astrocytes over the irradiated areas. Up to the 28th day, circumscribed necrosis foci (4 mm in diameter) was seen in the central area of the target. In the brain tissue around the necrosis, GFAP-positive astrocytes significantly increased (P < 0.01, compared with the control group). The swelling of cells in irradiated region was observed on the 1st day; after irradiation endothelial cells degenerated and red blood cells escaped from blood vessel on the 7th day; leakage of Evans blue dye was observed in the target region on the 14th day. There was a significant decrease of specific gravity in the irradiated brain tissue the 14th and 28th day after irradiation. The results suggest that GFAP can be used as a marker for the radiation-induced brain injury. The brain edema and disruption of brain-blood barrier can be occurred during the acute stage after irradiation.

Correlation between 99Tcm-HMPAO-SPECT brain image and a history of decompression illness or extent of diving experience in commercial divers.

PubMed Central

Shields, T G; Duff, P M; Evans, S A; Gemmell, H G; Sharp, P F; Smith, F W; Staff, R T; Wilcock, S E

1997-01-01

OBJECTIVES: To explore the use of 99technetiumm-hexamethyl propylene amine oxime single photon computed tomography (HMPAO-SPECT) of the brain as a means of detecting nervous tissue damage in divers and to determine if there is any correlation between brain image and a diver's history of diving or decompression illness (DCI). METHODS: 28 commercial divers with a history of DCI, 26 divers with no history of DCI, and 19 non-diving controls were examined with brain HMPAO-SPECT. Results were classified by observer assessment as normal (I) or as a pattern variants (II-V). The brain images of a subgroup of these divers (n = 44) and the controls (n = 17) were further analysed with a first order texture analysis technique based on a grey level histogram. RESULTS: 15 of 54 commercial divers (28%) were visually assessed as having HMPAO-SPECT images outside normal limits compared with 15.8% in appropriately identified non-diver control subjects. 18% of divers with a history of DCI were classified as having a pattern different from the normal image compared with 38% with no history of DCI. No association was established between the presence of a pattern variant from the normal image and history of DCI, diving, or other previous possible neurological insult. On texture analysis of the brain images, divers had a significantly lower mean grey level (MGL) than non-divers. Divers with a history of DCI (n = 22) had a significantly lower MGL when compared with divers with no history of DCI (n = 22). Divers with > 14 years professional diving or > 100 decompression days a year had a significantly lower MGL value. CONCLUSIONS: Observer assessment of HMPAO-SPECT brain images can lead to disparity in results. Texture analysis of the brain images supplies both an objective and consistent method of measurement. A significant correlation was found between a low measure of MGL and a history of DCI. There was also an indication that diving itself had an effect on texture measurement, implying that it had caused subclinical nervous tissue damage. PMID:9166130

Deep-tissue two-photon imaging in brain and peripheral nerve with a compact high-pulse energy ytterbium fiber laser

NASA Astrophysics Data System (ADS)

Fontaine, Arjun K.; Kirchner, Matthew S.; Caldwell, John H.; Weir, Richard F.; Gibson, Emily A.

2018-02-01

Two-photon microscopy is a powerful tool of current scientific research, allowing optical visualization of structures below the surface of tissues. This is of particular value in neuroscience, where optically accessing regions within the brain is critical for the continued advancement in understanding of neural circuits. However, two-photon imaging at significant depths have typically used Ti:Sapphire based amplifiers that are prohibitively expensive and bulky. In this study, we demonstrate deep tissue two-photon imaging using a compact, inexpensive, turnkey operated Ytterbium fiber laser (Y-Fi, KM Labs). The laser is based on all-normal dispersion (ANDi) that provides short pulse durations and high pulse energies. Depth measurements obtained in ex vivo mouse cortex exceed those obtainable with standard two-photon microscopes using Ti:Sapphire lasers. In addition to demonstrating the capability of deep-tissue imaging in the brain, we investigated imaging depth in highly-scattering white matter with measurements in sciatic nerve showing limited optical penetration of heavily myelinated nerve tissue relative to grey matter.

The adult brain tissue response to hollow fiber membranes of varying surface architecture with or without cotransplanted cells

NASA Astrophysics Data System (ADS)

Zhang, Ning

A variety of biomaterials have been chronically implanted into the central nervous system (CNS) for repair or therapeutic purposes. Regardless of the application, chronic implantation of materials into the CNS induces injury and elicits a wound healing response, eventually leading to the formation of a dense extracellular matrix (ECM)-rich scar tissue that is associated with the segregation of implanted materials from the surrounding normal tissue. Often this reaction results in impaired performance of indwelling CNS devices. In order to enhance the performance of biomaterial-based implantable devices in the CNS, this thesis investigated whether adult brain tissue response to implanted biomaterials could be manipulated by changing biomaterial surface properties or further by utilizing the biology of co-transplanted cells. Specifically, the adult rat brain tissue response to chronically implanted poly(acrylonitrile-vinylchloride) (PAN-PVC) hollow fiber membranes (HFMs) of varying surface architecture were examined temporally at 2, 4, and 12 weeks postimplantation. Significant differences were discovered in the brain tissue response to the PAN-PVC HFMs of varying surface architecture at 4 and 12 weeks. To extend this work, whether the soluble factors derived from a co-transplanted cellular component further affect the brain tissue response to an implanted HFM in a significant way was critically exploited. The cells used were astrocytes, whose ability to influence scar formation process following CNS injury by physical contact with the host tissue had been documented in the literature. Data indicated for the first time that astrocyte-derived soluble factors ameliorate the adult brain tissue reactivity toward HFM implants in an age-dependent manner. While immature astrocytes secreted soluble factors that suppressed the brain tissue reactivity around the implants, mature astrocytes secreted factors that enhanced the gliotic response. These findings prove the feasibility of ameliorating the CNS tissue reactivity toward biomaterials implants by varying biomaterial surface properties or incorporating scar-reductive factors derived from functional cells into implant constructs, therefore, provide guidance in the design of more integrative biomaterial-based implantable devices for CNS repair.

Effects of dietary selenium of organic form against lead toxicity on the antioxidant system in Cyprinus carpio.

PubMed

Özkan-Yilmaz, Ferbal; Özlüer-Hunt, Arzu; Gündüz, Suna Gül; Berköz, Mehmet; Yalin, Serap

2014-04-01

In this study was evaluated potential protective effect of organic selenium (Se) on heavy metal stress induced by lead (Pb) in Cyprinus carpio. For this reason, C. carpio was exposed to sublethal concentration of Pb (1.5 mg/L Pb(NO3)2) for 14 days. The fish were fed a basal (control; measured 0.55 mg/kg Se) diet or a basal diet supplemented with 2.50 mg/kg (measured 2.92 mg/kg Se) organic Se (Sel-Plex(®)) during the experiment period. The variations in glutathione peroxidase (GSH-Px), glutathione S-transferase (GST) activities, and levels of reduced glutathione (GSH) with malondialdehyde (MDA) in liver and brain tissues of C. carpio were investigated in experimental groups. GSH levels in liver and brain tissues were significantly decreased by exposure to Pb. GST activity was significantly increased (p < 0.05) in liver tissue, but decreased in brain of treated fish by exposure to Pb. Also, GSH-Px activity was significantly increased in liver tissue, but decreased in brain of Pb-treated fish. Levels of MDA were increased in liver and brain of Pb-treated fish. The organic Se treatment for Pb-intoxicated animals improved activities of GSH-Px, GST and levels of MDA within normal limits. Supplemented Se could be able to improve Pb-induced oxidative stress by decreasing lipid peroxidation and regulating antioxidant defense system in tissues.

Photodynamic therapy: a review of applications in neurooncology and neuropathology

NASA Astrophysics Data System (ADS)

Uzdensky, Anatoly B.; Berezhnaya, Elena; Kovaleva, Vera; Neginskaya, Marya; Rudkovskii, Mikhail; Sharifulina, Svetlana

2015-06-01

Photodynamic therapy (PDT) effect is a promising adjuvant modality for diagnosis and treatment of brain cancer. It is of importance that the bright fluorescence of most photosensitizers provides visualization of brain tumors. This is successfully used for fluorescence-guided tumor resection according to the principle "to see and to treat." Non-oncologic application of PDT effect for induction of photothrombotic infarct of the brain tissue is a well-controlled and reproducible stroke model, in which a local brain lesion is produced in the predetermined brain area. Since normal neurons and glial cells may also be damaged by PDT and this can lead to unwanted neurological consequences, PDT effects on normal neurons and glial cells should be comprehensively studied. We overviewed the current literature data on the PDT effect on a range of signaling and epigenetic proteins that control various cell functions, survival, necrosis, and apoptosis. We hypothesize that using cell-specific inhibitors or activators of some signaling proteins, one can selectively protect normal neurons and glia, and simultaneously exacerbate photodynamic damage of malignant gliomas.

Breaking ignorance: the case of the brain.

PubMed

Wekerle, H

2006-01-01

Immunological self-tolerance is maintained through diverse mechanisms, including deletion of autoreactive immune cells following confrontation with autoantigen in the thymus or in the periphery and active suppression by regulatory cells. A third way to prevent autoimmunity is by hiding self tissues behind a tissue barrier impermeable for circulating immune cells. The latter mechanism has been held responsible for self-tolerance within the nervous tissue. Indeed, the nervous tissues enjoy a conditionally privileged immune status: they are normally unreachable for self-reactive T and B cells, they lack lymphatic drainage, and they are deficient in local antigen-presenting cells. Yet the immune system is by no means fully ignorant of the nervous structures. An ever-growing number of brain specific autoantigens is expressed within the thymus, which ensures an early confrontation with the unfolding T cell repertoire, and there is evidence that B cells also contact CNS-like structures outside of the brain. Then pathological processes such as neurodegeneration commonly lift the brain's immune privilege, shifting the local milieus from immune-hostile to immune-friendly. Finally, brain-reactive T cells, which abound in the healthy immune repertoire, but remain innocuous throughout life, can be activated and gain access to their target tissues. On their way, they take an ordered migration through peripheral lymphoid tissues and blood circulation, and undergo a profound reprogramming of their gene expression profile, which renders them fit to enter the nervous system and to interact with local cellule elements.

Compact point-detection fluorescence spectroscopy system for quantifying intrinsic fluorescence redox ratio in brain cancer diagnostics

NASA Astrophysics Data System (ADS)

Liu, Quan; Grant, Gerald; Li, Jianjun; Zhang, Yan; Hu, Fangyao; Li, Shuqin; Wilson, Christy; Chen, Kui; Bigner, Darell; Vo-Dinh, Tuan

2011-03-01

We report the development of a compact point-detection fluorescence spectroscopy system and two data analysis methods to quantify the intrinsic fluorescence redox ratio and diagnose brain cancer in an orthotopic brain tumor rat model. Our system employs one compact cw diode laser (407 nm) to excite two primary endogenous fluorophores, reduced nicotinamide adenine dinucleotide, and flavin adenine dinucleotide. The spectra were first analyzed using a spectral filtering modulation method developed previously to derive the intrinsic fluorescence redox ratio, which has the advantages of insensitivty to optical coupling and rapid data acquisition and analysis. This method represents a convenient and rapid alternative for achieving intrinsic fluorescence-based redox measurements as compared to those complicated model-based methods. It is worth noting that the method can also extract total hemoglobin concentration at the same time but only if the emission path length of fluorescence light, which depends on the illumination and collection geometry of the optical probe, is long enough so that the effect of absorption on fluorescence intensity due to hemoglobin is significant. Then a multivariate method was used to statistically classify normal tissues and tumors. Although the first method offers quantitative tissue metabolism information, the second method provides high overall classification accuracy. The two methods provide complementary capabilities for understanding cancer development and noninvasively diagnosing brain cancer. The results of our study suggest that this portable system can be potentially used to demarcate the elusive boundary between a brain tumor and the surrounding normal tissue during surgical resection.

Protective effects of melatonin against 12C6+ beam irradiation-induced oxidative stress and DNA injury in the mouse brain

NASA Astrophysics Data System (ADS)

Wu, Z. H.; Zhang, H.; Wang, X. Y.; Yang, R.; Liu, B.; Liu, Y.; Zhao, W. P.; Feng, H. Y.; Xue, L. G.; Hao, J. F.; Niu, B. T.; Wang, Z. H.

2012-01-01

The purpose of this experiment was to estimate the protective effects of melatonin against radiation-induced brain damages in mice induced by heavy ion beams. Kun-Ming mice were randomly divided into five groups: normal control group, irradiation control group, and three different doses of melatonin (5, 10, and 20 mg/kg, i.p.) treated groups. Apart from the normal control group, the other four groups were exposed to whole-body 4.0 Gy carbon ion beam irradiation (approximately 0.5 Gy/min) after i.p. administration of normal saline or melatonin 1 h before irradiation. The oxidative redox status of brain tissue was assessed by measurement of malondiadehyde (MDA) levels, total superoxide dismutase (T-SOD), cytosolic superoxide dismutase (Cu/ZnSOD, SOD1) and mitochondrial superoxide dismutase (MnSOD, SOD2) activities at 8 h after irradiation. DNA damages were determined using the Comet assay and apoptosis and cell cycle distribution were detected by flow cytometric analyses. A dramatic dose-dependent decrease in MDA levels, tail moment, rates of tailing cells, and apoptosis, and a dose-dependent increase in T-SOD and SOD2 activities, in brain tissues in the melatonin-treated groups were detected compared with the irradiation only group. Furthermore, flow cytometric analysis demonstrated that the percentage of brain cells in the G0/G1 phase decreased significantly, while those in the S and G2/M stage increased dramatically, with mice pretreated with melatonin compared to the irradiation control group. These data indicate that melatonin has protective effects against irradiation-induced brain injury, and that its underlying protective mechanisms may relate to modulation of oxidative stress induced by heavy ionirradiation.

Immunohistochemical localization of beta-amyloid precursor protein sequences in Alzheimer and normal brain tissue by light and electron microscopy.

PubMed

McGeer, P L; Akiyama, H; Kawamata, T; Yamada, T; Walker, D G; Ishii, T

1992-03-01

Immunohistochemical staining with antibodies directed against four segments of the amyloid precursor protein (APP) was studied by light and electron microscopy in normal and Alzheimer (AD) brain tissue. The segments according to the Kang et al. sequence were: 18-38 (T97); 527-540 (R36); 597-620 (1-24 of beta-amyloid protein [BAP], R17); and 681-695 (R37) (Kang et al. [1987]: Nature 325:733-736). The antibodies recognized full length APP in Western blots of extracts of APP transfected cells. They stained cytoplasmic granules in some pyramidal neurons in normal appearing tissue from control and AD cases. In AD affected tissue, the antibodies to amino terminal sections of APP stained tangled neurons and neuropil threads, and intensely stained dystrophic neurites in senile plaques. By electron microscopy, this staining was localized to abnormal filaments. The antibody to the carboxy terminal segment failed to stain neurofibrillary tangles or neuropil threads; it did stain some neurites with globular swellings. It also stained globular and elongated deposits in senile plaque areas. The antibody against the BAP intensely stained extracellular material in senile plaques and diffuse deposits. By electron microscopy, the antibodies all stained intramicroglial deposits. Some of the extracellular and intracellular BAP-positive deposits were fibrillary. Communication between intramicroglial and extracellular fibrils was detected in plaque areas. These data suggest the following sequence of events. APP is normally concentrated in intraneuronal granules. In AD, it accumulates in damaged neuronal fibers. The amino terminal portion binds to abnormal neurofilaments. Major fragments of APP are phagocytosed and processed by microglia with the BAP portion being preserved. The preserved BAP is then extruded and accumulates in extracellular tissue.

Metabolomics and neuroanatomical evaluation of post-mortem changes in the hippocampus.

PubMed

Gonzalez-Riano, Carolina; Tapia-González, Silvia; García, Antonia; Muñoz, Alberto; DeFelipe, Javier; Barbas, Coral

2017-08-01

Understanding the human brain is the ultimate goal in neuroscience, but this is extremely challenging in part due to the fact that brain tissue obtained from autopsy is practically the only source of normal brain tissue and also since changes at different levels of biological organization (genetic, molecular, biochemical, anatomical) occur after death due to multiple mechanisms. Here we used metabolomic and anatomical techniques to study the possible relationship between post-mortem time (PT)-induced changes that may occur at both the metabolomics and anatomical levels in the same brains. Our experiments have mainly focused on the hippocampus of the mouse. We found significant metabolomic changes at 2 h PT, whereas the integrity of neurons and glia, at the anatomical/ neurochemical level, was not significantly altered during the first 5 h PT for the majority of histological markers.

Detecting brain tumor in pathological slides using hyperspectral imaging

PubMed Central

Ortega, Samuel; Fabelo, Himar; Camacho, Rafael; de la Luz Plaza, María; Callicó, Gustavo M.; Sarmiento, Roberto

2018-01-01

Hyperspectral imaging (HSI) is an emerging technology for medical diagnosis. This research work presents a proof-of-concept on the use of HSI data to automatically detect human brain tumor tissue in pathological slides. The samples, consisting of hyperspectral cubes collected from 400 nm to 1000 nm, were acquired from ten different patients diagnosed with high-grade glioma. Based on the diagnosis provided by pathologists, a spectral library of normal and tumor tissues was created and processed using three different supervised classification algorithms. Results prove that HSI is a suitable technique to automatically detect high-grade tumors from pathological slides. PMID:29552415

Detecting brain tumor in pathological slides using hyperspectral imaging.

PubMed

Ortega, Samuel; Fabelo, Himar; Camacho, Rafael; de la Luz Plaza, María; Callicó, Gustavo M; Sarmiento, Roberto

2018-02-01

Hyperspectral imaging (HSI) is an emerging technology for medical diagnosis. This research work presents a proof-of-concept on the use of HSI data to automatically detect human brain tumor tissue in pathological slides. The samples, consisting of hyperspectral cubes collected from 400 nm to 1000 nm, were acquired from ten different patients diagnosed with high-grade glioma. Based on the diagnosis provided by pathologists, a spectral library of normal and tumor tissues was created and processed using three different supervised classification algorithms. Results prove that HSI is a suitable technique to automatically detect high-grade tumors from pathological slides.

Intraoperative optical biopsy for brain tumors using spectro-lifetime properties of intrinsic fluorophores

NASA Astrophysics Data System (ADS)

Vasefi, Fartash; Kittle, David S.; Nie, Zhaojun; Falcone, Christina; Patil, Chirag G.; Chu, Ray M.; Mamelak, Adam N.; Black, Keith L.; Butte, Pramod V.

2016-04-01

We have developed and tested a system for real-time intra-operative optical identification and classification of brain tissues using time-resolved fluorescence spectroscopy (TRFS). A supervised learning algorithm using linear discriminant analysis (LDA) employing selected intrinsic fluorescence decay temporal points in 6 spectral bands was employed to maximize statistical significance difference between training groups. The linear discriminant analysis on in vivo human tissues obtained by TRFS measurements (N = 35) were validated by histopathologic analysis and neuronavigation correlation to pre-operative MRI images. These results demonstrate that TRFS can differentiate between normal cortex, white matter and glioma.

Brain tissue pulsatility mediates cognitive and electrophysiological changes in normal aging: Evidence from ultrasound tissue pulsatility imaging (TPI).

PubMed

Angel, Lucie; Bouazzaoui, Badiâa; Isingrini, Michel; Fay, Séverine; Taconnat, Laurence; Vanneste, Sandrine; Ledoux, Moïse; Gissot, Valérie; Hommet, Caroline; Andersson, Fréderic; Barantin, Laurent; Cottier, Jean-Philippe; Pasco, Jérémy; Desmidt, Thomas; Patat, Frédéric; Camus, Vincent; Remenieras, Jean-Pierre

2018-06-01

Aging is characterized by a cognitive decline of fluid abilities and is also associated with electrophysiological changes. The vascular hypothesis proposes that brain is sensitive to vascular dysfunction which may accelerate age-related brain modifications and thus explain age-related neurocognitive decline. To test this hypothesis, cognitive performance was measured in 39 healthy participants from 20 to 80 years, using tests assessing inhibition, fluid intelligence, attention and crystallized abilities. Brain functioning associated with attentional abilities was assessed by measuring the P3b ERP component elicited through an auditory oddball paradigm. To assess vascular health, we used an innovative measure of the pulsatility of deep brain tissue, due to variations in cerebral blood flow over the cardiac cycle. Results showed (1) a classical effect of age on fluid neurocognitive measures (inhibition, fluid intelligence, magnitude and latency of the P3b) but not on crystallized measures, (2) that brain pulsatility decreases with advancing age, (3) that brain pulsatility is positively correlated with fluid neurocognitive measures and (4) that brain pulsatility strongly mediated the age-related variance in cognitive performance and the magnitude of the P3b component. The mediating role of the brain pulsatility in age-related effect on neurocognitive measures supports the vascular hypothesis of cognitive aging. Copyright © 2018 Elsevier Inc. All rights reserved.

Nonthermal ablation in the rat brain using focused ultrasound and an ultrasound contrast agent: long-term effects

PubMed Central

McDannold, Nathan; Zhang, Yongzhi; Vykhodtseva, Natalia

2016-01-01

OBJECTIVE Thermal ablation with transcranial MRI-guided focused ultrasound (FUS) is currently under investigation as a less invasive alternative to radiosurgery and resection. A major limitation of the method is that its use is currently restricted to centrally located brain targets. The combination of FUS and a microbubble-based ultrasound contrast agent greatly reduces the ultrasound exposure level needed to ablate brain tissue and could be an effective means to increase the “treatment envelope” for FUS in the brain. This method, however, ablates tissue through a different mechanism: destruction of the microvasculature. It is not known whether nonthermal FUS ablation in substantial volumes of tissue can safely be performed without unexpected effects. The authors investigated this question by ablating volumes in the brains of normal rats. METHODS Overlapping sonications were performed in rats (n = 15) to ablate a volume in 1 hemisphere per animal. The sonications (10-msec bursts at 1 Hz for 60 seconds; peak negative pressure 0.8 MPa) were combined with the ultrasound contrast agent Optison (100 μl/kg). The rats were followed with MRI for 4–9 weeks after FUS, and the brains were examined with histological methods. RESULTS Two weeks after sonication and later, the lesions appeared as cyst-like areas in T2-weighted MR images that were stable over time. Histological examination demonstrated well-defined lesions consisting of a cyst-like cavity that remained lined by astrocytic tissue. Some white matter structures within the sonicated area were partially intact. CONCLUSIONS The results of this study indicate that nonthermal FUS ablation can be used to safely ablate tissue volumes in the brain without unexpected delayed effects. The findings are encouraging for the use of this ablation method in the brain. PMID:26848919

MicroRNA-211 expression is down-regulated and associated with poor prognosis in human glioma.

PubMed

Zhang, Jun; Lv, Jianguang; Zhang, Feng; Che, Hongmin; Liao, Qiwei; Huang, Wobin; Li, Shaopeng; Li, Yuqian

2017-07-01

Accumulating evidence has supported the role of microRNAs in the initiation and development of malignant tumors. MicroRNA-211 (miR-211), which was reported to involve in diverse physiological activities in several cancers, was investigated for its expression in human glioma and adjacent normal brain tissues, as well as its correlation with patient prognosis. Glioma tissues and adjacent normal brain tissues were obtained from 82 patients who underwent surgical resection, and quantitative real-time polymerase chain reaction was performed to assess the expression level of miR-211. Here, we found that miR-211 was significantly decreased in glioma tissues compared with adjacent normal brain tissues (glioma, 3.52 ± 0.14 vs. normal, 4.96 ± 0.17, p < 0.001), and inversely associated with ascending WHO classification (grade III-IV, 3.16 ± 0.21 vs. grade I-II, 4.22 ± 0.26, p < 0.001). Then, the correlation of miR-211 with clinicopathological factors was investigated by Pearson's Chi square test, indicating that miR-211 might be a potential biomarker to predict the malignant status of glioma. Further, Kaplan-Meier curves with log-rank analysis were carried out to determine the relationship between miR-211 expression level and the overall survival rate of glioma patients. Our data showed that there was a close correlation between down-regulated miR-211 and shorter survival time in 82 patients (p = 0.026). Finally, the multivariate Cox regression analysis indicated that WHO grade (HR = 2.437, 95% CI 1.251-4.966, p = 0.007), KPS (HR = 2.215, 95% CI 1.168-4.259, p = 0.016), and miR-211 expression level (HR = 3.614, 95% CI 2.152-6.748, p < 0.001) were considered as independent risk factors for glioma prognosis. These results suggested that lower miR-211 expression might be a marker for poor prognosis of glioma patients.

Robust skull stripping using multiple MR image contrasts insensitive to pathology.

PubMed

Roy, Snehashis; Butman, John A; Pham, Dzung L

2017-02-01

Automatic skull-stripping or brain extraction of magnetic resonance (MR) images is often a fundamental step in many neuroimage processing pipelines. The accuracy of subsequent image processing relies on the accuracy of the skull-stripping. Although many automated stripping methods have been proposed in the past, it is still an active area of research particularly in the context of brain pathology. Most stripping methods are validated on T 1 -w MR images of normal brains, especially because high resolution T 1 -w sequences are widely acquired and ground truth manual brain mask segmentations are publicly available for normal brains. However, different MR acquisition protocols can provide complementary information about the brain tissues, which can be exploited for better distinction between brain, cerebrospinal fluid, and unwanted tissues such as skull, dura, marrow, or fat. This is especially true in the presence of pathology, where hemorrhages or other types of lesions can have similar intensities as skull in a T 1 -w image. In this paper, we propose a sparse patch based Multi-cONtrast brain STRipping method (MONSTR), 2 where non-local patch information from one or more atlases, which contain multiple MR sequences and reference delineations of brain masks, are combined to generate a target brain mask. We compared MONSTR with four state-of-the-art, publicly available methods: BEaST, SPECTRE, ROBEX, and OptiBET. We evaluated the performance of these methods on 6 datasets consisting of both healthy subjects and patients with various pathologies. Three datasets (ADNI, MRBrainS, NAMIC) are publicly available, consisting of 44 healthy volunteers and 10 patients with schizophrenia. Other three in-house datasets, comprising 87 subjects in total, consisted of patients with mild to severe traumatic brain injury, brain tumors, and various movement disorders. A combination of T 1 -w, T 2 -w were used to skull-strip these datasets. We show significant improvement in stripping over the competing methods on both healthy and pathological brains. We also show that our multi-contrast framework is robust and maintains accurate performance across different types of acquisitions and scanners, even when using normal brains as atlases to strip pathological brains, demonstrating that our algorithm is applicable even when reference segmentations of pathological brains are not available to be used as atlases. Copyright © 2016 Elsevier Inc. All rights reserved.

Anatomy and imaging of the normal meninges.

PubMed

Patel, Neel; Kirmi, Olga

2009-12-01

The meninges are an important connective tissue envelope investing the brain. Their function is to provide a protective coating to the brain and also participate in the formation of blood-brain barrier. Understanding their anatomy is fundamental to understanding the location and spread of pathologies in relation to the layers. It also provides an insight into the characteristics of such pathologies when imaging them. This review aims to describe the anatomy of the meninges, and to demonstrate the imaging findings of specific features.

A combination of lipidomics, MS imaging, and PET scan imaging reveals differences in cerebral activity in rat pups according to the lipid quality of infant formulas.

PubMed

Aidoud, Nacima; Delplanque, Bernadette; Baudry, Charlotte; Garcia, Cyrielle; Moyon, Anais; Balasse, Laure; Guillet, Benjamin; Antona, Claudine; Darmaun, Dominique; Fraser, Karl; Ndiaye, Sega; Leruyet, Pascale; Martin, Jean-Charles

2018-03-22

We evaluated the effect of adding docosahexaenoic:arachidonic acids (3:2) (DHA+ARA) to 2 representative commercial infant formulas on brain activity and brain and eye lipids in an artificially reared rat pup model. The formula lipid background was either a pure plant oil blend, or dairy fat with a plant oil blend (1:1). Results at weaning were compared to breast milk-fed pups. Brain functional activity was determined by positron emission tomography scan imaging, the brain and eye fatty acid and lipid composition by targeted and untargeted lipidomics, and DHA brain regional location by mass-spectrometry imaging. The brain functional activity was normalized to controls with DHA+ARA added to the formulas. DHA in both brain and eyes was influenced by formula intake, but more than two-thirds of tissue DHA-glycerolipids remained insensitive to the dietary challenge. However, the DHA lipidome correlated better with brain function than sole DHA content ( r = 0.70 vs. r = 0.48; P < 0.05). Brain DHA regional distribution was more affected by the formula lipid background than the provision of PUFAs. Adding DHA+ARA to formulas alters the DHA content and lipidome of nervous tissue in the neonate, making it closer to dam milk-fed controls, and normalizes brain functional activity.-Aidoud, N., Delplanque, B., Baudry, C., Garcia, C., Moyon, A., Balasse, L., Guillet, B., Antona, C., Darmaun, D., Fraser, K., Ndiaye, S., Leruyet, P., Martin, J.-C. A combination of lipidomics, MS imaging, and PET scan imaging reveals differences in cerebral activity in rat pups according to the lipid quality of infant formulas.

Comparative survival study of glial cells and cells composing walls of blood vessels in crustacean ventral nerve cord after photodynamic treatment

NASA Astrophysics Data System (ADS)

Kolosov, Mikhail S.; Shubina, Elena

2015-03-01

Photodynamic therapy is a prospective treatment modality of brain cancers. It is of importance to have information about relative survival rate of different cell types in nerve tissue during photodynamic treatment. Particularly, for development of sparing strategy of the photodynamic therapy of brain tumors, which pursuits both total elimination of malignant cells, which are usually of glial origin, and, at the same time, preservation of normal blood circulation as well as normal glial cells in the brain. The aim of this work was to carry out comparative survival study of glial cells and cells composing walls of blood vessels after photodynamic treatment, using simple model object - ventral nerve cord of crustacean.

Radiolabeled probes for imaging Alzheimer’s plaques

NASA Astrophysics Data System (ADS)

Kulkarni, P. V.; Arora, V.; Roney, A. C.; White, C.; Bennett, M.; Antich, P. P.; Bonte, F. J.

2005-12-01

Alzheimer's disease (AD) is a debilitating disease characterized by the presence of extra-cellular plaques and intra-cellular neurofibrillary tangles (NFTs) in the brain. The major protein component of these plaques is beta amyloid peptide (Aβ), a 40-42 amino acid peptide cleaved from amyloid precursor protein (APP) by β-secretase and a putative γ-secretase. We radioiodinated quinoline derivatives (clioquinol and oxine) and evaluated them as potential amyloid imaging agents based on their ability to cross the blood brain barrier (BBB) and on their selectivity to metal binding sites on amyloid plaques. The uptake of theses tracers in the brains of normal swiss-webster mice was rapid and so was the clearance. Selectivity was demonstrated by higher binding to AD brain homogenates compared to normal brain. Autoradiographic studies demonstrated the localization of the tracers in the plaque regions of the AD brain sections as well as in liver tissue with amyloidosis. Further optimization and evaluations would likely lead to development of these molecules as AD plaque imaging agents.

Highly sensitive time-resolved thermography and multivariate image analysis of the cerebral cortex for intrasurgical diagnostics

NASA Astrophysics Data System (ADS)

Hollmach, Julia; Hoffmann, Nico; Schnabel, Christian; Küchler, Saskia; Sobottka, Stephan; Kirsch, Matthias; Schackert, Gabriele; Koch, Edmund; Steiner, Gerald

2013-03-01

Time-resolved thermography is a novel method to assess thermal variations and heterogeneities in tissue and blood. The recent generation of thermal cameras provides a sensitivity of less than mK. This high sensitivity in conjunction with non-invasive, label-free and radiation-free monitoring makes thermography a promising tool for intrasurgical diagnostics. In brain surgery, time-resolved thermography can be employed to distinguish between normal and anomalous tissue. In this study, we investigated and discussed the potential of time-resolved thermography in neurosurgery for the intraoperative detection and demarcation of tumor borders. Algorithms for segmentation, reduction of movement artifacts and image fusion were developed. The preprocessed image stacks were subjected to discrete wavelet transform to examine individual frequency components. K-means clustering was used for image evaluation to reveal similarities within the image sequence. The image evaluation shows significant differences for both types of tissue. Tumor and normal tissues have different time characteristics in heat production and transfer. Furthermore, tumor could be highlighted. These results demonstrate that time-resolved thermography is able to support the detection of tumors in a contactless manner without any side effects for the tissue. The intraoperative usage of time-resolved thermography improves the accuracy of tumor resections to prevent irreversible brain damage during surgery.

SU-G-IeP1-07: Inaccuracy of Lesion Blood Flow Quantification Related to the Proton Density Reference Image in Arterial Spin Labeling MRI of Brain Tumors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jen, M; Johnson, J; Hou, P

Purpose: Cerebral blood flow quantification in arterial spin labeling (ASL) MRI requires an estimate of the equilibrium magnetization of blood, which is often obtained by a set of proton density (PD) reference image. Normally, a constant blood-brain partition coefficient is assumed across the brain. However, this assumption may not be valid for brain lesions. This study aimed to evaluate the impact of lesion-related PD variations on ASL quantification in patients with brain tumors. Methods: MR images for posttreatment evaluation of 42 patients with brain tumors were retrospectively analyzed. These images were acquired on a 3T MRI scanner, including T2-weighted FLAIR,more » 3D pseudo-continuous ASL and post-contrast T1-weighted images. Anatomical images were coregistered with ASL images using the SPM software. Regions of interest (ROIs) of the enhancing and FLAIR lesions were manually drawn on the coregistered images. ROIs of the contralateral normal appearing tissues were also determined, with the consideration of approximating coil sensitivity patterns in lesion ROIs. Relative lesion blood flow (lesion/contralateral tissue) was calculated from both the CBF map (dependent on the PD) and the ΔM map for comparison. Results: The signal intensities in both enhancing and FLAIR lesions were significantly different than contralateral tissues on the PD reference image (p<0.001). The percent signal difference ranged from −15.9 to 19.2%, with a mean of 5.4% for the enhancing lesion, and from −2.8 to 22.9% with a mean of 10.1% for the FLAIR lesion. The high/low lesion-related PD signal resulted in inversely proportional under-/over-estimation of blood flow in both enhancing and FLAIR lesions. Conclusion: Significant signal differences were found between lesions and contralateral tissues in the PD reference image, which introduced errors in blood flow quantification in ASL. The error can be up to 20% in individual patients with an average of 5- 10% for the group of patients with brain tumors.« less

mTHPC-mediated photodynamic detection for fluorescence-guided resection of brain tumors

NASA Astrophysics Data System (ADS)

Kostron, Herwig; Zimmermann, Andreas; Obwegeser, Alois

1998-06-01

A most radical resection is of great importance in the treatment of brain tumors, however they can hardly be differentiated from normal brain parenchyma by the naked eye of the neurosurgeon. Photosensitizers are highly selective taken up into malignant tissues, therefore the fluorescence properties of photosensitizers could be utilized for optical differentiation of normal and malignant tissue. Ten patients presenting with brain malignancies were sensitized for photodynamic diagnosis (PDD) and photodynamic treatment (PDT) with 0.15 mg/kg b.w. m-THPC. On day 4 intraoperative PDD and fluorescence guided tumor resection (FGR) was performed, followed by intraoperative PDT. The fluorescence was induced by a xenon lamp at an excitation wavelength ranging from 370 to 440 nm. A sensitive CCD camera was employed for imaging, equipped with a long pass filter to shut off the excitation wavelength and to improve the signal to noise ratio. The pictures are converted digitally by a standard frame grabber and processed in real time and calculated for the tissue auto fluorescence in the emission band of m-THPC at 652 nm. Out of 10 0bservations, two were false negative and 2 were false positive. Our preliminary results indicate that fluorescence guided surgery is feasible and proved to be of significant help in delineating tumor margins and in resection of residual tumor that could not be detected by the surgeon, however the sensitivity and specificity needs to be further improved.

STUDIES ON THE DISTRIBUTION AND PHOSPHATE TURNOVER OF THE ACID-SOLUBLE PHOSPHORUS COMPOUNDS IN VARIOUS NORMAL AND NEOPLASTIC TISSUES OF RATS. II. COMPARISON OF THE CHROMATOGRAMS OBTAINED WITH VARIOUS TISSUES INCLUDING TUMOURS (ENGLISH TEXT)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Horie, S.

Using a modified semi-micro gradient elution method of chromatography, the distribution of the acid-soluble nucleotides in various normal and neoplastic tissues of rats was compared and the variations of the distribution are described. The distribution and phosphate turnover of the acid-soluble phosphorus compounds were also studied by intraperitoneal injection of P/sup 32/ followed by the chromatographic analysis. The distribution patterns of nucleotides and radioactivity in liver, muscle, heart, lung, thymus, spleen, testicles, brain, fetal liver, and experimental hepatomas are illustrated and the differences between these tissues were pointed out. The characteristics of the experimental hepatoma tissue as compared with themore » normal liver tissue are as follows: The concentration of oxidized DPN was low; the incorporation of P/sup 32/ inorganic phosphate into glucose 6-phosphate and L- alpha -glycerophosphate was absent or, if any, very low; radioactivity of inorganic phosphate in the total acid-soluble radioactivity was extraordinarily high as compared with other tissues besides the liver tissue. (Abstr. Japan Med., 1: No. 9, 1961)« less

Half brain irradiation in a murine model of breast cancer brain metastasis: magnetic resonance imaging and histological assessments of dose-response.

PubMed

Zarghami, Niloufar; Murrell, Donna H; Jensen, Michael D; Dick, Frederick A; Chambers, Ann F; Foster, Paula J; Wong, Eugene

2018-06-01

Brain metastasis is becoming increasingly prevalent in breast cancer due to improved extra-cranial disease control. With emerging availability of modern image-guided radiation platforms, mouse models of brain metastases and small animal magnetic resonance imaging (MRI), we examined brain metastases' responses from radiotherapy in the pre-clinical setting. In this study, we employed half brain irradiation to reduce inter-subject variability in metastases dose-response evaluations. Half brain irradiation was performed on a micro-CT/RT system in a human breast cancer (MDA-MB-231-BR) brain metastasis mouse model. Radiation induced DNA double stranded breaks in tumors and normal mouse brain tissue were quantified using γ-H2AX immunohistochemistry at 30 min (acute) and 11 days (longitudinal) after half-brain treatment for doses of 8, 16 and 24 Gy. In addition, tumor responses were assessed volumetrically with in-vivo longitudinal MRI and histologically for tumor cell density and nuclear size. In the acute setting, γ-H2AX staining in tumors saturated at higher doses while normal mouse brain tissue continued to increase linearly in the phosphorylation of H2AX. While γ-H2AX fluorescence intensities returned to the background level in the brain 11 days after treatment, the residual γ-H2AX phosphorylation in the radiated tumors remained elevated compared to un-irradiated contralateral tumors. With radiation, MRI-derived relative tumor growth was significantly reduced compared to the un-irradiated side. While there was no difference in MRI tumor volume growth between 16 and 24 Gy, there was a significant reduction in tumor cell density from histology with increasing dose. In the longitudinal study, nuclear size in the residual tumor cells increased significantly as the radiation dose was increased. Radiation damages to the DNAs in the normal brain parenchyma are resolved over time, but remain unrepaired in the treated tumors. Furthermore, there is a radiation dose response in nuclear size of surviving tumor cells. Increase in nuclear size together with unrepaired DNA damage indicated that the surviving tumor cells post radiation had continued to progress in the cell cycle with DNA replication, but failed cytokinesis. Half brain irradiation provides efficient evaluation of dose-response for cancer cell lines, a pre-requisite to perform experiments to understand radio-resistance in brain metastases.

Joint Segmentation and Deformable Registration of Brain Scans Guided by a Tumor Growth Model

PubMed Central

Gooya, Ali; Pohl, Kilian M.; Bilello, Michel; Biros, George; Davatzikos, Christos

2011-01-01

This paper presents an approach for joint segmentation and deformable registration of brain scans of glioma patients to a normal atlas. The proposed method is based on the Expectation Maximization (EM) algorithm that incorporates a glioma growth model for atlas seeding, a process which modifies the normal atlas into one with a tumor and edema. The modified atlas is registered into the patient space and utilized for the posterior probability estimation of various tissue labels. EM iteratively refines the estimates of the registration parameters, the posterior probabilities of tissue labels and the tumor growth model parameters. We have applied this approach to 10 glioma scans acquired with four Magnetic Resonance (MR) modalities (T1, T1-CE, T2 and FLAIR ) and validated the result by comparing them to manual segmentations by clinical experts. The resulting segmentations look promising and quantitatively match well with the expert provided ground truth. PMID:21995070

Joint segmentation and deformable registration of brain scans guided by a tumor growth model.

PubMed

Gooya, Ali; Pohl, Kilian M; Bilello, Michel; Biros, George; Davatzikos, Christos

2011-01-01

This paper presents an approach for joint segmentation and deformable registration of brain scans of glioma patients to a normal atlas. The proposed method is based on the Expectation Maximization (EM) algorithm that incorporates a glioma growth model for atlas seeding, a process which modifies the normal atlas into one with a tumor and edema. The modified atlas is registered into the patient space and utilized for the posterior probability estimation of various tissue labels. EM iteratively refines the estimates of the registration parameters, the posterior probabilities of tissue labels and the tumor growth model parameters. We have applied this approach to 10 glioma scans acquired with four Magnetic Resonance (MR) modalities (T1, T1-CE, T2 and FLAIR) and validated the result by comparing them to manual segmentations by clinical experts. The resulting segmentations look promising and quantitatively match well with the expert provided ground truth.

Effect of echo artifacts on characterization of pulsatile tissues in neonatal cranial ultrasonic movies

NASA Astrophysics Data System (ADS)

Fukuzawa, Masayuki; Takahashi, Kazuki; Tabata, Yuki; Kitsunezuka, Yoshiki

2016-04-01

Effect of echo artifacts on characterization of pulsatile tissues has been examined in neonatal cranial ultrasonic movies by characterizing pulsatile intensities with different regions of interest (ROIs). The pulsatile tissue, which is a key point in pediatric diagnosis of brain tissue, was detected from a heartbeat-frequency component in Fourier transform of a time-variation of 64 samples of echo intensity at each pixel in a movie fragment. The averages of pulsatile intensity and power were evaluated in two ROIs: common fan-shape and individual cranial-shape. The area of pulsatile region was also evaluated as the number of pixels where the pulsatile intensity exceeds a proper threshold. The extracranial pulsatile region was found mainly in the sections where mirror image was dominant echo artifact. There was significant difference of pulsatile area between two ROIs especially in the specific sections where mirror image was included, suggesting the suitability of cranial-shape ROI for statistical study on pulsatile tissues in brain. The normalized average of pulsatile power in the cranial-shape ROI exhibited most similar tendency to the normalized pulsatile area which was treated as a conventional measure in spite of its requirement of thresholding. It suggests the potential of pulsatile power as an alternative measure for pulsatile area in further statistical study of pulsatile tissues because it was neither affected by echo artifacts nor threshold.

A New Ghost Cell/Level Set Method for Moving Boundary Problems: Application to Tumor Growth

PubMed Central

Macklin, Paul

2011-01-01

In this paper, we present a ghost cell/level set method for the evolution of interfaces whose normal velocity depend upon the solutions of linear and nonlinear quasi-steady reaction-diffusion equations with curvature-dependent boundary conditions. Our technique includes a ghost cell method that accurately discretizes normal derivative jump boundary conditions without smearing jumps in the tangential derivative; a new iterative method for solving linear and nonlinear quasi-steady reaction-diffusion equations; an adaptive discretization to compute the curvature and normal vectors; and a new discrete approximation to the Heaviside function. We present numerical examples that demonstrate better than 1.5-order convergence for problems where traditional ghost cell methods either fail to converge or attain at best sub-linear accuracy. We apply our techniques to a model of tumor growth in complex, heterogeneous tissues that consists of a nonlinear nutrient equation and a pressure equation with geometry-dependent jump boundary conditions. We simulate the growth of glioblastoma (an aggressive brain tumor) into a large, 1 cm square of brain tissue that includes heterogeneous nutrient delivery and varied biomechanical characteristics (white matter, gray matter, cerebrospinal fluid, and bone), and we observe growth morphologies that are highly dependent upon the variations of the tissue characteristics—an effect observed in real tumor growth. PMID:21331304

Towards High-Resolution Tissue Imaging Using Nanospray Desorption Electrospray Ionization Mass Spectrometry Coupled to Shear Force Microscopy

NASA Astrophysics Data System (ADS)

Nguyen, Son N.; Sontag, Ryan L.; Carson, James P.; Corley, Richard A.; Ansong, Charles; Laskin, Julia

2018-02-01

Constant mode ambient mass spectrometry imaging (MSI) of tissue sections with high lateral resolution of better than 10 μm was performed by combining shear force microscopy with nanospray desorption electrospray ionization (nano-DESI). Shear force microscopy enabled precise control of the distance between the sample and nano-DESI probe during MSI experiments and provided information on sample topography. Proof-of-concept experiments were performed using lung and brain tissue sections representing spongy and dense tissues, respectively. Topography images obtained using shear force microscopy were comparable to the results obtained using contact profilometry over the same region of the tissue section. Variations in tissue height were found to be dependent on the tissue type and were in the range of 0-5 μm for lung tissue and 0-3 μm for brain tissue sections. Ion images of phospholipids obtained in this study are in good agreement with literature data. Normalization of nano-DESI MSI images to the signal of the internal standard added to the extraction solvent allowed us to construct high-resolution ion images free of matrix effects.

Time-frequency analyses of fluid-solid interaction under sinusoidal translational shear deformation of the viscoelastic rat cerebrum

NASA Astrophysics Data System (ADS)

Leahy, Lauren N.; Haslach, Henry W.

2018-02-01

During normal extracellular fluid (ECF) flow in the brain glymphatic system or during pathological flow induced by trauma resulting from impacts and blast waves, ECF-solid matter interactions result from sinusoidal shear waves in the brain and cranial arterial tissue, both heterogeneous biological tissues with high fluid content. The flow in the glymphatic system is known to be forced by pulsations of the cranial arteries at about 1 Hz. The experimental shear stress response to sinusoidal translational shear deformation at 1 Hz and 25% strain amplitude and either 0% or 33% compression is compared for rat cerebrum and bovine aortic tissue. Time-frequency analyses aim to correlate the shear stress signal frequency components over time with the behavior of brain tissue constituents to identify the physical source of the shear nonlinear viscoelastic response. Discrete fast Fourier transformation analysis and the novel application to the shear stress signal of harmonic wavelet decomposition both show significant 1 Hz and 3 Hz components. The 3 Hz component in brain tissue, whose magnitude is much larger than in aortic tissue, may result from interstitial fluid induced drag forces. The harmonic wavelet decomposition locates 3 Hz harmonics whose magnitudes decrease on subsequent cycles perhaps because of bond breaking that results in easier fluid movement. Both tissues exhibit transient shear stress softening similar to the Mullins effect in rubber. The form of a new mathematical model for the drag force produced by ECF-solid matter interactions captures the third harmonic seen experimentally.

MO-F-CAMPUS-T-02: Optimizing Orientations of Hundreds of Intensity-Modulated Beams to Treat Multiple Brain Targets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ma, L; Dong, P; Larson, D

Purpose: To investigate a new modulated beam orientation optimization (MBOO) approach maximizing treatment planning quality for the state-of-the-art flattening filter free (FFF) beam that has enabled rapid treatments of multiple brain targets. Methods: MBOO selects and optimizes a large number of intensity-modulated beams (400 or more) from all accessible beam angles surrounding a patient’s skull. The optimization algorithm was implemented on a standalone system that interfaced with the 3D Dicom images and structure sets. A standard published data set that consisted of 1 to 12 metastatic brain tumor combinations was selected for MBOO planning. The planning results from various coplanarmore » and non-coplanar configurations via MBOO were then compared with the results obtained from a clinical volume modulated arc therapy (VMAT) delivery system (Truebeam RapidArc, Varian Oncology). Results: When planning a few number of targets (n<4), MBOO produced results equivalent to non-coplanar multi-arc VMAT planning in terms of target volume coverage and normal tissue sparing. For example, the 12-Gy and 4-Gy normal brain volumes for the 3-target plans differed by less than 1 mL ( 3.0 mLvs 3.8 mL; and 35.2 mL vs 36.3 mL, respectively) for MBOO versus VMAT. However, when planning a larger number of targets (n≥4), MBOO significantly reduced the dose to the normal brain as compared to VMAT, though the target volume coverage was equivalent. For example, the 12-Gy and 4-Gy normal brain volumes for the 12-target plans were 10.8 mL vs. 18.0 mL and 217.9 mL vs. 390.0 mL, respectively for the non-coplanar MBOO versus the non-coplanar VMAT treatment plans, yielding a reduction in volume of more than 60% for the case. Conclusion: MBOO is a unique approach for maximizing normal tissue sparing when treating a large number (n≥4) of brain tumors with FFF linear accelerators. Dr Ma and Dr Sahgal are currently on the board of international society of stereotactic radiosurgery. Dr Sahgal has received support for educational presentations from Elekta company.« less

Deep Convolutional Neural Networks for Multi-Modality Isointense Infant Brain Image Segmentation

PubMed Central

Zhang, Wenlu; Li, Rongjian; Deng, Houtao; Wang, Li; Lin, Weili; Ji, Shuiwang; Shen, Dinggang

2015-01-01

The segmentation of infant brain tissue images into white matter (WM), gray matter (GM), and cerebrospinal fluid (CSF) plays an important role in studying early brain development in health and disease. In the isointense stage (approximately 6–8 months of age), WM and GM exhibit similar levels of intensity in both T1 and T2 MR images, making the tissue segmentation very challenging. Only a small number of existing methods have been designed for tissue segmentation in this isointense stage; however, they only used a single T1 or T2 images, or the combination of T1 and T2 images. In this paper, we propose to use deep convolutional neural networks (CNNs) for segmenting isointense stage brain tissues using multi-modality MR images. CNNs are a type of deep models in which trainable filters and local neighborhood pooling operations are applied alternatingly on the raw input images, resulting in a hierarchy of increasingly complex features. Specifically, we used multimodality information from T1, T2, and fractional anisotropy (FA) images as inputs and then generated the segmentation maps as outputs. The multiple intermediate layers applied convolution, pooling, normalization, and other operations to capture the highly nonlinear mappings between inputs and outputs. We compared the performance of our approach with that of the commonly used segmentation methods on a set of manually segmented isointense stage brain images. Results showed that our proposed model significantly outperformed prior methods on infant brain tissue segmentation. In addition, our results indicated that integration of multi-modality images led to significant performance improvement. PMID:25562829

Brain tumor modeling: glioma growth and interaction with chemotherapy

NASA Astrophysics Data System (ADS)

Banaem, Hossein Y.; Ahmadian, Alireza; Saberi, Hooshangh; Daneshmehr, Alireza; Khodadad, Davood

2011-10-01

In last decade increasingly mathematical models of tumor growths have been studied, particularly on solid tumors which growth mainly caused by cellular proliferation. In this paper we propose a modified model to simulate the growth of gliomas in different stages. Glioma growth is modeled by a reaction-advection-diffusion. We begin with a model of untreated gliomas and continue with models of polyclonal glioma following chemotherapy. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter. Tumor growth is characterized by a dangerous change in the control mechanisms, which normally maintain a balance between the rate of proliferation and the rate of apoptosis (controlled cell death). Result shows that this model closes to clinical finding and can simulate brain tumor behavior properly.

Ribosome Profiling Reveals a Cell-Type-Specific Translational Landscape in Brain Tumors

PubMed Central

Gonzalez, Christian; Sims, Jennifer S.; Hornstein, Nicholas; Mela, Angeliki; Garcia, Franklin; Lei, Liang; Gass, David A.; Amendolara, Benjamin; Bruce, Jeffrey N.

2014-01-01

Glioma growth is driven by signaling that ultimately regulates protein synthesis. Gliomas are also complex at the cellular level and involve multiple cell types, including transformed and reactive cells in the brain tumor microenvironment. The distinct functions of the various cell types likely lead to different requirements and regulatory paradigms for protein synthesis. Proneural gliomas can arise from transformation of glial progenitors that are driven to proliferate via mitogenic signaling that affects translation. To investigate translational regulation in this system, we developed a RiboTag glioma mouse model that enables cell-type-specific, genome-wide ribosome profiling of tumor tissue. Infecting glial progenitors with Cre-recombinant retrovirus simultaneously activates expression of tagged ribosomes and delivers a tumor-initiating mutation. Remarkably, we find that although genes specific to transformed cells are highly translated, their translation efficiencies are low compared with normal brain. Ribosome positioning reveals sequence-dependent regulation of ribosomal activity in 5′-leaders upstream of annotated start codons, leading to differential translation in glioma compared with normal brain. Additionally, although transformed cells express a proneural signature, untransformed tumor-associated cells, including reactive astrocytes and microglia, express a mesenchymal signature. Finally, we observe the same phenomena in human disease by combining ribosome profiling of human proneural tumor and non-neoplastic brain tissue with computational deconvolution to assess cell-type-specific translational regulation. PMID:25122893

Potential for intensity-modulated radiation therapy to permit dose escalation for canine nasal cancer.

PubMed

Vaudaux, Catherine; Schneider, Uwe; Kaser-Hotz, Barbara

2007-01-01

We evaluated the impact of inverse planned intensity-modulated radiation therapy (IMRT) on the dose-volume histograms (DVHs) and on the normal tissue complication probabilities (NTCPs) of brain and eyes in dogs with nasal tumors. Nine dogs with large, caudally located nasal tumors were planned using conventional techniques and inverse planned IMRT for a total prescribed dose of 52.5 Gy in 3.5 Gy fractions. The equivalent uniform dose for brain and eyes was calculated to estimate the normal tissue complication probability (NTCP) of these organs. The NTCP values as well as the DVHs were used to compare the treatment plans. The dose distribution in IMRT plans was more conformal than in conventional plans. The average dose delivered to one-third of the brain was 10 Gy lower with the IMRT plan compared with conventional planning. The mean partial brain volume receiving 43.6 Gy or more was reduced by 25.6% with IMRT. As a consequence, the NTCPs were also significantly lower in the IMRT plans. The mean NTCP of brain was two times lower and at least one eye could be saved in all patients planed with IMRT. Another possibility with IMRT is dose escalation in the target to improve tumor control while keeping the NTCPs at the same level as for conventional planning. Veterinary

The effect of saponification on the mucopolysaccharides of the ground substance of the human brain: the relation to focal edema and multiple sclerosis.

PubMed

Feigin, I

1981-03-01

The acid mucopolysaccharides of brain tissues are disclosed by their metachromatic staining with toluidine blue following saponification with potassium hydroxide, presumably as a result of the liberation of acid groups previously esterified. Earlier histochemical studies had disclosed the presence of neutral mucopolysaccharides by staining with the periodic acid-Schiff technique, and such staining is intensified by prior saponification. Many biochemical studies have reported the presence of both acid and neutral mucopolysaccharides in brain tissues. Within the white matter following brain edema, the quantity of stained mucopolysaccharides is decreased in the plaques of multiple sclerosis and pontine myelinolysis, and in the lesions of diffuse sclerosis. All of these are characterized by myelin loss with relative preservation of axons. The known physiological effects of the mucopolysaccharides on the water content of normal tissues, and on the properties and diffusability of the increments of fluid that constitute edema, lead to the suggestion that edema may play a major role in the pathogenesis of the demyelinating diseases, including multiple sclerosis.

Intracavitary moderator balloon combined with (252)Cf brachytherapy and boron neutron capture therapy, improving dosimetry in brain tumour and infiltrations.

PubMed

Brandão, S F; Campos, T P R

2015-07-01

This article proposes a combination of californium-252 ((252)Cf) brachytherapy, boron neutron capture therapy (BNCT) and an intracavitary moderator balloon catheter applied to brain tumour and infiltrations. Dosimetric evaluations were performed on three protocol set-ups: (252)Cf brachytherapy combined with BNCT (Cf-BNCT); Cf-BNCT with a balloon catheter filled with light water (LWB) and the same set-up with heavy water (HWB). Cf-BNCT-HWB has presented dosimetric advantages to Cf-BNCT-LWB and Cf-BNCT in infiltrations at 2.0-5.0 cm from the balloon surface. However, Cf-BNCT-LWB has shown superior dosimetry up to 2.0 cm from the balloon surface. Cf-BNCT-HWB and Cf-BNCT-LWB protocols provide a selective dose distribution for brain tumour and infiltrations, mainly further from the (252)Cf source, sparing the normal brain tissue. Malignant brain tumours grow rapidly and often spread to adjacent brain tissues, leading to death. Improvements in brain radiation protocols have been continuously achieved; however, brain tumour recurrence is observed in most cases. Cf-BNCT-LWB and Cf-BNCT-HWB represent new modalities for selectively combating brain tumour infiltrations and metastasis.

Examination of Physiological Function and Biochemical Disorders in a Rat Model of Prolonged Asphyxia-Induced Cardiac Arrest followed by Cardio Pulmonary Bypass Resuscitation

PubMed Central

Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A.; Pappan, Kirk L.; Lampe, Joshua W.; Becker, Lance B.

2014-01-01

Background Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. Method A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. Results After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. Conclusion The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage. PMID:25383962

Examination of physiological function and biochemical disorders in a rat model of prolonged asphyxia-induced cardiac arrest followed by cardio pulmonary bypass resuscitation.

PubMed

Kim, Junhwan; Yin, Tai; Yin, Ming; Zhang, Wei; Shinozaki, Koichiro; Selak, Mary A; Pappan, Kirk L; Lampe, Joshua W; Becker, Lance B

2014-01-01

Cardiac arrest induces whole body ischemia, which causes damage to multiple organs particularly the heart and the brain. There is clinical and preclinical evidence that neurological injury is responsible for high mortality and morbidity of patients even after successful cardiopulmonary resuscitation. A better understanding of the metabolic alterations in the brain during ischemia will enable the development of better targeted resuscitation protocols that repair the ischemic damage and minimize the additional damage caused by reperfusion. A validated whole body model of rodent arrest followed by resuscitation was utilized; animals were randomized into three groups: control, 30 minute asphyxial arrest, or 30 minutes asphyxial arrest followed by 60 min cardiopulmonary bypass (CPB) resuscitation. Blood gases and hemodynamics were monitored during the procedures. An untargeted metabolic survey of heart and brain tissues following cardiac arrest and after CPB resuscitation was conducted to better define the alterations associated with each condition. After 30 min cardiac arrest and 60 min CPB, the rats exhibited no observable brain function and weakened heart function in a physiological assessment. Heart and brain tissues harvested following 30 min ischemia had significant changes in the concentration of metabolites in lipid and carbohydrate metabolism. In addition, the brain had increased lysophospholipid content. CPB resuscitation significantly normalized metabolite concentrations in the heart tissue, but not in the brain tissue. The observation that metabolic alterations are seen primarily during cardiac arrest suggests that the events of ischemia are the major cause of neurological damage in our rat model of asphyxia-CPB resuscitation. Impaired glycolysis and increased lysophospholipids observed only in the brain suggest that altered energy metabolism and phospholipid degradation may be a central mechanism in unresuscitatable brain damage.

Combining Segmented Grey and White Matter Images Improves Voxel-based Morphometry for the Case of Dilated Lateral Ventricles.

PubMed

Goto, Masami; Abe, Osamu; Aoki, Shigeki; Kamagata, Koji; Hori, Masaaki; Miyati, Tosiaki; Gomi, Tsutomu; Takeda, Tohoru

2018-01-18

To evaluate the error in segmented tissue images and to show the usefulness of the brain image in voxel-based morphometry (VBM) using Statistical Parametric Mapping (SPM) 12 software and 3D T 1 -weighted magnetic resonance images (3D-T 1 WIs) processed to simulate idiopathic normal pressure hydrocephalus (iNPH). VBM analysis was performed on sagittal 3D-T 1 WIs obtained in 22 healthy volunteers using a 1.5T MR scanner. Regions of interest for the lateral ventricles of all subjects were carefully outlined on the original 3D-T 1 WIs, and two types of simulated 3D-T 1 WI were also prepared (non-dilated 3D-T 1 WI as normal control and dilated 3D-T 1 WI to simulate iNPH). All simulated 3D-T 1 WIs were segmented into gray matter, white matter, and cerebrospinal fluid images, and normalized to standard space. A brain image was made by adding the gray and white matter images. After smoothing with a 6-mm isotropic Gaussian kernel, group comparisons (dilated vs non-dilated) were made for gray and white matter, cerebrospinal fluid, and brain images using a paired t-test. In evaluation of tissue volume, estimation error was larger using gray or white matter images than using the brain image, and estimation errors in gray and white matter volume change were found for the brain surface. To our knowledge, this is the first VBM study to show the possibility that VBM of gray and white matter volume on the brain surface may be more affected by individual differences in the level of dilation of the lateral ventricles than by individual differences in gray and white matter volumes. We recommend that VBM evaluation in patients with iNPH should be performed using the brain image rather than the gray and white matter images.

Relationships between brain and body temperature, clinical and imaging outcomes after ischemic stroke

PubMed Central

Karaszewski, Bartosz; Carpenter, Trevor K; Thomas, Ralph G R; Armitage, Paul A; Lymer, Georgina Katherine S; Marshall, Ian; Dennis, Martin S; Wardlaw, Joanna M

2013-01-01

Pyrexia soon after stroke is associated with severe stroke and poor functional outcome. Few studies have assessed brain temperature after stroke in patients, so little is known of its associations with body temperature, stroke severity, or outcome. We measured temperatures in ischemic and normal-appearing brain using 1H-magnetic resonance spectroscopy and its correlations with body (tympanic) temperature measured four-hourly, infarct growth by 5 days, early neurologic (National Institute of Health Stroke Scale, NIHSS) and late functional outcome (death or dependency). Among 40 patients (mean age 73 years, median NIHSS 7, imaged at median 17 hours), temperature in ischemic brain was higher than in normal-appearing brain on admission (38.6°C-core, 37.9°C-contralateral hemisphere, P=0.03) but both were equally elevated by 5 days; both were higher than tympanic temperature. Ischemic lesion temperature was not associated with NIHSS or 3-month functional outcome; in contrast, higher contralateral normal-appearing brain temperature was associated with worse NIHSS, infarct expansion and poor functional outcome, similar to associations for tympanic temperature. We conclude that brain temperature is higher than body temperature; that elevated temperature in ischemic brain reflects a local tissue response to ischemia, whereas pyrexia reflects the systemic response to stroke, occurs later, and is associated with adverse outcomes. PMID:23571281

Binding and release of brain calcium by low-level electromagnetic fields: A review

NASA Astrophysics Data System (ADS)

Adey, W. R.; Bawin, S. M.

Evidence has accumulated that sensitivity of brain tissue to specific weak oscillating electromagnetic fields occurs in the absence of significant tissue heating (less than 0.1°C). This review focuses on the ‘windowed’ character of sensitivities of calcium binding and electrical activity in brain tissue to low-frequency modulation and intensity characteristics of impressed RF fields. ELF fields decrease calcium efflux from isolated chick and cat cerebral tissue by about 15% only in narrow amplitude and frequency ‘windows,’ between 6 and 20 Hz and between 10 and 100 V/m (approximate tissue gradient, 10-7 V/cm). VHF (147 MHz) and UHF (450 MHz) fields increase calcium efflux from isolated chick brain by about 15% when amplitude modulated between 6 and 20 Hz, but only for incident fields in the vicinity of 1.0 mW/cm2. We have now shown that this increased efflux in response to 16-Hz amplitude-modulated 450-MHz, 0.75-mW/cm2 field exposure is insensitive to variations in calcium concentration from 0 to 4.16 mM in the testing solution but is enhanced by addition of hydrogen ions (0.108 mM 0.1 N HCl) and inhibited in the absence of normal bicarbonate ion levels (2.4 mM). In the presence of lanthanum ions (2.0 mM), which block transmembrane movement of calcium, exposure to these EM fields decreases the 45Ca2 + efflux. Low-frequency gradients may be transduced in a specific class of extracellular binding sites, normally occupied by calcium ions and susceptible to competitive hydrogen ion binding. Transductive coupling may involve coherent charge states between anionic sites on membrane surface glycoproteins, with longrange cooperative interactions triggered by weak extracellular electric fields. Proton ‘tunneling’ may occur at boundaries between coherent and noncoherent charge zones.

Computer aided detection of tumor and edema in brain FLAIR magnetic resonance image using ANN

NASA Astrophysics Data System (ADS)

Pradhan, Nandita; Sinha, A. K.

2008-03-01

This paper presents an efficient region based segmentation technique for detecting pathological tissues (Tumor & Edema) of brain using fluid attenuated inversion recovery (FLAIR) magnetic resonance (MR) images. This work segments FLAIR brain images for normal and pathological tissues based on statistical features and wavelet transform coefficients using k-means algorithm. The image is divided into small blocks of 4×4 pixels. The k-means algorithm is used to cluster the image based on the feature vectors of blocks forming different classes representing different regions in the whole image. With the knowledge of the feature vectors of different segmented regions, supervised technique is used to train Artificial Neural Network using fuzzy back propagation algorithm (FBPA). Segmentation for detecting healthy tissues and tumors has been reported by several researchers by using conventional MRI sequences like T1, T2 and PD weighted sequences. This work successfully presents segmentation of healthy and pathological tissues (both Tumors and Edema) using FLAIR images. At the end pseudo coloring of segmented and classified regions are done for better human visualization.

FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents.

PubMed

Patil, Abhijit A; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D; Roylance, Anthony; Kriplani, Deepti H; Myers, Katie N; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A; Collis, Spencer J

2014-08-15

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge, where survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome.

FANCD2 re-expression is associated with glioma grade and chemical inhibition of the Fanconi Anaemia pathway sensitises gliomas to chemotherapeutic agents

PubMed Central

Patil, Abhijit A.; Sayal, Parag; Depondt, Marie-Lise; Beveridge, Ryan D.; Roylance, Anthony; Kriplani, Deepti H.; Myers, Katie N.; Cox, Angela; Jellinek, David; Fernando, Malee; Carroll, Thomas A.; Collis, Spencer J.

2014-01-01

Brain tumours kill more children and adults under 40 than any other cancer. Around half of primary brain tumours are glioblastoma multiforme (GBMs) where treatment remains a significant challenge. GBM survival rates have improved little over the last 40 years, thus highlighting an unmet need for the identification/development of novel therapeutic targets and agents to improve GBM treatment. Using archived and fresh glioma tissue, we show that in contrast to normal brain or benign schwannomas GBMs exhibit re-expression of FANCD2, a key protein of the Fanconi Anaemia (FA) DNA repair pathway, and possess an active FA pathway. Importantly, FANCD2 expression levels are strongly associated with tumour grade, revealing a potential exploitable therapeutic window to allow inhibition of the FA pathway in tumour cells, whilst sparing normal brain tissue. Using several small molecule inhibitors of the FA pathway in combination with isogenic FA-proficient/deficient glioma cell lines as well as primary GBM cultures, we demonstrate that inhibition of the FA pathway sensitises gliomas to the chemotherapeutic agents Temozolomide and Carmustine. Our findings therefore provide a strong rationale for the development of novel and potent inhibitors of the FA pathway to improve the treatment of GBMs, which may ultimately impact on patient outcome. PMID:25071006

Three-Dimensional Magnetic Resonance Spectroscopic Imaging of Brain and Prostate Cancer1

PubMed Central

Kurhanewicz, John; Vigneron, Daniel B; Nelson, Sarah J

2000-01-01

Abstract Clinical applications of magnetic resonance spectroscopic imaging (MRSI) for the study of brain and prostate cancer have expanded significantly over the past 10 years. Proton MRSI studies of the brain and prostate have demonstrated the feasibility of noninvasively assessing human cancers based on metabolite levels before and after therapy in a clinically reasonable amount of time. MRSI provides a unique biochemical “window” to study cellular metabolism noninvasively. MRSI studies have demonstrated dramatic spectral differences between normal brain tissue (low choline and high N-acetyl aspartate, NAA) and prostate (low choline and high citrate) compared to brain (low NAA, high choline) and prostate (low citrate, high choline) tumors. The presence of edema and necrosis in both the prostate and brain was reflected by a reduction of the intensity of all resonances due to reduced cell density. MRSI was able to discriminate necrosis (absence of all metabolites, except lipids and lactate) from viable normal tissue and cancer following therapy. The results of current MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy as well as the magnitude and time course of metabolic changes after therapy can improve our understanding of cancer aggressiveness and mechanisms of therapeutic response. Clinically, combined MRI/MRSI has already demonstrated the potential for improved diagnosis, staging and treatment planning of brain and prostate cancer. Additionally, studies are under way to determine the accuracy of anatomic and metabolic parameters in providing an objective quantitative basis for assessing disease progression and response to therapy. PMID:10933075

[Chromogranin A derived peptide CGA47-66 inhibits hyper-permeability of blood brain barrier in mice with sepsis].

PubMed

Zeng, Yan; Zhang, Dan; Jiang, Liping; Wei, Fu; Xu, Shan

2016-02-01

To explore the effect of chromofungin (CHR), a chromogranin A (CGA) derived peptide CGA47-66, on hyper-permeability of blood brain barrier in septic mice. 120 healthy male C57BL/6 mice were randomly divided into groups, with 12 mice in each group. Seventy-two mice were used for dynamic observation of the contents of water and Evan blue (EB) in brain tissue after being treated with lipopolysaccharide (LPS). Another 48 mice were divided into normal saline control group (NS group), LPS induced sepsis model group (LPS group), low-dose CHR pretreatment group (CL+LPS group), and high-dose CHR pretreatment group (CH+LPS group). The septic model was reproduced by intraperitoneal injection of 10 mg/kg LPS 0.1 mL, and the mice in NS group was given equal volume of normal saline. The mice in CL+LPS group and CH+LPS group were intraperitoneally injected with 15.5 μg/kg and 77.5 μg/kg CHR 10 minutes before LPS injection. Six hours after LPS injection, 4 mL/kg of 2% EB was injected via caudal vein, the contents of water and EB in brain tissue were determined, and EB immune fluorescence in brain tissue was determined to assess the changes in permeability of blood brain barrier. Brain pathology was observed with hematoxylin and eosin (HE) staining. With the extension of time after LPS injection, the contents of water and EB in brain tissue were gradually increased, and the time of difference with statistical significance appeared earlier when compared with that of control group in the contents of water than that in EB contents (3 hours and 6 hours, respectively). The contents of water and EB in brain tissue in LPS group were significantly increased as compared with NS group [water content: (79.77±0.62)% vs. (78.28±0.44)%, P < 0.01; EB content (μg/g): 13.87±4.50 vs. 7.13±1.76, P < 0.05]. CHR pretreatment with either of two dosages could reverse the increase in water and EB contents in brain tissue induced by LPS, and the effect was more significant in CH+LPS group [water content: (78.15±0.73)% vs. (79.77±0.62)%, EB (μg/g): 7.09±2.59 vs. 13.87±4.50, both P < 0.05]. It was shown by EB fluorescence observation that the fluorescence signal displayed only in the meninges in NS group, and EB fluorescence was widely distributed in brain parenchyma in LPS group, indicating that the EB leakage in LPS group was more marked than that of NS group. In CHR pretreatment groups, EB fluorescence was decreased in brain parenchyma, indicating that EB leakage was significantly less marked, while it was more obvious in high dose CHR group. It was shown by HE staining that cerebral blood vessel structure was intact in NS group, and the gap around blood vessel was not significant increased. On the other hand, brain structure in LPS group appeared loose, with widening of small perivascular spaces and obvious edema. Brain edema in CHR pretreatment groups was improved as compared with that of the LPS group, and it was more apparent in high dose CHR group. LPS induced change in blood brain barrier permeability in mice in a time-dependent manner. Exogenous CGA derived peptides CHR can inhibit LPS induced hyper-permeability of blood brain barrier in septic mice, thus reduces brain edema, protects the brain tissue, and the effect is more obvious with a high dose of CHR (77.5 μg/kg).

Distribution of Non-Persistent Endocrine Disruptors in Two Different Regions of the Human Brain

PubMed Central

van der Meer, Thomas P.; Artacho-Cordón, Francisco; Swaab, Dick F.; Struik, Dicky; Makris, Konstantinos C.; Wolffenbuttel, Bruce H. R.; Frederiksen, Hanne; van Vliet-Ostaptchouk, Jana V.

2017-01-01

Non-persistent endocrine disrupting chemicals (npEDCs) can affect multiple organs and systems in the body. Whether npEDCs can accumulate in the human brain is largely unknown. The major aim of this pilot study was to examine the presence of environmental phenols and parabens in two distinct brain regions: the hypothalamus and white-matter tissue. In addition, a potential association between these npEDCs concentrations and obesity was investigated. Post-mortem brain material was obtained from 24 individuals, made up of 12 obese and 12 normal-weight subjects (defined as body mass index (BMI) > 30 and BMI < 25 kg/m2, respectively). Nine phenols and seven parabens were measured by isotope dilution TurboFlow-LC-MS/MS. In the hypothalamus, seven suspect npEDCs (bisphenol A, triclosan, triclocarban and methyl-, ethyl-, n-propyl-, and benzyl paraben) were detected, while five npEDCs (bisphenol A, benzophenone-3, triclocarban, methyl-, and n-propyl paraben) were found in the white-matter brain tissue. We observed higher levels of methylparaben (MeP) in the hypothalamic tissue of obese subjects as compared to controls (p = 0.008). Our findings indicate that some suspected npEDCs are able to cross the blood–brain barrier. Whether the presence of npEDCs can adversely affect brain function and to which extent the detected concentrations are physiologically relevant needs to be further investigated. PMID:28902174

In vivo NMR imaging of sodium-23 in the human head.

PubMed

Hilal, S K; Maudsley, A A; Ra, J B; Simon, H E; Roschmann, P; Wittekoek, S; Cho, Z H; Mun, S K

1985-01-01

We report the first clinical nuclear magnetic resonance (NMR) images of cerebral sodium distribution in normal volunteers and in patients with a variety of pathological lesions. We have used a 1.5 T NMR magnet system. When compared with proton distribution, sodium shows a greater variation in its concentration from tissue to tissue and from normal to pathological conditions. Image contrast calculated on the basis of sodium concentration is 7 to 18 times greater than that of proton spin density. Normal images emphasize the extracellular compartments. In the clinical studies, areas of recent or old cerebral infarction and tumors show a pronounced increase of sodium content (300-400%). Actual measurements of image density values indicate that there is probably a further accentuation of the contrast by the increased "NMR visibility" of sodium in infarcted tissue. Sodium imaging may prove to be a more sensitive means for early detection of some brain disorders than other imaging methods.

Mathematical modeling of the malignancy of cancer using graph evolution.

PubMed

Gunduz-Demir, Cigdem

2007-10-01

We report a novel computational method based on graph evolution process to model the malignancy of brain cancer called glioma. In this work, we analyze the phases that a graph passes through during its evolution and demonstrate strong relation between the malignancy of cancer and the phase of its graph. From the photomicrographs of tissues, which are diagnosed as normal, low-grade cancerous and high-grade cancerous, we construct cell-graphs based on the locations of cells; we probabilistically generate an edge between every pair of cells depending on the Euclidean distance between them. For a cell-graph, we extract connectivity information including the properties of its connected components in order to analyze the phase of the cell-graph. Working with brain tissue samples surgically removed from 12 patients, we demonstrate that cell-graphs generated for different tissue types evolve differently and that they exhibit different phase properties, which distinguish a tissue type from another.

Raman spectroscopy for diagnosis of glioblastoma multiforme

NASA Astrophysics Data System (ADS)

Clary, Candace Elise

Glioblastoma multiforme (GBM), the most common and most fatal malignant brain tumor, is highly infiltrative and incurable. Although improved prognosis has been demonstrated by surgically resecting the bulk tumor, a lack of clear borders at the tumor margins complicates the selection decision during surgery. This dissertation investigates the potential of Raman spectroscopy for distinguishing between normal and malignant brain tissue and sets the groundwork for a surgical diagnostic guide for resection of gross malignant gliomas. These studies revealed that Raman spectroscopy was capable of discriminating between normal scid mouse brain tissue and human xenograft tumors induced in those mice. The spectra of normal and malignant tissue were normalized by dividing by the respective magnitudes of the peaks near 1440 cm -1. Spectral differences include the shape of the broad peaks near 1440 cm-1 and 1660 cm-1 and the relative magnitudes of the peaks at 1264 cm-1, 1287 cm-1, 1297 cm-1, 1556 cm -1, 1586 cm-1, 1614 cm-1, and 1683 cm-1. From these studies emerged questions regarding how to objectively normalize and compare spectra for future automation. Some differences in the Raman spectra were shown to be inherent in the disease states of the cells themselves via differences in the Raman spectra of normal human astrocytes in culture and cultured cells derived from GBM tumors. The spectra of astrocytes and glioma cells were normalized by dividing by the respective magnitudes of the peaks near 1450 cm-1. The differences between the Raman spectra of normal and transformed cells include the ratio of the 1450 cm-1/1650 cm-1 peaks and the relative magnitudes of the peaks at 1181 cm-1, 1191 cm-1, 1225 cm-1, 1263 cm -1, 1300 cm-1, 1336 cm-1, 1477 cm-1, 1494 cm-1, and 1695 cm -1. Previous Raman spectroscopic studies of biological cells have shown that the magnitude of the Raman signal decreases over time, indicating sample damage. Cells exposed to laser excitation at similar power densities were evaluated in terms of mitochondrial oxidative/reductive activity as well as protein, RNA, and DNA syntheses. Although cell death was not significant, the cells' abilities to synthesize DNA, RNA, and protein were profoundly affected by the laser irradiation.

Hierarchical brain tissue segmentation and its application in multiple sclerosis and Alzheimer's disease

NASA Astrophysics Data System (ADS)

Lei, Tianhu; Udupa, Jayaram K.; Moonis, Gul; Schwartz, Eric; Balcer, Laura

2005-04-01

Based on Fuzzy Connectedness (FC) object delineation principles and algorithms, a hierarchical brain tissue segmentation technique has been developed for MR images. After MR image background intensity inhomogeneity correction and intensity standardization, three FC objects for cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM) are generated via FC object delineation, and an intracranial (IC) mask is created via morphological operations. Then, the IC mask is decomposed into parenchymal (BP) and CSF masks, while the BP mask is separated into WM and GM masks. WM mask is further divided into pure and dirty white matter masks (PWM and DWM). In Multiple Sclerosis studies, a severe white matter lesion (LS) mask is defined from DWM mask. Based on the segmented brain tissue images, a histogram-based method has been developed to find disease-specific, image-based quantitative markers for characterizing the macromolecular manifestation of the two diseases. These same procedures have been applied to 65 MS (46 patients and 19 normal subjects) and 25 AD (15 patients and 10 normal subjects) data sets, each of which consists of FSE PD- and T2-weighted MR images. Histograms representing standardized PD and T2 intensity distributions and their numerical parameters provide an effective means for characterizing the two diseases. The procedures are systematic, nearly automated, robust, and the results are reproducible.

Dynamic changes in oxygenation of intracranial tumor and contralateral brain during tumor growth and carbogen breathing: A multisite EPR oximetry with implantable resonators

PubMed Central

Hou, Huagang; Dong, Ruhong; Li, Hongbin; Williams, Benjamin; Lariviere, Jean P.; Hekmatyar, S.K.; Kauppinen, Risto A.; Khan, Nadeem; Swartz, Harold

2013-01-01

Introduction Several techniques currently exist for measuring tissue oxygen; however technical difficulties have limited their usefulness and general application. We report a recently developed electron paramagnetic resonance (EPR) oximetry approach with multiple probe implantable resonators (IRs) that allow repeated measurements of oxygen in tissue at depths of greater than 10 mm. Methods The EPR signal to noise (S/N) ratio of two probe IRs was compared with that of LiPc deposits. The feasibility of intracranial tissue pO2 measurements by EPR oximetry using IRs was tested in normal rats and rats bearing intracerebral F98 tumors. The dynamic changes in the tissue pO2 were assessed during repeated hyperoxia with carbogen breathing. Results A 6–10 times increase in the S/N ratio was observed with IRs as compared to LiPc deposits. The mean brain pO2 of normal rats was stable and increased significantly during carbogen inhalation in experiments repeated for 3 months. The pO2 of F98 glioma declined gradually, while the pO2 of contralateral brain essentially remained the same. Although a significant increase in the glioma pO2 was observed during carbogen inhalation, this effect declined in experiments repeated over days. Conclusion EPR oximetry with IRs provides a significant increase in S/N ratio. The ability to repeatedly assess orthotopic glioma pO2 is likely to play a vital role in understanding the dynamics of tissue pO2 during tumor growth and therapies designed to modulate tumor hypoxia. This information could then be used to optimize chemoradiation by scheduling treatments at times of increased glioma oxygenation. PMID:22033225

Virtual wall-based haptic-guided teleoperated surgical robotic system for single-port brain tumor removal surgery.

PubMed

Seung, Sungmin; Choi, Hongseok; Jang, Jongseong; Kim, Young Soo; Park, Jong-Oh; Park, Sukho; Ko, Seong Young

2017-01-01

This article presents a haptic-guided teleoperation for a tumor removal surgical robotic system, so-called a SIROMAN system. The system was developed in our previous work to make it possible to access tumor tissue, even those that seat deeply inside the brain, and to remove the tissue with full maneuverability. For a safe and accurate operation to remove only tumor tissue completely while minimizing damage to the normal tissue, a virtual wall-based haptic guidance together with a medical image-guided control is proposed and developed. The virtual wall is extracted from preoperative medical images, and the robot is controlled to restrict its motion within the virtual wall using haptic feedback. Coordinate transformation between sub-systems, a collision detection algorithm, and a haptic-guided teleoperation using a virtual wall are described in the context of using SIROMAN. A series of experiments using a simplified virtual wall are performed to evaluate the performance of virtual wall-based haptic-guided teleoperation. With haptic guidance, the accuracy of the robotic manipulator's trajectory is improved by 57% compared to one without. The tissue removal performance is also improved by 21% ( p < 0.05). The experiments show that virtual wall-based haptic guidance provides safer and more accurate tissue removal for single-port brain surgery.

A Device for Long-Term Perfusion, Imaging, and Electrical Interfacing of Brain Tissue In vitro

PubMed Central

Killian, Nathaniel J.; Vernekar, Varadraj N.; Potter, Steve M.; Vukasinovic, Jelena

2016-01-01

Distributed microelectrode array (MEA) recordings from consistent, viable, ≥500 μm thick tissue preparations over time periods from days to weeks may aid in studying a wide range of problems in neurobiology that require in vivo-like organotypic morphology. Existing tools for electrically interfacing with organotypic slices do not address necrosis that inevitably occurs within thick slices with limited diffusion of nutrients and gas, and limited removal of waste. We developed an integrated device that enables long-term maintenance of thick, functionally active, brain tissue models using interstitial perfusion and distributed recordings from thick sections of explanted tissue on a perforated multi-electrode array. This novel device allows for automated culturing, in situ imaging, and extracellular multi-electrode interfacing with brain slices, 3-D cell cultures, and potentially other tissue culture models. The device is economical, easy to assemble, and integrable with standard electrophysiology tools. We found that convective perfusion through the culture thickness provided a functional benefit to the preparations as firing rates were generally higher in perfused cultures compared to their respective unperfused controls. This work is a step toward the development of integrated tools for days-long experiments with more consistent, healthier, thicker, and functionally more active tissue cultures with built-in distributed electrophysiological recording and stimulation functionality. The results may be useful for the study of normal processes, pathological conditions, and drug screening strategies currently hindered by the limitations of acute (a few hours long) brain slice preparations. PMID:27065793

Noninvasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI-guided focused ultrasound

PubMed Central

Miller, G. Wilson; Song, Ji; Louttit, Cameron; Klibanov, Alexander L; Shih, Ting-Yu; Swaminathan, Ganesh; Tamargo, Rafael J.; Woodworth, Graeme F.; Hanes, Justin; Price, Richard J.

2014-01-01

The blood-brain barrier (BBB) presents a significant obstacle for the treatment of many central nervous system (CNS) disorders, including invasive brain tumors, Alzheimer’s, Parkinson’s and stroke. Therapeutics must be capable of bypassing the BBB and also penetrate the brain parenchyma to achieve a desired effect within the brain. In this study, we test the unique combination of a noninvasive approach to BBB permeabilization with a therapeutically relevant polymeric nanoparticle platform capable of rapidly penetrating within the brain microenvironment. MR-guided focused ultrasound (FUS) with intravascular microbubbles (MBs) is able to locally and reversibly disrupt the BBB with submillimeter spatial accuracy. Densely poly(ethylene-co-glycol) (PEG) coated, brain-penetrating nanoparticles (BPNs) are long-circulating and diffuse 10-fold slower in normal rat brain tissue compared to diffusion in water. Following intravenous administration of model and biodegradable BPN in normal healthy rats, we demonstrate safe, pressure-dependent delivery of 60 nm BPNs to the brain parenchyma in regions where the BBB is disrupted by FUS and MBs. Delivery of BPNs with MR-guided FUS has the potential to improve efficacy of treatments for many CNS diseases, while reducing systemic side effects by providing sustained, well-dispersed drug delivery into select regions of the brain. PMID:24979210

Baicalin Attenuates Subarachnoid Hemorrhagic Brain Injury by Modulating Blood-Brain Barrier Disruption, Inflammation, and Oxidative Damage in Mice

PubMed Central

Fu, Yongjian; Zhang, SongSong; Ding, Hao; Chen, Jin

2017-01-01

In subarachnoid hemorrhagic brain injury, the early crucial events are edema formation due to inflammatory responses and blood-brain barrier disruption. Baicalin, a flavone glycoside, has antineuroinflammatory and antioxidant properties. We examined the effect of baicalin in subarachnoid hemorrhagic brain injury. Subarachnoid hemorrhage was induced through filament perforation and either baicalin or vehicle was administered 30 min prior to surgery. Brain tissues were collected 24 hours after surgery after evaluation of neurological scores. Brain tissues were processed for water content, real-time PCR, and immunoblot analyses. Baicalin improved neurological score and brain water content. Decreased levels of tight junction proteins (occludin, claudin-5, ZO-1, and collagen IV) required for blood-brain barrier function were restored to normal level by baicalin. Real-time PCR data demonstrated that baicalin attenuated increased proinflammatory cytokine (IL-1β, IL-6, and CXCL-3) production in subarachnoid hemorrhage mice. In addition to that, baicalin attenuated microglial cell secretion of IL-1β and IL-6 induced by lipopolysaccharide (100 ng/ml) dose dependently. Finally, baicalin attenuated induction of NOS-2 and NOX-2 in SAH mice at the mRNA and protein level. Thus, we demonstrated that baicalin inhibited microglial cell activation and reduced inflammation, oxidative damage, and brain edema. PMID:28912935

R2* mapping for brain iron: associations with cognition in normal aging.

PubMed

Ghadery, Christine; Pirpamer, Lukas; Hofer, Edith; Langkammer, Christian; Petrovic, Katja; Loitfelder, Marisa; Schwingenschuh, Petra; Seiler, Stephan; Duering, Marco; Jouvent, Eric; Schmidt, Helena; Fazekas, Franz; Mangin, Jean-Francois; Chabriat, Hugues; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

2015-02-01

Brain iron accumulates during aging and has been associated with neurodegenerative disorders including Alzheimer's disease. Magnetic resonance (MR)-based R2* mapping enables the in vivo detection of iron content in brain tissue. We investigated if during normal brain aging iron load relates to cognitive impairment in region-specific patterns in a community-dwelling cohort of 336 healthy, middle aged, and older adults from the Austrian Stroke Prevention Family Study. MR imaging and R2* mapping in the basal ganglia and neocortex were done at 3T. Comprehensive neuropsychological testing assessed memory, executive function, and psychomotor speed. We found the highest iron concentration in the globus pallidus, and pallidal and putaminal iron was significantly and inversely associated with cognitive performance in all cognitive domains, except memory. These associations were iron load dependent. Vascular brain lesions and brain volume did not mediate the relationship between iron and cognitive performance. We conclude that higher R2*-determined iron in the basal ganglia correlates with cognitive impairment during brain aging independent of concomitant brain abnormalities. The prognostic significance of this finding needs to be determined. Copyright © 2015 Elsevier Inc. All rights reserved.

Optimized magnetic resonance diffusion protocol for ex-vivo whole human brain imaging with a clinical scanner

NASA Astrophysics Data System (ADS)

Scherrer, Benoit; Afacan, Onur; Stamm, Aymeric; Singh, Jolene; Warfield, Simon K.

2015-03-01

Diffusion-weighted magnetic resonance imaging (DW-MRI) provides a novel insight into the brain to facilitate our understanding of the brain connectivity and microstructure. While in-vivo DW-MRI enables imaging of living patients and longitudinal studies of brain changes, post-mortem ex-vivo DW-MRI has numerous advantages. Ex-vivo imaging benefits from greater resolution and sensitivity due to the lack of imaging time constraints; the use of tighter fitting coils; and the lack of movement artifacts. This allows characterization of normal and abnormal tissues with unprecedented resolution and sensitivity, facilitating our ability to investigate anatomical structures that are inaccessible in-vivo. This also offers the opportunity to develop today novel imaging biomarkers that will, with tomorrow's MR technology, enable improved in-vivo assessment of the risk of disease in an individual. Post-mortem studies, however, generally rely on the fixation of specimen to inhibit tissue decay which starts as soon as tissue is deprived from its blood supply. Unfortunately, fixation of tissues substantially alters tissue diffusivity profiles. In addition, ex-vivo DW-MRI requires particular care when packaging the specimen because the presence of microscopic air bubbles gives rise to geometric and intensity image distortion. In this work, we considered the specific requirements of post-mortem imaging and designed an optimized protocol for ex-vivo whole brain DW-MRI using a human clinical 3T scanner. Human clinical 3T scanners are available to a large number of researchers and, unlike most animal scanners, have a bore diameter large enough to image a whole human brain. Our optimized protocol will facilitate widespread ex-vivo investigations of large specimen.

Predictive modeling of neuroanatomic structures for brain atrophy detection

NASA Astrophysics Data System (ADS)

Hu, Xintao; Guo, Lei; Nie, Jingxin; Li, Kaiming; Liu, Tianming

2010-03-01

In this paper, we present an approach of predictive modeling of neuroanatomic structures for the detection of brain atrophy based on cross-sectional MRI image. The underlying premise of applying predictive modeling for atrophy detection is that brain atrophy is defined as significant deviation of part of the anatomy from what the remaining normal anatomy predicts for that part. The steps of predictive modeling are as follows. The central cortical surface under consideration is reconstructed from brain tissue map and Regions of Interests (ROI) on it are predicted from other reliable anatomies. The vertex pair-wise distance between the predicted vertex and the true one within the abnormal region is expected to be larger than that of the vertex in normal brain region. Change of white matter/gray matter ratio within a spherical region is used to identify the direction of vertex displacement. In this way, the severity of brain atrophy can be defined quantitatively by the displacements of those vertices. The proposed predictive modeling method has been evaluated by using both simulated atrophies and MRI images of Alzheimer's disease.

Evaluation of reference genes for quantitative real-time RT-PCR analysis of gene expression in Nile tilapia (Oreochromis niloticus).

PubMed

Yang, Chang Geng; Wang, Xian Li; Tian, Juan; Liu, Wei; Wu, Fan; Jiang, Ming; Wen, Hua

2013-09-15

Quantitative real-time reverse-transcriptase polymerase chain reaction (RT-qPCR) has been used frequently to study gene expression related to fish immunology. In such studies, a stable reference gene should be selected to correct the expression of the target gene. In this study, seven candidate reference genes (glyceraldehyde-3-phosphate dehydrogenase (GADPH), ubiquitin-conjugating enzyme (UBCE), 18S ribosomal RNA (18S rRNA), beta-2-microglobulin (B2M), elongation factor 1 alpha (EF1A), tubulin alpha chain-like (TUBA) and beta actin (ACTB)), were selected to analyze their stability and normalization in seven tissues (liver, spleen, kidney, brain, heart, muscle and intestine) of Nile tilapia (Oreochromis niloticus) challenged with Streptococcus agalactiae or Streptococcus iniae, respectively. The results showed that all the candidate reference genes exhibited tissue-dependent transcriptional variations. With PBS injection as a control, UBCE was the most stable and suitable single reference gene in the intestine, liver, brain, kidney, and spleen after S. iniae infection, and in the liver, kidney, and spleen after S. agalactiae infection. EF1A was the most suitable in heart and muscle after S. iniae or S. agalactiae infection. GADPH was the most suitable gene in intestine and brain after S. agalactiae infection. In normal conditions, UBCE and 18S rRNA were the most stably expressed genes across the various tissues. These results showed that for RT-qPCR analysis of tilapia, selecting two or more reference genes may be more suitable for cross-tissue analysis of gene expression. Copyright © 2013 Elsevier B.V. All rights reserved.

Application of Texture Analysis to Study Small Vessel Disease and Blood-Brain Barrier Integrity.

PubMed

Valdés Hernández, Maria Del C; González-Castro, Victor; Chappell, Francesca M; Sakka, Eleni; Makin, Stephen; Armitage, Paul A; Nailon, William H; Wardlaw, Joanna M

2017-01-01

We evaluate the alternative use of texture analysis for evaluating the role of blood-brain barrier (BBB) in small vessel disease (SVD). We used brain magnetic resonance imaging from 204 stroke patients, acquired before and 20 min after intravenous gadolinium administration. We segmented tissues, white matter hyperintensities (WMH) and applied validated visual scores. We measured textural features in all tissues pre- and post-contrast and used ANCOVA to evaluate the effect of SVD indicators on the pre-/post-contrast change, Kruskal-Wallis for significance between patient groups and linear mixed models for pre-/post-contrast variations in cerebrospinal fluid (CSF) with Fazekas scores. Textural "homogeneity" increase in normal tissues with higher presence of SVD indicators was consistently more overt than in abnormal tissues. Textural "homogeneity" increased with age, basal ganglia perivascular spaces scores ( p  < 0.01) and SVD scores ( p  < 0.05) and was significantly higher in hypertensive patients ( p  < 0.002) and lacunar stroke ( p  = 0.04). Hypertension (74% patients), WMH load (median = 1.5 ± 1.6% of intracranial volume), and age (mean = 65.6 years, SD = 11.3) predicted the pre/post-contrast change in normal white matter, WMH, and index stroke lesion. CSF signal increased with increasing SVD post-contrast. A consistent general pattern of increasing textural "homogeneity" with increasing SVD and post-contrast change in CSF with increasing WMH suggest that texture analysis may be useful for the study of BBB integrity.

Role of mechanical factors in cortical folding development

NASA Astrophysics Data System (ADS)

Razavi, Mir Jalil; Zhang, Tuo; Li, Xiao; Liu, Tianming; Wang, Xianqiao

2015-09-01

Deciphering mysteries of the structure-function relationship in cortical folding has emerged as the cynosure of recent research on brain. Understanding the mechanism of convolution patterns can provide useful insight into the normal and pathological brain function. However, despite decades of speculation and endeavors the underlying mechanism of the brain folding process remains poorly understood. This paper focuses on the three-dimensional morphological patterns of a developing brain under different tissue specification assumptions via theoretical analyses, computational modeling, and experiment verifications. The living human brain is modeled with a soft structure having outer cortex and inner core to investigate the brain development. Analytical interpretations of differential growth of the brain model provide preliminary insight into the critical growth ratio for instability and crease formation of the developing brain followed by computational modeling as a way to offer clues for brain's postbuckling morphology. Especially, tissue geometry, growth ratio, and material properties of the cortex are explored as the most determinant parameters to control the morphogenesis of a growing brain model. As indicated in results, compressive residual stresses caused by the sufficient growth trigger instability and the brain forms highly convoluted patterns wherein its gyrification degree is specified with the cortex thickness. Morphological patterns of the developing brain predicted from the computational modeling are consistent with our neuroimaging observations, thereby clarifying, in part, the reason of some classical malformation in a developing brain.

Real-time hemodynamic response and mitochondrial function changes with intracarotid mannitol injection

PubMed Central

Joshi, Shailendra; Singh-Moon, Rajinder; Wang, Mei; Bruce, Jeffrey N.; Bigio, Irving J.; Mayevsky, Avraham

2014-01-01

Disruption of blood brain barrier (BBB) is used to enhance chemotherapeutic drug delivery. The purpose of this study was to understand the time course of hemodynamic and metabolic response to intraarterial (IA) mannitol infusions in order to optimize the delivery of drugs for treating brain tumors. Principal results We compared hemodynamic response, EEG changes, and mitochondrial function as judged by relative changes in tissue NADH concentrations, after intracarotid (IC) infusion of equal volumes of normal saline and mannitol in our rabbit IC drug delivery model. We observed significantly greater, though transient, hyperemic response to IC infusion of mannitol compared to normal saline. Infusion of mannitol also resulted in a greater increase in tissue NADH concentrations relative to the baseline. These hemodynamic, and metabolic changes returned to baseline within 5 min of mannitol injection. Conclusion Significant, though transient, changes in blood flow and brain metabolism occur with IA mannitol infusion. The observed transient hyperemia would suggest that intravenous (IV) chemotherapy should be administered either just before, or concurrent with IA mannitol injections. On the other hand, IA chemotherapy should be delayed until the peak hyperemic response has subsided. PMID:24440631

Transmembrane protein CD9 is glioblastoma biomarker, relevant for maintenance of glioblastoma stem cells

PubMed Central

Podergajs, Neža; Motaln, Helena; Rajčević, Uroš; Verbovšek, Urška; Koršič, Marjan; Obad, Nina; Espedal, Heidi; Vittori, Miloš; Herold-Mende, Christel; Miletic, Hrvoje; Bjerkvig, Rolf; Turnšek, Tamara Lah

2016-01-01

The cancer stem cell model suggests that glioblastomas contain a subpopulation of stem-like tumor cells that reproduce themselves to sustain tumor growth. Targeting these cells thus represents a novel treatment strategy and therefore more specific markers that characterize glioblastoma stem cells need to be identified. In the present study, we performed transcriptomic analysis of glioblastoma tissues compared to normal brain tissues revealing sensible up-regulation of CD9 gene. CD9 encodes the transmembrane protein tetraspanin which is involved in tumor cell invasion, apoptosis and resistance to chemotherapy. Using the public REMBRANDT database for brain tumors, we confirmed the prognostic value of CD9, whereby a more than two fold up-regulation correlates with shorter patient survival. We validated CD9 gene and protein expression showing selective up-regulation in glioblastoma stem cells isolated from primary biopsies and in primary organotypic glioblastoma spheroids as well as in U87-MG and U373 glioblastoma cell lines. In contrast, no or low CD9 gene expression was observed in normal human astrocytes, normal brain tissue and neural stem cells. CD9 silencing in three CD133+ glioblastoma cell lines (NCH644, NCH421k and NCH660h) led to decreased cell proliferation, survival, invasion, and self-renewal ability, and altered expression of the stem-cell markers CD133, nestin and SOX2. Moreover, CD9-silenced glioblastoma stem cells showed altered activation patterns of the Akt, MapK and Stat3 signaling transducers. Orthotopic xenotransplantation of CD9-silenced glioblastoma stem cells into nude rats promoted prolonged survival. Therefore, CD9 should be further evaluated as a target for glioblastoma treatment. PMID:26573230

Leptin action in the ventromedial hypothalamic nucleus is sufficient, but not necessary, to normalize diabetic hyperglycemia.

PubMed

Meek, Thomas H; Matsen, Miles E; Dorfman, Mauricio D; Guyenet, Stephan J; Damian, Vincent; Nguyen, Hong T; Taborsky, Gerald J; Morton, Gregory J

2013-09-01

In rodent models of type 1 diabetes, leptin administration into brain ventricles normalizes blood glucose at doses that have no effect when given peripherally. The ventromedial nucleus of the hypothalamus (VMN) is a potential target for leptin's antidiabetic effects because leptin-sensitive neurons in this brain area are implicated in glucose homeostasis. To test this hypothesis, we injected leptin directly into the bilateral VMN of rats with streptozotocin-induced uncontrolled diabetes mellitus. This intervention completely normalized both hyperglycemia and the elevated rates of hepatic glucose production and plasma glucagon levels but had no effect on tissue glucose uptake in the skeletal muscle or brown adipose tissue as measured using tracer dilution techniques during a basal clamp. To determine whether VMN leptin signaling is required for leptin-mediated normalization of diabetic hyperglycemia, we studied mice in which the leptin receptor gene was deleted in VMN steroidogenic factor 1 neurons using cre-loxP technology. Our findings indicate leptin action within these neurons is not required for the correction of diabetic hyperglycemia by central leptin infusion. We conclude that leptin signaling in the VMN is sufficient to mediate leptin's antidiabetic action but may not be necessary for this effect. Leptin action within a distributed neuronal network may mediate its effects on glucose homeostasis.

Towards High-Resolution Tissue Imaging Using Nanospray Desorption Electrospray Ionization Mass Spectrometry Coupled to Shear Force Microscopy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Son N.; Sontag, Ryan L.; Carson, James P.

Constant mode ambient mass spectrometry imaging (MSI) of tissue sections with high lateral resolution of better than 10 µm was performed by combining shear force microscopy with nanospray desorption electrospray ionization (nano-DESI). Shear force microscopy enabled precise control of the distance between the sample and nano-DESI probe during MSI experiments and provided information on sample topography. Proof-of-concept experiments were performed using lung and brain tissue sections representing spongy and dense tissues, respectively. Topography images obtained using shear force microscopy were comparable to the results obtained using contact profilometry over the same region of the tissue section. Variations in tissue heightmore » were found to be dependent on the tissue type and were in the range of 0-5 µm for lung tissue and 0-3 µm for brain tissue sections. Ion images of phospholipids obtained in this study are in good agreement with literature data. Normalization of nano-DESI MSI images to the signal of the internal standard added to the extraction solvent allowed us to construct high-resolution ion images free of matrix effects.« less

Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker

PubMed Central

Valdés, Pablo A.; Leblond, Frederic; Kim, Anthony; Harris, Brent T.; Wilson, Brian C.; Fan, Xiaoyao; Tosteson, Tor D.; Hartov, Alex; Ji, Songbai; Erkmen, Kadir; Simmons, Nathan E.; Paulsen, Keith D.; Roberts, David W.

2011-01-01

Object Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies. Methods The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board–approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo. Results A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeon's visual perception were classified correctly in an analysis of all tumors. Conclusions These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of intracranial tumors. PMID:21438658

Good news–bad news: the Yin and Yang of immune privilege in the eye

PubMed Central

Forrester, John V.; Xu, Heping

2012-01-01

The eye and the brain are prototypical tissues manifesting immune privilege (IP) in which immune responses to foreign antigens, particularly alloantigens are suppressed, and even completely inhibited. Explanations for this phenomenon are numerous and mostly reflect our evolving understanding of the molecular and cellular processes underpinning immunological responses generally. IP is now viewed as a property of many tissues and the level of expression of IP varies not only with the tissue but with the nature of the foreign antigen and changes in the limited conditions under which privilege can operate as a mechanism of immunological tolerance. As a result, IP functions normally as a homeostatic mechanism preserving normal function in tissues, particularly those with highly specialized function and limited capacity for renewal such as the eye and brain. However, IP is relatively easily bypassed in the face of a sufficiently strong immunological response, and the privileged tissues may be at greater risk of collateral damage because its natural defenses are more easily breached than in a fully immunocompetent tissue which rapidly rejects foreign antigen and restores integrity. This two-edged sword cuts its swathe through the eye: under most circumstances, IP mechanisms such as blood–ocular barriers, intraocular immune modulators, induction of T regulatory cells, lack of lymphatics, and other properties maintain tissue integrity; however, when these are breached, various degrees of tissue damage occur from severe tissue destruction in retinal viral infections and other forms of uveoretinal inflammation, to less severe inflammatory responses in conditions such as macular degeneration. Conversely, ocular IP and tumor-related IP can combine to permit extensive tumor growth and increased risk of metastasis thus threatening the survival of the host. PMID:23230433

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khatoon, S.; Slevin, J.T.; Haley, B.E.

A decrease occurs (80-100%) in the (/sup 32/P)8N/sub 3/GTP photoinsertion into a cytosolic protein (55K M/sub r/) of Alzheimer's (AD) brain, tentatively identified as the ..beta..-subunit of tubulin (co-migration with purified tubulin, concentration dependence of interaction with GTP, ATP and their 8-azido photoprobes, and similar effects of Ca/sup 2 +/ and EDTA on photoinsertion). This agrees with prior observations of (/sup 32/P)8N/sub 3/GTP interactions with brain tubulin and a recent report on faulty microtubular assembly in AD brain. The decrease in (/sup 32/P)8N/sub 3/GTP photoinsertion into the 55K M/sub r/ protein of AD brain was in contrast with other photolabeledmore » proteins, which remained at equal levels in AD and age-matched normal brain tissues. The 55K and 45K M/sub r/ were the two major (/sup 32/P)8N/sub 3/GTP photoinsertion species in non-AD brain. Of 5 AD brains, the photoinsertion of (/sup 32/P)8N/sub 3/GTP into the 55K M/sub r/ region was low or absent in 4 (55K/45K=0.1); one was 75% below normals (55K/45K=0.24). Total protein migrating at 55K M/sub r/ was similar in AD and controls. AD brain tubulin, while present, has its exchangeable GTP binding site on ..beta..-tubulin blocked/modified such that (/sup 32/P)8N/sub 3/GTP cannot interact normally with this site.« less

In vivo administration of fluorescent dextrans for the specific and sensitive localization of brain vascular pericytes and their characterization in normal and neurotoxin exposed brains.

PubMed

Sarkar, Sumit; Schmued, Larry

2012-06-01

We have aimed to develop novel histochemical markers for the labeling of brain pericytes and characterize their morphology in the normal and the excitotoxin-exposed brain, as this class of cells has received little attention until recently. Pericyte labeling was accomplished by the intracerebroventricular injection of certain fluorescent dextran conjugates, such as Fluoro-Gold-dextran, FR-dextran, FITC-dextran and Fluoro-Turquoise (FT)-dextran. 1-7 days after the tracer injection, extensive labeling of vascular pericytes was seen throughout the entire brain. These cells were found distal to the endothelial cells and exhibited large dye containing vacuoles. The morphology of the pericytes was somewhat variable, exhibiting round or amoeboid shapes within larger intracellular vesicles, while those wrapping around capillaries exhibited a more elongated appearance with finger-like projections. The use of FG-dextran resulted in bluish yellow fluorescently labeled pericytes, while FR-dextran resulted in red fluorescent labeled pericytes, FITC-dextran exhibited green fluorescent pericytes and FT-dextran showed fluorescent blue pericytes in the brain. We have used these tracers to study possible changes in morphology and pericyte number following kainic acid insult, observing that the number of pericytes in the injured or lesioned areas of the brain is dramatically reduced compared to the non-injured areas. These novel fluorochromes should be of use for studies involving the detection and localization of pericytes in both normal and pathological brain tissues. Published by Elsevier B.V.

Intracavitary moderator balloon combined with 252Cf brachytherapy and boron neutron capture therapy, improving dosimetry in brain tumour and infiltrations

PubMed Central

Brandão, S F

2015-01-01

Objective: This article proposes a combination of californium-252 (252Cf) brachytherapy, boron neutron capture therapy (BNCT) and an intracavitary moderator balloon catheter applied to brain tumour and infiltrations. Methods: Dosimetric evaluations were performed on three protocol set-ups: 252Cf brachytherapy combined with BNCT (Cf-BNCT); Cf-BNCT with a balloon catheter filled with light water (LWB) and the same set-up with heavy water (HWB). Results: Cf-BNCT-HWB has presented dosimetric advantages to Cf-BNCT-LWB and Cf-BNCT in infiltrations at 2.0–5.0 cm from the balloon surface. However, Cf-BNCT-LWB has shown superior dosimetry up to 2.0 cm from the balloon surface. Conclusion: Cf-BNCT-HWB and Cf-BNCT-LWB protocols provide a selective dose distribution for brain tumour and infiltrations, mainly further from the 252Cf source, sparing the normal brain tissue. Advances in knowledge: Malignant brain tumours grow rapidly and often spread to adjacent brain tissues, leading to death. Improvements in brain radiation protocols have been continuously achieved; however, brain tumour recurrence is observed in most cases. Cf-BNCT-LWB and Cf-BNCT-HWB represent new modalities for selectively combating brain tumour infiltrations and metastasis. PMID:25927876

Brain structure in sagittal craniosynostosis

NASA Astrophysics Data System (ADS)

Paniagua, Beatriz; Kim, Sunghyung; Moustapha, Mahmoud; Styner, Martin; Cody-Hazlett, Heather; Gimple-Smith, Rachel; Rumple, Ashley; Piven, Joseph; Gilmore, John; Skolnick, Gary; Patel, Kamlesh

2017-03-01

Craniosynostosis, the premature fusion of one or more cranial sutures, leads to grossly abnormal head shapes and pressure elevations within the brain caused by these deformities. To date, accepted treatments for craniosynostosis involve improving surgical skull shape aesthetics. However, the relationship between improved head shape and brain structure after surgery has not been yet established. Typically, clinical standard care involves the collection of diagnostic medical computed tomography (CT) imaging to evaluate the fused sutures and plan the surgical treatment. CT is known to provide very good reconstructions of the hard tissues in the skull but it fails to acquire good soft brain tissue contrast. This study intends to use magnetic resonance imaging to evaluate brain structure in a small dataset of sagittal craniosynostosis patients and thus quantify the effects of surgical intervention in overall brain structure. Very importantly, these effects are to be contrasted with normative shape, volume and brain structure databases. The work presented here wants to address gaps in clinical knowledge in craniosynostosis focusing on understanding the changes in brain volume and shape secondary to surgery, and compare those with normally developing children. This initial pilot study has the potential to add significant quality to the surgical care of a vulnerable patient population in whom we currently have limited understanding of brain developmental outcomes.

Visualising Androgen Receptor Activity in Male and Female Mice

PubMed Central

Dart, D. Alwyn; Waxman, Jonathan; Aboagye, Eric O.; Bevan, Charlotte L.

2013-01-01

Androgens, required for normal development and fertility of males and females, have vital roles in the reproductive tract, brain, cardiovascular system, smooth muscle and bone. Androgens function via the androgen receptor (AR), a ligand-dependent transcription factor. To assay and localise AR activity in vivo we generated the transgenic “ARE-Luc” mouse, expressing a luciferase reporter gene under the control of activated endogenous AR. In vivo imaging of androgen-mediated luciferase activity revealed several strongly expressing tissues in the male mouse as expected and also in certain female tissues. In males the testes, prostate, seminal vesicles and bone marrow all showed high AR activity. In females, strong activity was seen in the ovaries, uterus, omentum tissue and mammary glands. In both sexes AR expression and activity was also found in salivary glands, the eye (and associated glands), adipose tissue, spleen and, notably, regions of the brain. Luciferase protein expression was found in the same cell layers as androgen receptor expression. Additionally, mouse AR expression and activity correlated well with AR expression in human tissues. The anti-androgen bicalutamide reduced luciferase signal in all tissues. Our model demonstrates that androgens can act in these tissues directly via AR, rather than exclusively via androgen aromatisation to estrogens and activation of the estrogen receptor. Additionally, it visually demonstrates the fundamental importance of AR signalling outside the normal role in the reproductive organs. This model represents an important tool for physiological and developmental analysis of androgen signalling, and for characterization of known and novel androgenic or antiandrogenic compounds. PMID:23940781

Axonal abnormalities in vanishing white matter.

PubMed

Klok, Melanie D; Bugiani, Marianna; de Vries, Sharon I; Gerritsen, Wouter; Breur, Marjolein; van der Sluis, Sophie; Heine, Vivi M; Kole, Maarten H P; Baron, Wia; van der Knaap, Marjo S

2018-04-01

We aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter. Axons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single- and double-mutant mice and patient brain tissue. In addition, astrocyte-forebrain co-culture studies were performed. In the corpus callosum of Eif2b5- mutant mice, myelin sheath thickness, axonal diameter, and G-ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G-ratio in Eif2b5- mutant mice. In more severely affected Eif2b4-Eif2b5 double-mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5 -mutant mice. Co-cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal. In vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

Breakthrough: Fighting Cancer with Nanoparticles

ScienceCinema

Rozhkova, Elena

2018-05-07

Argonne nanoscientist Elena Rozhkova is studying ways to enlist nanoparticles to treat brain cancer. This nano-bio technology may eventually provide an alternative form of therapy that targets only cancer cells and does not affect normal living tissue. Read more at http://1.usa.gov/JAXh7Q.

Normalization of white matter intensity on T1-weighted images of patients with acquired central nervous system demyelination.

PubMed

Ghassemi, Rezwan; Brown, Robert; Narayanan, Sridar; Banwell, Brenda; Nakamura, Kunio; Arnold, Douglas L

2015-01-01

Intensity variation between magnetic resonance images (MRI) hinders comparison of tissue intensity distributions in multicenter MRI studies of brain diseases. The available intensity normalization techniques generally work well in healthy subjects but not in the presence of pathologies that affect tissue intensity. One such disease is multiple sclerosis (MS), which is associated with lesions that prominently affect white matter (WM). To develop a T1-weighted (T1w) image intensity normalization method that is independent of WM intensity, and to quantitatively evaluate its performance. We calculated median intensity of grey matter and intraconal orbital fat on T1w images. Using these two reference tissue intensities we calculated a linear normalization function and applied this to the T1w images to produce normalized T1w (NT1) images. We assessed performance of our normalization method for interscanner, interprotocol, and longitudinal normalization variability, and calculated the utility of the normalization method for lesion analyses in clinical trials. Statistical modeling showed marked decreases in T1w intensity differences after normalization (P < .0001). We developed a WM-independent T1w MRI normalization method and tested its performance. This method is suitable for longitudinal multicenter clinical studies for the assessment of the recovery or progression of disease affecting WM. Copyright © 2014 by the American Society of Neuroimaging.

Antenatal taurine reduces cerebral cell apoptosis in fetal rats with intrauterine growth restriction.

PubMed

Liu, Jing; Wang, Xiaofeng; Liu, Ying; Yang, Na; Xu, Jing; Ren, Xiaotun

2013-08-15

From pregnancy to parturition, Sprague-Dawley rats were daily administered a low protein diet to establish a model of intrauterine growth restriction. From the 12(th) day of pregnancy, 300 mg/kg rine was daily added to food until spontaneous delivery occurred. Brain tissues from normal neonatal rats at 6 hours after delivery, neonatal rats with intrauterine growth restriction, and neonatal rats with intrauterine growth restriction undergoing taurine supplement were obtained for further experiments. The terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling assay revealed that the number of apoptotic cells in the brain tissue of neonatal rats with intrauterine growth restriction significantly increased. Taurine supplement in pregnant rats reduced cell apoptosis in brain tissue from neonatal rats with intrauterine growth restriction. nohistochemical staining revealed that taurine supplement increased glial cell line-derived neurotrophic factor expression and decreased caspase-3 expression in the cerebral cortex of intrauterine growth-restricted fetal rats. These results indicate that taurine supplement reduces cell apoptosis through the glial cell line-derived neurotrophic factor-caspase-3 signaling pathway, resulting in a protective effect on the intrauterine growth-restricted fetal rat brain.

Antenatal taurine reduces cerebral cell apoptosis in fetal rats with intrauterine growth restriction

PubMed Central

Liu, Jing; Wang, Xiaofeng; Liu, Ying; Yang, Na; Xu, Jing; Ren, Xiaotun

2013-01-01

From pregnancy to parturition, Sprague-Dawley rats were daily administered a low protein diet to establish a model of intrauterine growth restriction. From the 12th day of pregnancy, 300 mg/kg rine was daily added to food until spontaneous delivery occurred. Brain tissues from normal neonatal rats at 6 hours after delivery, neonatal rats with intrauterine growth restriction, and neonatal rats with intrauterine growth restriction undergoing taurine supplement were obtained for further experiments. The terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling assay revealed that the number of apoptotic cells in the brain tissue of neonatal rats with intrauterine growth restriction significantly increased. Taurine supplement in pregnant rats reduced cell apoptosis in brain tissue from neonatal rats with intrauterine growth restriction. nohistochemical staining revealed that taurine supplement increased glial cell line-derived neurotrophic factor expression and decreased caspase-3 expression in the cerebral cortex of intrauterine growth-restricted fetal rats. These results indicate that taurine supplement reduces cell apoptosis through the glial cell line-derived neurotrophic factor-caspase-3 signaling pathway, resulting in a protective effect on the intrauterine growth-restricted fetal rat brain. PMID:25206528

A Head and Neck Simulator for Radiology and Radiotherapy

NASA Astrophysics Data System (ADS)

Thompson, Larissa; Campos, Tarcísio P. R.

2013-06-01

Phantoms are suitable tools to simulate body tissues and organs in radiology and radiation therapy. This study presents the development of a physical head and neck phantom and its radiological response for simulating brain pathology. The following features on the phantom are addressed and compared to human data: mass density, chemical composition, anatomical shape, computerized tomography images and Hounsfield Units. Mass attenuation and kerma coefficients of the synthetic phantom and normal tissues, as well as their deviations, were also investigated. Radiological experiments were performed, including brain tumors and subarachnoid hemorrhage simulations. Computerized tomography images of such pathologies in phantom and human were obtained. The anthropometric dimensions of the phantom present anatomical conformation similar to a human head and neck. Elemental weight percentages of the equivalent tissues match the human ones. Hounsfield Unit values of the main developed structures are presented, approaching human data. Kerma and mass attenuation coefficients spectra from human and phantom are presented, demonstrating smaller deviations in the radiological X-ray spectral domain. In conclusion, the phantom presented suitable normal and pathological radiological responses relative to those observed in humans. It may improve radiological protocols and education in medical imaging.

An Intraoperative Visualization System Using Hyperspectral Imaging to Aid in Brain Tumor Delineation

PubMed Central

Ortega, Samuel; M. Callicó, Gustavo; Juárez, Eduardo; Bulters, Diederik; Szolna, Adam; Piñeiro, Juan F.; Sosa, Coralia; J. O’Shanahan, Aruma; Bisshopp, Sara; Hernández, María; Morera, Jesús; Ravi, Daniele; Kiran, B. Ravi; Vega, Aurelio; Báez-Quevedo, Abelardo; Yang, Guang-Zhong; Stanciulescu, Bogdan; Sarmiento, Roberto

2018-01-01

Hyperspectral imaging (HSI) allows for the acquisition of large numbers of spectral bands throughout the electromagnetic spectrum (within and beyond the visual range) with respect to the surface of scenes captured by sensors. Using this information and a set of complex classification algorithms, it is possible to determine which material or substance is located in each pixel. The work presented in this paper aims to exploit the characteristics of HSI to develop a demonstrator capable of delineating tumor tissue from brain tissue during neurosurgical operations. Improved delineation of tumor boundaries is expected to improve the results of surgery. The developed demonstrator is composed of two hyperspectral cameras covering a spectral range of 400–1700 nm. Furthermore, a hardware accelerator connected to a control unit is used to speed up the hyperspectral brain cancer detection algorithm to achieve processing during the time of surgery. A labeled dataset comprised of more than 300,000 spectral signatures is used as the training dataset for the supervised stage of the classification algorithm. In this preliminary study, thematic maps obtained from a validation database of seven hyperspectral images of in vivo brain tissue captured and processed during neurosurgical operations demonstrate that the system is able to discriminate between normal and tumor tissue in the brain. The results can be provided during the surgical procedure (~1 min), making it a practical system for neurosurgeons to use in the near future to improve excision and potentially improve patient outcomes. PMID:29389893

An Intraoperative Visualization System Using Hyperspectral Imaging to Aid in Brain Tumor Delineation.

PubMed

Fabelo, Himar; Ortega, Samuel; Lazcano, Raquel; Madroñal, Daniel; M Callicó, Gustavo; Juárez, Eduardo; Salvador, Rubén; Bulters, Diederik; Bulstrode, Harry; Szolna, Adam; Piñeiro, Juan F; Sosa, Coralia; J O'Shanahan, Aruma; Bisshopp, Sara; Hernández, María; Morera, Jesús; Ravi, Daniele; Kiran, B Ravi; Vega, Aurelio; Báez-Quevedo, Abelardo; Yang, Guang-Zhong; Stanciulescu, Bogdan; Sarmiento, Roberto

2018-02-01

Hyperspectral imaging (HSI) allows for the acquisition of large numbers of spectral bands throughout the electromagnetic spectrum (within and beyond the visual range) with respect to the surface of scenes captured by sensors. Using this information and a set of complex classification algorithms, it is possible to determine which material or substance is located in each pixel. The work presented in this paper aims to exploit the characteristics of HSI to develop a demonstrator capable of delineating tumor tissue from brain tissue during neurosurgical operations. Improved delineation of tumor boundaries is expected to improve the results of surgery. The developed demonstrator is composed of two hyperspectral cameras covering a spectral range of 400-1700 nm. Furthermore, a hardware accelerator connected to a control unit is used to speed up the hyperspectral brain cancer detection algorithm to achieve processing during the time of surgery. A labeled dataset comprised of more than 300,000 spectral signatures is used as the training dataset for the supervised stage of the classification algorithm. In this preliminary study, thematic maps obtained from a validation database of seven hyperspectral images of in vivo brain tissue captured and processed during neurosurgical operations demonstrate that the system is able to discriminate between normal and tumor tissue in the brain. The results can be provided during the surgical procedure (~1 min), making it a practical system for neurosurgeons to use in the near future to improve excision and potentially improve patient outcomes.

ALA-induced PpIX spectroscopy for brain tumor image-guided surgery

NASA Astrophysics Data System (ADS)

Valdes, Pablo A.; Leblond, Frederic; Kim, Anthony; Harris, Brent T.; Wilson, Brian C.; Paulsen, Keith D.; Roberts, David W.

2011-03-01

Maximizing the extent of brain tumor resection correlates with improved survival and quality of life outcomes in patients. Optimal surgical resection requires accurate discrimination between normal and abnormal, cancerous tissue. We present our recent experience using quantitative optical spectroscopy in 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence-guided resection. Exogenous administration of ALA leads to preferential accumulation in tumor tissue of the fluorescent compound, PpIX, which can be used for in vivo surgical guidance. Using the state of the art approach with a fluorescence surgical microscope, we have been able to visualize a subset of brain tumors, but the sensitivity and accuracy of fluorescence detection for tumor tissue with this system are low. To take full advantage of the biological selectivity of PpIX accumulation in brain tumors, we used a quantitative optical spectroscopy system for in vivo measurements of PpIX tissue concentrations. We have shown that, using our quantitative approach for determination of biomarker concentrations, ALA-induced PpIX fluorescence-guidance can achieve accuracies of greater than 90% for most tumor histologies. Here we show multivariate analysis of fluorescence and diffuse reflectance signals in brain tumors with comparable diagnostic performance to our previously reported quantitative approach. These results are promising, since they show that technological improvements in current fluorescence-guided surgical technologies and more biologically relevant approaches are required to take full advantage of fluorescent biomarkers, achieve better tumor identification, increase extent of resection, and subsequently, lead to improve survival and quality of life in patients.

Long non-coding RNA DANCR facilitates glioma malignancy by sponging miR-33a-5p.

PubMed

Yang, J X; Sun, Y; Gao, L; Meng, Q; Yang, B Y

2018-06-26

Glioma is among the most fatal brain tumors characterized by a highly malignancy and rapid progression and early metastasis. Dysregulation of long non-coding RNA differentiation antagonizing non-protein coding RNA (LncRNA DANCR) is associated with the development, progression and metastasis of various cancers. In the present study, we investigated functional role of LncRNA DANCR in the malignancy of glioma. The results showed that LncRNA DANCR was increased in glioma tissues and cells compared with normal brain tissues and cells. DANCR expression was positively correlated with the malignancy and poor prognosis of glioma patients. DANCR contained a binding site of miR-33a-5p. miR-33a-5p was decreased in glioma tissues and cells compared with normal brain tissues and cells. Downregulation of miR-33a-5p was positively correlated with the malignancy and poor prognosis of glioma patients. In glioma tissues, the expression of DANCR was negatively correlated with the expression of miR-33a-5p. Downregulation of DANCR increased miR-33a-5p expression. miR-33a-5p mimic reduced the luciferase of DANCR-WT but not DANCR-MUT. DANCR pull-down showed the expression of miR-33a-5p. miR-33a-5p mimic enhanced knockdown of DANCR -induced inhibition of cell proliferation, migration, and EMT, and increase of apoptosis. Anti-miR-33a-5p reversed the effects of si- DANCR on cell malignancy. Knockdown of DANCR remarkably reduced the increase of tumor volumes in xenograft mouse models. In tumor tissues, knockdown of DANCR increased the expression of miR-33a-5p, reduced EMT and increased apoptosis. Our study provides novel insights in the functions of LncRNA DANCR-miR-33a-5p axis in tumorigenesis of glioma.

MO-F-CAMPUS-T-01: Radiosurgery of Multiple Brain Metastases with Single-Isocenter VMAT: Optimizing Treatment Geometry to Reduce Normal Brain Dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wu, Q; Snyder, K; Liu, C

Purpose: To develop an optimization algorithm to reduce normal brain dose by optimizing couch and collimator angles for single isocenter multiple targets treatment of stereotactic radiosurgery. Methods: Three metastatic brain lesions were retrospectively planned using single-isocenter volumetric modulated arc therapy (VMAT). Three matrices were developed to calculate the projection of each lesion on Beam’s Eye View (BEV) by the rotating couch, collimator and gantry respectively. The island blocking problem was addressed by computing the total area of open space between any two lesions with shared MLC leaf pairs. The couch and collimator angles resulting in the smallest open areas weremore » the optimized angles for each treatment arc. Two treatment plans with and without couch and collimator angle optimization were developed using the same objective functions and to achieve 99% of each target volume receiving full prescription dose of 18Gy. Plan quality was evaluated by calculating each target’s Conformity Index (CI), Gradient Index (GI), and Homogeneity index (HI), and absolute volume of normal brain V8Gy, V10Gy, V12Gy, and V14Gy. Results: Using the new couch/collimator optimization strategy, dose to normal brain tissue was reduced substantially. V8, V10, V12, and V14 decreased by 2.3%, 3.6%, 3.5%, and 6%, respectively. There were no significant differences in the conformity index, gradient index, and homogeneity index between two treatment plans with and without the new optimization algorithm. Conclusion: We have developed a solution to the island blocking problem in delivering radiation to multiple brain metastases with shared isocenter. Significant reduction in dose to normal brain was achieved by using optimal couch and collimator angles that minimize total area of open space between any of the two lesions with shared MLC leaf pairs. This technique has been integrated into Eclipse treatment system using scripting API.« less

Resected Brain Tissue, Seizure Onset Zone and Quantitative EEG Measures: Towards Prediction of Post-Surgical Seizure Control

PubMed Central

Andrzejak, Ralph G.; Hauf, Martinus; Pollo, Claudio; Müller, Markus; Weisstanner, Christian; Wiest, Roland; Schindler, Kaspar

2015-01-01

Background Epilepsy surgery is a potentially curative treatment option for pharmacoresistent patients. If non-invasive methods alone do not allow to delineate the epileptogenic brain areas the surgical candidates undergo long-term monitoring with intracranial EEG. Visual EEG analysis is then used to identify the seizure onset zone for targeted resection as a standard procedure. Methods Despite of its great potential to assess the epileptogenicty of brain tissue, quantitative EEG analysis has not yet found its way into routine clinical practice. To demonstrate that quantitative EEG may yield clinically highly relevant information we retrospectively investigated how post-operative seizure control is associated with four selected EEG measures evaluated in the resected brain tissue and the seizure onset zone. Importantly, the exact spatial location of the intracranial electrodes was determined by coregistration of pre-operative MRI and post-implantation CT and coregistration with post-resection MRI was used to delineate the extent of tissue resection. Using data-driven thresholding, quantitative EEG results were separated into normally contributing and salient channels. Results In patients with favorable post-surgical seizure control a significantly larger fraction of salient channels in three of the four quantitative EEG measures was resected than in patients with unfavorable outcome in terms of seizure control (median over the whole peri-ictal recordings). The same statistics revealed no association with post-operative seizure control when EEG channels contributing to the seizure onset zone were studied. Conclusions We conclude that quantitative EEG measures provide clinically relevant and objective markers of target tissue, which may be used to optimize epilepsy surgery. The finding that differentiation between favorable and unfavorable outcome was better for the fraction of salient values in the resected brain tissue than in the seizure onset zone is consistent with growing evidence that spatially extended networks might be more relevant for seizure generation, evolution and termination than a single highly localized brain region (i.e. a “focus”) where seizures start. PMID:26513359

New long-wavelength Nd:YAG laser at 1.44 micron: effect on brain.

PubMed

Martiniuk, R; Bauer, J A; McKean, J D; Tulip, J; Mielke, B W

1989-02-01

A wavelength-shifted Nd:YAG laser, tuned to coincide with the infrared absorption peak of water at 1.44 microns, was used to make lesions in normal rabbit brain. A total of 48 lesions were made with power up to 20 W, with energy up to 40 joules, and with two different spot sizes. These lesions were compared to lesions made with 1.06 microns radiation from an Nd:YAG laser under identical operating conditions. Measurements of blood-brain barrier damage and width, depth, and volume of tissue affected were obtained 30 minutes after placement of the lesions. It was found that 1.44-microns lesions produced photoevaporative tissue loss at the highest intensities used. The layer of coagulated tissue remaining after photovaporization had a mean thickness of 0.6 mm irrespective of the volume of tissue removed. There was no photovaporization in the 1.06-microns lesions. In addition, the amount of peripheral edema per unit volume of tissue coagulated was approximately half at the 1.44-microns wavelength. These findings suggest that the 1.44-microns Nd:YAG laser may be a useful surgical instrument since it combines the photoevaporative effect of the CO2 laser while maintaining the advantages of the conventional Nd:YAG laser (quartz fiber delivery and effective hemostasis).

Alternative promoter usage generates novel shorter MAPT mRNA transcripts in Alzheimer's disease and progressive supranuclear palsy brains.

PubMed

Huin, Vincent; Buée, Luc; Behal, Hélène; Labreuche, Julien; Sablonnière, Bernard; Dhaenens, Claire-Marie

2017-10-03

Alternative promoter usage is an important mechanism for transcriptome diversity and the regulation of gene expression. Indeed, this alternative usage may influence tissue/subcellular specificity, protein translation and function of the proteins. The existence of an alternative promoter for MAPT gene was considered for a long time to explain differential tissue specificity and differential response to transcription and growth factors between mRNA transcripts. The alternative promoter usage could explain partly the different tau proteins expression patterns observed in tauopathies. Here, we report on our discovery of a functional alternative promoter for MAPT, located upstream of the gene's second exon (exon 1). By analyzing genome databases and brain tissue from control individuals and patients with Alzheimer's disease or progressive supranuclear palsy, we identified novel shorter transcripts derived from this alternative promoter. These transcripts are increased in patients' brain tissue as assessed by 5'RACE-PCR and qPCR. We suggest that these new MAPT isoforms can be translated into normal or amino-terminal-truncated tau proteins. We further suggest that activation of MAPT's alternative promoter under pathological conditions leads to the production of truncated proteins, changes in protein localization and function, and thus neurodegeneration.

[Changes in 2,3-diphosphoglycerate Levels in Blood and Brain Tissue after Craniocerebral Trauma and Cardiac Surgery].

PubMed

Hausdörfer, J; Heller, W; Junger, H; Oldenkott, P; Stunkat, R

1976-10-01

The response of the 2,3-diphosphoglycerate (DPG) levels in the blood and brain tissue to a craniocerebral trauma of varying severity was studied in anaesthetized rats. A trauma producing cerebral contusion was followed within two hours by a highly significant rise in DPG concentration in the blood as compared with the control animals or only mildly traumatized rats. The DPG levels in the brain tissue showed no significant differences. Similar changes in DPG concentration were observed in the blood of patients with craniocerebral injuries. The DPG-mediated increased release of oxygen to the tissues represents a compensatory mechanism and is pathognomic for craniocerebral trauma. Patients undergoing surgery with extracorporeal circulation lack this mechanism for counteracting hypoxaemia; already during thoracotomy the DPG concentration in the blood fell significantly and did not reach its original level until 72 hours after the operation. In stored, ACD stabilized, blood the DPG concentration gradually decreases. Estimations carried out over 28 days showed a continuous statistically significant loss of DPG. After 24 hours the DPG levels in stored blood had already dropped to the lower limits of normal - a fact that has to be taken into account in massive blood transfusions.

Imaging Nicotine in Rat Brain Tissue by Use of Nanospray Desorption Electrospray Ionization Mass Spectrometry

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lanekoff, Ingela T.; Thomas, Mathew; Carson, James P.

Imaging mass spectrometry offers simultaneous detection of drugs, drug metabolites and endogenous substances in a single experiment. This is important when evaluating effects of a drug on a complex organ system such as the brain, where there is a need to understand how regional drug distribution impacts function. Nicotine is an addictive drug and its action in the brain is of high interest. Here we use nanospray desorption electrospray ionization, nano-DESI, imaging to discover the localization of nicotine in rat brain tissue after in vivo administration of nicotine. Nano-DESI is a new ambient technique that enables spatially-resolved analysis of tissuemore » samples without special sample pretreatment. We demonstrate high sensitivity of nano-DESI imaging that enables detection of only 0.7 fmole nicotine per pixel in the complex brain matrix. Furthermore, by adding deuterated nicotine to the solvent, we examined how matrix effects, ion suppression, and normalization affect the observed nicotine distribution. Finally, we provide preliminary results suggesting that nicotine localizes to the hippocampal substructure called dentate gyrus.« less

3D brain tumor localization and parameter estimation using thermographic approach on GPU.

PubMed

Bousselham, Abdelmajid; Bouattane, Omar; Youssfi, Mohamed; Raihani, Abdelhadi

2018-01-01

The aim of this paper is to present a GPU parallel algorithm for brain tumor detection to estimate its size and location from surface temperature distribution obtained by thermography. The normal brain tissue is modeled as a rectangular cube including spherical tumor. The temperature distribution is calculated using forward three dimensional Pennes bioheat transfer equation, it's solved using massively parallel Finite Difference Method (FDM) and implemented on Graphics Processing Unit (GPU). Genetic Algorithm (GA) was used to solve the inverse problem and estimate the tumor size and location by minimizing an objective function involving measured temperature on the surface to those obtained by numerical simulation. The parallel implementation of Finite Difference Method reduces significantly the time of bioheat transfer and greatly accelerates the inverse identification of brain tumor thermophysical and geometrical properties. Experimental results show significant gains in the computational speed on GPU and achieve a speedup of around 41 compared to the CPU. The analysis performance of the estimation based on tumor size inside brain tissue also presented. Copyright © 2017 Elsevier Ltd. All rights reserved.

Various clinical application of phase contrast X-ray

NASA Astrophysics Data System (ADS)

Oh, Chilhwan; Park, Sangyong; Ha, Seunghan; Park, Gyuman; Lee, Gunwoo; Lee, Onseok; Je, Jungho

2008-02-01

In biomedical application study using phase contrast X-ray, both sample thickness or density and absorption difference are very important factors in aspects of contrast enhancement. We present experimental evidence that synchrotron hard X-ray are suitable for radiological imaging of biological samples down to the cellular level. We investigated the potential of refractive index radiology using un-monochromatized synchrotron hard X-rays for the imaging of cell and tissue in various diseases. Material had been adopted various medical field, such as apoE knockout mouse in cardiologic field, specimen from renal and prostatic carcinoma patient in urology, basal cell epithelioma in dermatology, brain tissue from autosy sample of pakinson's disease, artificially induced artilrtis tissue from rabbits and extracted tooth from patients of crack tooth syndrome. Formalin and paraffin fixed tissue blocks were cut in 3 mm thickness for the X-ray radiographic imaging. From adjacent areas, 4 μm thickness sections were also prepared for hematoxylin-eosin staining. Radiographic images of dissected tissues were obtained using the hard X-rays from the 7B2 beamline of the Pohang Light Source (PLS). The technique used for the study was the phase contrast images were compared with the optical microscopic images of corresponding histological slides. Radiographic images of various diseased tissues showed clear histological details of organelles in normal tissues. Most of cancerous lesions were well differentiated from adjacent normal tissues and detailed histological features of each tumor were clearly identified. Also normal microstructures were identifiable by the phase contrast imaging. Tissue in cancer or other disease showed clearly different findings from those of surrounding normal tissue. For the first time we successfully demonstrated that synchrotron hard X-rays can be used for radiological imaging of relatively thick tissue samples with great histological details.

Ontogeny of brain and blood serotonin levels in 5-HT receptor knockout mice: potential relevance to the neurobiology of autism.

PubMed

Janusonis, Skirmantas; Anderson, George M; Shifrovich, Ilya; Rakic, Pasko

2006-11-01

The most consistent neurochemical finding in autism has been elevated group mean levels of blood platelet 5-hydroxytryptamine (5-HT, serotonin). The origin and significance of this platelet hyperserotonemia remain poorly understood. The 5-HT(1A) receptor plays important roles in the developing brain and is also expressed in the gut, the main source of platelet 5-HT. Post-natal tissue levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan were examined in the brain, duodenum and blood of 5-HT(1A) receptor-knockout and wild-type mice. At 3 days after birth, the knockout mice had lower mean brain 5-HT levels and normal mean platelet 5-HT levels. Also, at 3 days after birth, the mean tryptophan levels in the brain, duodenum and blood of the knockout mice were around 30% lower than those of the wild-type mice. By 2 weeks after birth, the mean brain 5-HT levels of the knockout mice normalized, but their mean platelet 5-HT levels became 24% higher than normal. The possible causes of these dynamic shifts were explored by examining correlations between central and peripheral levels of 5-HT, 5-HIAA and tryptophan. The results are discussed in relation to the possible role of 5-HT in the ontogeny of autism.

Ascorbic Acid and the Brain: Rationale for the Use against Cognitive Decline

PubMed Central

Harrison, Fiona E.; Bowman, Gene L.; Polidori, Maria Cristina

2014-01-01

This review is focused upon the role of ascorbic acid (AA, vitamin C) in the promotion of healthy brain aging. Particular attention is attributed to the biochemistry and neuronal metabolism interface, transport across tissues, animal models that are useful for this area of research, and the human studies that implicate AA in the continuum between normal cognitive aging and age-related cognitive decline up to Alzheimer’s disease. Vascular risk factors and comorbidity relationships with cognitive decline and AA are discussed to facilitate strategies for advancing AA research in the area of brain health and neurodegeneration. PMID:24763117

A systematic survey of lipids across mouse tissues

PubMed Central

Jain, Mohit; Ngoy, Soeun; Sheth, Sunil A.; Swanson, Raymond A.; Rhee, Eugene P.; Liao, Ronglih; Clish, Clary B.; Mootha, Vamsi K.

2014-01-01

Lipids are a diverse collection of macromolecules essential for normal physiology, but the tissue distribution and function for many individual lipid species remain unclear. Here, we report a mass spectrometry survey of lipid abundance across 18 mouse tissues, detecting ∼1,000 mass spectrometry features, of which we identify 179 lipids from the glycerolipids, glycerophospholipids, lysophospholipids, acylcarnitines, sphingolipids, and cholesteryl ester classes. Our data reveal tissue-specific organization of lipids and can be used to generate testable hypotheses. For example, our data indicate that circulating triglycerides positively and negatively associated with future diabetes in humans are enriched in mouse adipose tissue and liver, respectively, raising hypotheses regarding the tissue origins of these diabetes-associated lipids. We also integrate our tissue lipid data with gene expression profiles to predict a number of substrates of lipid-metabolizing enzymes, highlighting choline phosphotransferases and sterol O-acyltransferases. Finally, we identify several tissue-specific lipids not present in plasma under normal conditions that may be of interest as biomarkers of tissue injury, and we show that two of these lipids are released into blood following ischemic brain injury in mice. This resource complements existing compendia of tissue gene expression and may be useful for integrative physiology and lipid biology. PMID:24518676

γ-H2AX as a Marker for Dose Deposition in the Brain of Wistar Rats after Synchrotron Microbeam Radiation

PubMed Central

Fernandez-Palomo, Cristian; Mothersill, Carmel; Bräuer-Krisch, Elke; Laissue, Jean; Seymour, Colin; Schültke, Elisabeth

2015-01-01

Objective Synchrotron radiation has shown high therapeutic potential in small animal models of malignant brain tumours. However, more studies are needed to understand the radiobiological effects caused by the delivery of high doses of spatially fractionated x-rays in tissue. The purpose of this study was to explore the use of the γ-H2AX antibody as a marker for dose deposition in the brain of rats after synchrotron microbeam radiation therapy (MRT). Methods Normal and tumour-bearing Wistar rats were exposed to 35, 70 or 350 Gy of MRT to their right cerebral hemisphere. The brains were extracted either at 4 or 8 hours after irradiation and immediately placed in formalin. Sections of paraffin-embedded tissue were incubated with anti γ-H2AX primary antibody. Results While the presence of the C6 glioma does not seem to modulate the formation of γ-H2AX in normal tissue, the irradiation dose and the recovery versus time are the most important factors affecting the development of γ-H2AX foci. Our results also suggest that doses of 350 Gy can trigger the release of bystander signals that significantly amplify the DNA damage caused by radiation and that the γ-H2AX biomarker does not only represent DNA damage produced by radiation, but also damage caused by bystander effects. Conclusion In conclusion, we suggest that the γ-H2AX foci should be used as biomarker for targeted and non-targeted DNA damage after synchrotron radiation rather than a tool to measure the actual physical doses. PMID:25799425

Comparative evaluation of methylene blue and demeclocycline for enhancing optical contrast of brain neoplasms

NASA Astrophysics Data System (ADS)

Wirth, Dennis J.

Brain tumors cause significant morbidity and mortality even when benign. Completeness of resection of brain tumors has been associated with better quality of life. However, that is often difficult to accomplish. The goal of this study was to evaluate the feasibility of using contrast enhanced multimodal confocal imaging for intraoperative detection of brain neoplasms. Different types of benign and malignant, primary and metastatic brain tumors, stained with Methylene Blue (MB) as a contrast agent, were imaged. MB is a traditional histopathologic stain that absorbs light in the red spectral range and fluoresces in the near infrared. It is FDA-approved for in vivo staining of human skin and breast tissue. Optical images showed good correlation with histopathology, demonstrating the potential of contrast enhanced multimodal confocal imaging for intraoperative detection of brain neoplasms ex vivo. However, the safety of MB for staining human brain in vivo is questionable. Demeclocycline (DMN), an antibiotic of the tetracycline family, has shown to be effective in differentiating normal from cancerous tissue in various organs. DMN is a fluorophore, which absorbs light in the violet spectral range and has a broad emission band covering green and yellow wavelengths. It is commonly used to treat infection and inflammatory disorders, and could provide a safer alternative to MB. To test this hypothesis, fresh excess human brain tissues were bisected and stained with aqueous solutions of either MB or DMN and then imaged. Reflectance and fluorescence images acquired from tissues stained with the two dyes were compared, and correlated with processed H&E histopathology. Comparison showed similar staining patterns and contrast of diagnostic features in glioblastomas, stained using either MB or DMN. The results show potential of both MB and DMN for the intraoperative detection of microscopic nests of brain neoplasms. Further studies will establish safety and efficacy of these agents in vivo.

Glymphatic MRI in idiopathic normal pressure hydrocephalus.

PubMed

Ringstad, Geir; Vatnehol, Svein Are Sirirud; Eide, Per Kristian

2017-10-01

The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer's disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Terahertz reflectometry imaging for low and high grade gliomas

NASA Astrophysics Data System (ADS)

Ji, Young Bin; Oh, Seung Jae; Kang, Seok-Gu; Heo, Jung; Kim, Sang-Hoon; Choi, Yuna; Song, Seungri; Son, Hye Young; Kim, Se Hoon; Lee, Ji Hyun; Haam, Seung Joo; Huh, Yong Min; Chang, Jong Hee; Joo, Chulmin; Suh, Jin-Suck

2016-10-01

Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes.

Iron biomineralization of brain tissue and neurodegenerative disorders

NASA Astrophysics Data System (ADS)

Mikhaylova (Mikhailova), Albina

The brain is an organ with a high concentration of iron in specific areas, particularly in the globus pallidus, the substantia nigra, and the red nucleus. In certain pathological states, such as iron overload disease and neurodegenerative disorders, a disturbed iron metabolism can lead to increased accumulation of iron not only in these areas, but also in the brain regions that are typically low in iron content. Recent studies of the physical and magnetic properties of metalloproteins, and in particular the discovery of biogenic magnetite in human brain tissue, have raised new questions about the role of biogenic iron formations in living organisms. Further investigations revealed the presence of magnetite-like crystalline structures in human ferritin, and indicated that released ferritin iron might act as promoter of oxidative damage to tissue, therefore contributing to pathogenesis of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. The purpose of this work was to examine the elemental composition and structure of iron deposits in normal brain tissue as well as tissue affected by neurodegenerative disorders. Employing the methods of X-ray microfocus fluorescence mapping, X-ray Absorption Near Edge Structure (XANES), X-ray Absorption Fine Structure spectroscopy (XAFS), and light and electron microscopic examinations allows one to obtain qualitative as well as quantitative data with respect to the cellular distribution and chemical state of iron at levels not detected previously. The described tissue preparation technique allows not only satisfactory XAS iron elemental imaging in situ but also multimodal examination with light and electron microscopes of the same samples. The developed protocol has assured consistent and reproducible results on relatively large sections of flat-embedded tissue. The resulting tissue samples were adequate for XAS examination as well as sufficiently well-preserved for future microscopy studies. The continued development of this technique should lead to major advances in mapping iron anomalies and the related chemical and structural information directly to cells and tissue structures in human brain tissue. At present this is done primarily by iron staining methods and any information on the relationship between iron distribution and cellular structures obtained this way is limited. Iron staining also offers no information on the specific compounds of iron that are present. This can be vitally important as the form of iron [including its oxidation state] in the human body can determine whether it plays a detrimental or beneficial role in neurophysiological processes.

Analysis of neoplastic lesions in magnetic resonance imaging using self-organizing maps.

PubMed

Mei, Paulo Afonso; de Carvalho Carneiro, Cleyton; Fraser, Stephen J; Min, Li Li; Reis, Fabiano

2015-12-15

To provide an improved method for the identification and analysis of brain tumors in MRI scans using a semi-automated computational approach, that has the potential to provide a more objective, precise and quantitatively rigorous analysis, compared to human visual analysis. Self-Organizing Maps (SOM) is an unsupervised, exploratory data analysis tool, which can automatically domain an image into selfsimilar regions or clusters, based on measures of similarity. It can be used to perform image-domain of brain tissue on MR images, without prior knowledge. We used SOM to analyze T1, T2 and FLAIR acquisitions from two MRI machines in our service from 14 patients with brain tumors confirmed by biopsies--three lymphomas, six glioblastomas, one meningioma, one ganglioglioma, two oligoastrocytomas and one astrocytoma. The SOM software was used to analyze the data from the three image acquisitions from each patient and generated a self-organized map for each containing 25 clusters. Damaged tissue was separated from the normal tissue using the SOM technique. Furthermore, in some cases it allowed to separate different areas from within the tumor--like edema/peritumoral infiltration and necrosis. In lesions with less precise boundaries in FLAIR, the estimated damaged tissue area in the resulting map appears bigger. Our results showed that SOM has the potential to be a powerful MR imaging analysis technique for the assessment of brain tumors. Copyright © 2015. Published by Elsevier B.V.

Hybrid Clustering And Boundary Value Refinement for Tumor Segmentation using Brain MRI

NASA Astrophysics Data System (ADS)

Gupta, Anjali; Pahuja, Gunjan

2017-08-01

The method of brain tumor segmentation is the separation of tumor area from Brain Magnetic Resonance (MR) images. There are number of methods already exist for segmentation of brain tumor efficiently. However it’s tedious task to identify the brain tumor from MR images. The segmentation process is extraction of different tumor tissues such as active, tumor, necrosis, and edema from the normal brain tissues such as gray matter (GM), white matter (WM), as well as cerebrospinal fluid (CSF). As per the survey study, most of time the brain tumors are detected easily from brain MR image using region based approach but required level of accuracy, abnormalities classification is not predictable. The segmentation of brain tumor consists of many stages. Manually segmenting the tumor from brain MR images is very time consuming hence there exist many challenges in manual segmentation. In this research paper, our main goal is to present the hybrid clustering which consists of Fuzzy C-Means Clustering (for accurate tumor detection) and level set method(for handling complex shapes) for the detection of exact shape of tumor in minimal computational time. using this approach we observe that for a certain set of images 0.9412 sec of time is taken to detect tumor which is very less in comparison to recent existing algorithm i.e. Hybrid clustering (Fuzzy C-Means and K Means clustering).

EGFR-directed Affibody for fluorescence-guided glioma surgery: time-dose analysis (Conference Presentation)

NASA Astrophysics Data System (ADS)

Ribeiro de Souza, Ana Luiza; Marra, Kayla; Gunn, Jason R.; Elliott, Jonathan T.; Samkoe, Kimberley S.; Paulsen, Keith D.; Draney, Daniel R.; Feldwisch, Joachim

2016-03-01

The key to fluorescence guided surgical oncology is the ability to create specific contrast between normal and glioma tissue. The blood brain barrier that limits the delivery of substances to the normal brain is broken in tumors, allowing accumulation of agents in the tumor interior. However, for a clinical success, imaging agents should be in the infiltrative edges to minimize the resection of normal brain while enable the removal of tumor. The aberrant overexpression and/or activation of EGFR is associated with many types of cancers, including glioblastoma and the injection of a fluorescent molecule targeted to these receptors would improve tumor contrast during fluorescence guided surgery. Affibody molecules have intentional medium affinity and high potential specificity, which are the desirable features of a good surgical imaging agent. The aim of this study was evaluate the brain/glioma uptake of ABY029 labeled with near-infrared dye IRDye800CW after intravenous injection. Rats were either inoculated with orthotopic implantations of U251 human glioma cell line or PBS (shams control) in the brain. The tumors were allowed to grow for 2-3 weeks before carrying out fluorescent tracer experiments. Fluorescent imaging of ex vivo brain slices from rats was acquired at different time points after infection of fluorescently labeled EGFR-specific affibody to verify which time provided maximal contrast tumor to normal brain. Although the tumor was most clearly visualized after 1h of IRDye800CW-labeled ABY029 injection, the tumor location could be identified from the background after 48h. These results suggest that the NIR-labeled affibody examined shows excellent potential to increase surgical visualization for confirmed EGFR positive tumors.

A Method for Whole Brain Ex Vivo Magnetic Resonance Imaging with Minimal Susceptibility Artifacts

PubMed Central

Shatil, Anwar S.; Matsuda, Kant M.; Figley, Chase R.

2016-01-01

Magnetic resonance imaging (MRI) is a non-destructive technique that is capable of localizing pathologies and assessing other anatomical features (e.g., tissue volume, microstructure, and white matter connectivity) in postmortem, ex vivo human brains. However, when brains are removed from the skull and cerebrospinal fluid (i.e., their normal in vivo magnetic environment), air bubbles and air–tissue interfaces typically cause magnetic susceptibility artifacts that severely degrade the quality of ex vivo MRI data. In this report, we describe a relatively simple and cost-effective experimental setup for acquiring artifact-free ex vivo brain images using a clinical MRI system with standard hardware. In particular, we outline the necessary steps, from collecting an ex vivo human brain to the MRI scanner setup, and have also described changing the formalin (as might be necessary in longitudinal postmortem studies). Finally, we share some representative ex vivo MRI images that have been acquired using the proposed setup in order to demonstrate the efficacy of this approach. We hope that this protocol will provide both clinicians and researchers with a straight-forward and cost-effective solution for acquiring ex vivo MRI data from whole postmortem human brains. PMID:27965620

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

PubMed Central

Kundakovic, Marija; Jaric, Ivana

2017-01-01

Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders. PMID:28335457

Shorter sleep duration and better sleep quality are associated with greater tissue density in the brain.

PubMed

Takeuchi, Hikaru; Taki, Yasuyuki; Nouchi, Rui; Yokoyama, Ryoichi; Kotozaki, Yuka; Nakagawa, Seishu; Sekiguchi, Atsushi; Iizuka, Kunio; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Miyauchi, Carlos Makoto; Shinada, Takamitsu; Sakaki, Kohei; Nozawa, Takayuki; Ikeda, Shigeyuki; Yokota, Susumu; Daniele, Magistro; Sassa, Yuko; Kawashima, Ryuta

2018-04-11

Poor sleep quality is associated with unfavorable psychological measurements, whereas sleep duration has complex relationships with such measurements. The aim of this study was to identify the associations between microstructural properties of the brain and sleep duration/sleep quality in a young adult. The associations between mean diffusivity (MD), a measure of diffusion tensor imaging (DTI), and sleep duration/sleep quality were investigated in a study cohort of 1201 normal young adults. Positive correlations between sleep duration and MD of widespread areas of the brain, including the prefrontal cortex (PFC) and the dopaminergic systems, were identified. Negative correlations between sleep quality and MD of the widespread areas of the brain, including the PFC and the right hippocampus, were also detected. Lower MD has been previously associated with more neural tissues in the brain. Further, shorter sleep duration was associated with greater persistence and executive functioning (lower Stroop interference), whereas good sleep quality was associated with states and traits relevant to positive affects. These results suggest that bad sleep quality and longer sleep duration were associated with aberrant neurocognitive measurements in the brain in healthy young adults.

The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma.

PubMed

Yin, Haoyuan; Shao, Ying; Chen, Xuan

2017-01-01

To analyze the effects of extracellular matrix metalloproteinase inducer (CD147) on glioma proliferation, apoptosis, invasion, and angiogenesis. Tissue samples were obtained from 101 glioma cases while normal brain tissues were obtained from 30 brain injury cases. Immunohistochemical assay was performed to detect the expressions of CD147, CD34, and VEGF in tissue samples. QRT-PCR was performed to detect the relative expression of CD147 mRNA in human glioma cell lines. CD147 siRNA was transfected into glioma cell line U251. Cell proliferation, apoptosis, invasion, and angiogenesis were tested by MTT, flow cytometry, Transwell assay, and vasculogenic mimicry assay, respectively. Expressions of relative proteins were analyzed with western blot. CD147 was positively expressed with the percentage of 0, 37.5, 44.8, 67.9, and 85.7 % in normal tissues and glioma tissues with WHO grades I-IV, respectively, and the scores of MVDand VEGF were associated with the expression of CD147. CD147 was significantly upregulated in the human glioma cell lines (P < 0.05). Downregulated the expression of CD147 suppressed cell proliferation, blocked cell cycle, induced apoptosis, inhibited cell invasion and angiogenesis in glioma cells in vitro. The expression of CD147 was significantly associated with WHO tumor grade and angiogenesis; silencing of CD147 contributed to inhibition of glioma proliferation, invasion, and angiogenesis. Our study provided firm evidence that CD 147 is a potential glioma target for anti-angiogenic therapies.

Pairwise mixture model for unmixing partial volume effect in multi-voxel MR spectroscopy of brain tumour patients

NASA Astrophysics Data System (ADS)

Olliverre, Nathan; Asad, Muhammad; Yang, Guang; Howe, Franklyn; Slabaugh, Gregory

2017-03-01

Multi-Voxel Magnetic Resonance Spectroscopy (MV-MRS) provides an important and insightful technique for the examination of the chemical composition of brain tissue, making it an attractive medical imaging modality for the examination of brain tumours. MRS, however, is affected by the issue of the Partial Volume Effect (PVE), where the signals of multiple tissue types can be found within a single voxel and provides an obstacle to the interpretation of the data. The PVE results from the low resolution achieved in MV-MRS images relating to the signal to noise ratio (SNR). To counteract PVE, this paper proposes a novel Pairwise Mixture Model (PMM), that extends a recently reported Signal Mixture Model (SMM) for representing the MV-MRS signal as normal, low or high grade tissue types. Inspired by Conditional Random Field (CRF) and its continuous variant the PMM incorporates the surrounding voxel neighbourhood into an optimisation problem, the solution of which provides an estimation to a set of coefficients. The values of the estimated coefficients represents the amount of each tissue type (normal, low or high) found within a voxel. These coefficients can then be visualised as a nosological rendering using a coloured grid representing the MV-MRS image overlaid on top of a structural image, such as a Magnetic Resonance Image (MRI). Experimental results show an accuracy of 92.69% in classifying patient tumours as either low or high grade compared against the histopathology for each patient. Compared to 91.96% achieved by the SMM, the proposed PMM method demonstrates the importance of incorporating spatial coherence into the estimation as well as its potential clinical usage.

A case report describing detection of Rhodoturola minuta fungemia in an ewe lamb

USDA-ARS?s Scientific Manuscript database

An eight-month-old crossbred ewe that was normal upon physical examination was humanely euthanized for tissue collection. Prior to euthanasia, whole blood was collected via jugular venipuncture into 60-ml syringes containing EDTA anticoagulant. After sacrifice, the brain was removed and the choroi...

Fluorescent Affibody Molecule Administered In Vivo at a Microdose Level Labels EGFR Expressing Glioma Tumor Regions.

PubMed

de Souza, Ana Luiza Ribeiro; Marra, Kayla; Gunn, Jason; Samkoe, Kimberley S; Hoopes, P Jack; Feldwisch, Joachim; Paulsen, Keith D; Pogue, Brian W

2017-02-01

Fluorescence guidance in surgical oncology provides the potential to realize enhanced molecular tumor contrast with dedicated targeted tracers, potentially with a microdose injection level. For most glioma tumors, the blood brain barrier is compromised allowing some exogenous drug/molecule delivery and accumulation for imaging. The aberrant overexpression and/or activation of epidermal growth factor receptor (EGFR) is associated with many types of cancers, including glioblastoma, and so the use of a near-infrared (NIR) fluorescent molecule targeted to the EGFR receptor provides the potential for improving tumor contrast during surgery. Fluorescently labeled affibody molecule (ABY-029) has high EGFR affinity and high potential specificity with reasonably fast plasma clearance. In this study, ABY-29 was evaluated in glioma versus normal brain uptake from intravenous injection at a range of doses, down to a microdose injection level. Nude rats were inoculated with the U251 human glioma cell line in the brain. Tumors were allowed to grow for 3-4 weeks. ABY-029 fluorescence ex vivo imaging of brain slices was acquired at different time points (1-48 h) and varying injection doses from 25 to 122 μg/kg (from human protein microdose equivalent to five times microdose levels). The tumor was most clearly visualized at 1-h post-injection with 8- to 16-fold average contrast relative to normal brain. However, the tumor still could be identified after 48 h. In all cases, the ABY-029 fluorescence appeared to localize preferentially in EGFR-positive regions. Increasing the injected dose from a microdose level to five times, a microdose level increased the signal by 10-fold, and the contrast was from 8 to 16, showing that there was value in doses slightly higher than the microdose restriction. Normal tissue uptake was found to be affected by the tumor size, indicating that edema was a likely factor affecting the expected tumor to normal tissue contrast. These results suggest that the NIR-labeled affibody molecules provide an excellent potential to increase surgical visualization of EGFR-positive tumor regions.

Safety evaluation of mercury based Ayurvedic formulation (Sidh Makardhwaj) on brain cerebrum, liver & kidney in rats

PubMed Central

Kumar, Gajendra; Srivastava, Amita; Sharma, Surinder Kumar; Gupta, Yogendra Kumar

2014-01-01

Background & objectives: Sidh Makardhwaj (SM) is a mercury based Ayurvedic formulation used in rheumatoid arthritis and neurological disorders. However, toxicity concerns due to mercury content are often raised. Therefore, the present study was carried out to evaluate the effect of SM on brain cerebrum, liver and kidney in rats. Methods: Graded doses of SM (10, 50, 100 mg/kg), mercuric chloride (1 mg/kg) and normal saline were administered orally to male Wistar rats for 28 days. Behavioural parameters were assessed on days 1, 7, 14 and 28 using Morris water maze, passive avoidance, elevated plus maze and rota rod. Liver and kidney function tests were done on day 28. Animals were sacrificed and brain cerebrum acetylcholinesterase activity, levels of malondialdehyde (MDA), reduced glutathione (GSH) in brain cerebrum, liver, kidney were estimated. The levels of mercury in brain cerebrum, liver and kidney were estimated and histopathology of these tissues was also performed. Results: SM in the doses used did not cause significant change in neurobehavioural parameters, brain cerebrum AChE activity, liver (ALT, AST, ALP bilirubin) and kidney (serum urea and creatinine) function tests as compared to control. The levels of mercury in brain cerebrum, liver, and kidney were found to be raised in dose dependent manner. However, the levels of MDA and GSH in these tissues did not show significant changes at doses of 10 and 50 mg/kg. Also, there was no histopathological change in cytoarchitecture of brain cerebrum, liver, and kidney tissues at doses of 10 and 50 mg/kg. Interpretation & conclusions: The findings of the present study suggest that Sidh Makardhwaj upto five times the equivalent human dose administered for 28 days did not show any toxicological effects on rat brain cerebrum, liver and kidney. PMID:24927349

Safety evaluation of mercury based Ayurvedic formulation (Sidh Makardhwaj) on brain cerebrum, liver & kidney in rats.

PubMed

Kumar, Gajendra; Srivastava, Amita; Sharma, Surinder Kumar; Gupta, Yogendra Kumar

2014-04-01

Sidh Makardhwaj (SM) is a mercury based Ayurvedic formulation used in rheumatoid arthritis and neurological disorders. However, toxicity concerns due to mercury content are often raised. Therefore, the present study was carried out to evaluate the effect of SM on brain cerebrum, liver and kidney in rats. Graded doses of SM (10, 50, 100 mg/kg), mercuric chloride (1 mg/kg) and normal saline were administered orally to male Wistar rats for 28 days. Behavioural parameters were assessed on days 1, 7, 14 and 28 using Morris water maze, passive avoidance, elevated plus maze and rota rod. Liver and kidney function tests were done on day 28. Animals were sacrificed and brain cerebrum acetylcholinesterase activity, levels of malondialdehyde (MDA), reduced glutathione (GSH) in brain cerebrum, liver, kidney were estimated. The levels of mercury in brain cerebrum, liver and kidney were estimated and histopathology of these tissues was also performed. SM in the doses used did not cause significant change in neurobehavioural parameters, brain cerebrum AChE activity, liver (ALT, AST, ALP bilirubin) and kidney (serum urea and creatinine) function tests as compared to control. The levels of mercury in brain cerebrum, liver, and kidney were found to be raised in dose dependent manner. However, the levels of MDA and GSH in these tissues did not show significant changes at doses of 10 and 50 mg/kg. Also, there was no histopathological change in cytoarchitecture of brain cerebrum, liver, and kidney tissues at doses of 10 and 50 mg/kg. The findings of the present study suggest that Sidh Makardhwaj upto five times the equivalent human dose administered for 28 days did not show any toxicological effects on rat brain cerebrum, liver and kidney.

Biodistribution and Pharmacodynamics of Recombinant Human Alpha-L-Iduronidase (rhIDU) in Mucopolysaccharidosis Type I-Affected Cats Following Multiple Intrathecal Administrations

PubMed Central

Vite, Charles H.; Wang, Ping; Patel, Reema T.; Walton, Raquel M.; Walkley, Steven U.; Sellers, Rani S.; Ellinwood, N. Matthew; Cheng, Alphonsus S.; White, Joleen T.; O’Neill, Charles A.; Haskins, Mark

2011-01-01

The storage disorder mucopolysaccharidosis type I (MPS I) is caused by a deficiency in lysosomal α-L-iduronidase activity. The inability to degrade glycosaminoglycans (GAG) results in lysosomal accumulation and widespread tissue lesions. Many symptoms of MPS I are amenable to treatment with recombinant human α-L-iduronidase (rhIDU), however, peripherally administered rhIDU does not cross the blood-brain barrier and has no beneficial effects in the central nervous system (CNS). A feline model of MPS I was used to evaluate the CNS effects of rhIDU following repeated intrathecal (IT) administration. Twelve animals were randomized into four groups based on the time of euthanasia and tissue evaluation following three repeat IT administrations of 0.1 mg/kg rhIDU or placebo on Study Days 1, 4 or 5, and 9. Two days after the final IT injection, the mean tissue α-L-iduronidase (IDU) activity in the brains of the two treated animals were approximately 3-times higher (50.1 and 54.9 U/mg protein) than the activity found in normal cat brains (mean of 18.3 U/mg), and remained higher than untreated MPS1 brain at 1 month (2.4 and 4.1 U/mg protein) before returning to near-baseline levels after 2 months. This activity corresponded with decreased brain GAG concentrations after 2 days (1.4 and 2.0 mcg/mg) and 1 month (0.9 and 1.1 mcg/mg) which approached levels observed in normal animals (0.7 mcg/mg). Attenuation of GAG, gangliosides GM2 and GM3, and cholesterol reaccumulation was identified at both two days and one month following final IT injection. No adverse effects or rhIDU antibody response attributable to IT rhIDU administration were observed. IT rhIDU may be an effective means for providing enzyme replacement therapy for the central manifestations of MPS I. PMID:21482164

Delineating Normal from Diseased Brain by Aminolevulinic Acid-Induced Fluorescence

NASA Astrophysics Data System (ADS)

Stepp, Herbert; Stummer, Walter

5-Aminolevulinic acid (5-ALA) as a precursor of protoporphyrin IX (PpIX) has been established as an orally applied drug to guide surgical resection of malignant brain tumors by exciting the red fluorescence of PpIX. The accumulation of PpIX in glioblastoma multiforme (GBM) is highly selective and provides excellent contrast to normal brain when using surgical microscopes with appropriately filtered light sources and cameras. The positive predictive value of fluorescent tissue is very high, enabling safe gross total resection of GBM and other brain tumors and improving prognosis of patients. Compared to other intraoperative techniques that have been developed with the aim of increasing the rate of safe gross total resections of malignant gliomas, PpIX fluorescence is considerably simpler, more cost effective, and comparably reliable. We present the basics of 5-ALA-based fluorescence-guided resection, and discuss the clinical results obtained for GBM and the experience with the fluorescence staining of other primary brain tumors and metastases as well as the results for spinal cord tumors. The phototoxicity of PpIX, increasingly used for photodynamic therapy of brain tumors, is mentioned briefly in this chapter.

Revealing pathologies in the liquid crystalline structures of the brain by polarimetric studies (Presentation Recording)

NASA Astrophysics Data System (ADS)

Bakhshetyan, Karen; Melkonyan, Gurgen G.; Galstian, Tigran V.; Saghatelyan, Armen

2015-10-01

Natural or "self" alignment of molecular complexes in living tissue represents many similarities with liquid crystals (LC), which are anisotropic liquids. The orientational characteristics of those complexes may be related to many important functional parameters and their study may reveal important pathologies. The know-how, accumulated thanks to the study of LC materials, may thus be used to this end. One of the traditionally used methods, to characterize those materials, is the polarized light imaging (PLI) that allows for label-free analysis of anisotropic structures in the brain tissue and can be used, for example, for the analysis of myelinated fiber bundles. In the current work, we first attempted to apply the PLI on the mouse histological brain sections to create a map of anisotropic structures using cross-polarizer transmission light. Then we implemented the PLI for comparative study of histological sections of human postmortem brain samples under normal and pathological conditions, such as Parkinson's disease (PD). Imaging the coronal, sagittal and horizontal sections of mouse brain allowed us to create a false color-coded fiber orientation map under polarized light. In human brain datasets for both control and PD groups we measured the pixel intensities in myelin-rich subregions of internal capsule and normalized these to non-myelinated background signal from putamen and caudate nucleus. Quantification of intensities revealed a statistically significant reduction of fiber intensity of PD compared to control subjects (2.801 +/- 0.303 and 3.724 +/- 0.07 respectively; *p < 0.05). Our study confirms the validity of PLI method for visualizing myelinated axonal fibers. This relatively simple technique can become a promising tool for study of neurodegenerative diseases where labeling-free imaging is an important benefit.

Resonance Raman spectroscopy for human cancer detection of key molecules with clinical diagnosis

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Li, Jiyou; Zhou, Lixin; He, Jingsheng; Sun, Yi; Pu, Yang; Zhu, Ke; Liu, Yulong; Li, Qingbo; Cheng, Gangge; Alfano, Robert R.

2013-03-01

Resonance Raman (RR) has the potential to reveal the differences between cancerous and normal breast and brain tissues in vitro. This differences caused by the changes of specific biomolecules in the tissues were displayed in resonance enhanced of vibrational fingerprints. It observed that the changes of reduced collagen contents and the number of methyl may show the sub-methylation of DNA in cancer cells. Statistical theoretical models of Bayesian, principal component analysis (PCA) and support vector machine (SVM) were used for distinguishing cancer from normal based on the RR spectral data of breast and meninges tissues yielding the diagnostic sensitivity of 80% and 90.9%, and specificity of 100% and 100%, respectively. The results demonstrated that the RR spectroscopic technique could be applied as clinical optical pathology tool with a high accuracy and reliability.

Brain stiffens post mortem.

PubMed

Weickenmeier, J; Kurt, M; Ozkaya, E; de Rooij, R; Ovaert, T C; Ehman, R L; Butts Pauly, K; Kuhl, E

2018-04-22

Alterations in brain rheology are increasingly recognized as a diagnostic marker for various neurological conditions. Magnetic resonance elastography now allows us to assess brain rheology repeatably, reproducibly, and non-invasively in vivo. Recent elastography studies suggest that brain stiffness decreases one percent per year during normal aging, and is significantly reduced in Alzheimer's disease and multiple sclerosis. While existing studies successfully compare brain stiffnesses across different populations, they fail to provide insight into changes within the same brain. Here we characterize rheological alterations in one and the same brain under extreme metabolic changes: alive and dead. Strikingly, the storage and loss moduli of the cerebrum increased by 26% and 60% within only three minutes post mortem and continued to increase by 40% and 103% within 45 minutes. Immediate post mortem stiffening displayed pronounced regional variations; it was largest in the corpus callosum and smallest in the brainstem. We postulate that post mortem stiffening is a manifestation of alterations in polarization, oxidation, perfusion, and metabolism immediately after death. Our results suggest that the stiffness of our brain-unlike any other organ-is a dynamic property that is highly sensitive to the metabolic environment. Our findings emphasize the importance of characterizing brain tissue in vivo and question the relevance of ex vivo brain tissue testing as a whole. Knowing the true stiffness of the living brain has important consequences in diagnosing neurological conditions, planning neurosurgical procedures, and modeling the brain's response to high impact loading. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

DNA double-strand break repair of blood lymphocytes and normal tissues analysed in a preclinical mouse model: implications for radiosensitivity testing.

PubMed

Rübe, Claudia E; Grudzenski, Saskia; Kühne, Martin; Dong, Xiaorong; Rief, Nicole; Löbrich, Markus; Rübe, Christian

2008-10-15

Radiotherapy is an effective cancer treatment, but a few patients suffer severe radiation toxicities in neighboring normal tissues. There is increasing evidence that the variable susceptibility to radiation toxicities is caused by the individual genetic predisposition, by subtle mutations, or polymorphisms in genes involved in cellular responses to ionizing radiation. Double-strand breaks (DSB) are the most deleterious form of radiation-induced DNA damage, and DSB repair deficiencies lead to pronounced radiosensitivity. Using a preclinical mouse model, the highly sensitive gammaH2AX-foci approach was tested to verify even subtle, genetically determined DSB repair deficiencies known to be associated with increased normal tissue radiosensitivity. By enumerating gammaH2AX-foci in blood lymphocytes and normal tissues (brain, lung, heart, and intestine), the induction and repair of DSBs after irradiation with therapeutic doses (0.1-2 Gy) was investigated in repair-proficient and repair-deficient mouse strains in vivo and blood samples irradiated ex vivo. gammaH2AX-foci analysis allowed to verify the different DSB repair deficiencies; even slight impairments caused by single polymorphisms were detected similarly in both blood lymphocytes and solid tissues, indicating that DSB repair measured in lymphocytes is valid for different and complex organs. Moreover, gammaH2AX-foci analysis of blood samples irradiated ex vivo was found to reflect repair kinetics measured in vivo and, thus, give reliable information about the individual DSB repair capacity. gammaH2AX analysis of blood and tissue samples allows to detect even minor genetically defined DSB repair deficiencies, affecting normal tissue radiosensitivity. Future studies will have to evaluate the clinical potential to identify patients more susceptible to radiation toxicities before radiotherapy.

Increased Steady-State Mutant Huntingtin mRNA in Huntington's Disease Brain.

PubMed

Liu, Wanzhao; Chaurette, Joanna; Pfister, Edith L; Kennington, Lori A; Chase, Kathryn O; Bullock, Jocelyn; Vonsattel, Jean Paul G; Faull, Richard L M; Macdonald, Douglas; DiFiglia, Marian; Zamore, Phillip D; Aronin, Neil

2013-01-01

Huntington's disease is caused by expansion of CAG trinucleotide repeats in the first exon of the huntingtin gene, which is essential for both development and neurogenesis. Huntington's disease is autosomal dominant. The normal allele contains 6 to 35 CAG triplets (average, 18) and the mutant, disease-causing allele contains >36 CAG triplets (average, 42). We examined 279 postmortem brain samples, including 148 HD and 131 non-HD controls. A total of 108 samples from 87 HD patients that are heterozygous at SNP rs362307, with a normal allele (18 to 27 CAG repeats) and a mutant allele (39 to 73 CAG repeats) were used to measure relative abundance of mutant and wild-type huntingtin mRNA. We used allele-specific, quantitative RT-PCR based on SNP heterozygosity to estimate the relative amount of mutant versus normal huntingtin mRNA in postmortem brain samples from patients with Huntington's disease. In the cortex and striatum, the amount of mRNA from the mutant allele exceeds that from the normal allele in 75% of patients. In the cerebellum, no significant difference between the two alleles was evident. Brain tissues from non-HD controls show no significant difference between two alleles of huntingtin mRNAs. Allelic differences were more pronounced at early neuropathological grades (grades 1 and 2) than at late grades (grades 3 and 4). More mutant HTT than normal could arise from increased transcription of mutant HTT allele, or decreased clearance of mutant HTT mRNA, or both. An implication is that equimolar silencing of both alleles would increase the mutant HTT to normal HTT ratio.

Heterogeneous Binding and Central Nervous System Distribution of the Multitargeted Kinase Inhibitor Ponatinib Restrict Orthotopic Efficacy in a Patient-Derived Xenograft Model of Glioblastoma.

PubMed

Laramy, Janice K; Kim, Minjee; Gupta, Shiv K; Parrish, Karen E; Zhang, Shuangling; Bakken, Katrina K; Carlson, Brett L; Mladek, Ann C; Ma, Daniel J; Sarkaria, Jann N; Elmquist, William F

2017-11-01

This study investigated how differences in drug distribution and free fraction at different tumor and tissue sites influence the efficacy of the multikinase inhibitor ponatinib in a patient-derived xenograft model of glioblastoma (GBM). Efficacy studies in GBM6 flank (heterotopic) and intracranial (orthotopic) models showed that ponatinib is effective in the flank but not in the intracranial model, despite a relatively high brain-to-plasma ratio. In vitro binding studies indicated that flank tumor had a higher free (unbound) drug fraction than normal brain. The total and free drug concentrations, along with the tissue-to-plasma ratio (Kp) and its unbound derivative (Kp,uu), were consistently higher in the flank tumor than the normal brain at 1 and 6 hours after a single dose in GBM6 flank xenografts. In the orthotopic xenografts, the intracranial tumor core displayed higher Kp and Kp,uu values compared with the brain-around-tumor (BAT). The free fractions and the total drug concentrations, hence free drug concentrations, were consistently higher in the core than in the BAT at 1 and 6 hours postdose. The delivery disadvantages in the brain and BAT were further evidenced by the low total drug concentrations in these areas that did not consistently exceed the in vitro cytotoxic concentration (IC 50 ). Taken together, the regional differences in free drug exposure across the intracranial tumor may be responsible for compromising efficacy of ponatinib in orthotopic GBM6. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Transcranial light-emitting diode therapy for neuropsychological improvement after traumatic brain injury: a new perspective for diffuse axonal lesion management

PubMed Central

dos Santos, João Gustavo Rocha Peixoto; Paiva, Wellingson Silva; Teixeira, Manoel Jacobsen

2018-01-01

The cost of traumatic brain injury (TBI) for public health policies is undeniable today. Even patients who suffer from mild TBI may persist with cognitive symptoms weeks after the accident. Most of them show no lesion in computed tomography or conventional magnetic resonance imaging, but microstructural white matter abnormalities (diffuse axonal lesion) can be found in diffusion tensor imaging. Different brain networks work together to form an important part of the cognition process, and they can be affected by TBI. The default mode network (DMN) plays an important central role in normal brain activities, presenting greater relative deactivation during more cognitively demanding tasks. After deactivation, it allows a distinct network to activate. This network (the central executive network) acts mainly during tasks involving executive functions. The salience network is another network necessary for normal executive function, and its activation leads to deactivation of the DMN. The use of red or near-infrared (NIR) light to stimulate or regenerate tissue is known as photobiomodulation. It was discovered that NIR (wavelength 800–900 nm) and red (wavelength 600 nm) light-emitting diodes (LEDs) are able to penetrate through scalp and skull and have the potential to improve the subnormal, cellular activity of compromised brain tissue. Based on this, different experimental and clinical studies were done to test LED therapy for TBI, and promising results were found. It leads us to consider developing different approaches to maximize the positive effects of this therapy and improve the quality of life of TBI patients. PMID:29731669

Metabolism and possible health effects of aluminum.

PubMed Central

Ganrot, P O

1986-01-01

Literature regarding the biochemistry of aluminum and eight similar ions is reviewed. Close and hitherto unknown similarities were found. A hypothetical model is presented for the metabolism, based on documented direct observations of Al3+ and analogies from other ions. Main characteristics are low intestinal absorption, rapid urinary excretion, and slow tissue uptake, mostly in skeleton and reticuloendothelial cells. Intracellular Al3+ is probably first confined in the lysosomes but then slowly accumulates in the cell nucleus and chromatin. Large, long-lived cells, e.g., neurons, may be the most liable to this accumulation. In heterochromatin, Al3+ levels can be found comparable to those used in leather tannage. It is proposed that an accumulation may take place at a subcellular level without any significant increase in the corresponding tissue concentration. The possible effects of this accumulation are discussed. As Al3+ is neurotoxic, the brain metabolism is most interesting. The normal and the lethally toxic brain levels of Al3+ are well documented and differ only by a factor of 3-10. The normal brain uptake of Al3+ is estimated from data on intestinal uptake of Al3+ and brain uptake of radionuclides of similar ions administered intravenously. The uptake is very slow, 1 mg in 36 years, and is consistent with an assumption that Al3+ taken up by the brain cannot be eliminated and is therefore accumulated. The possibility that Al3+ may cause or contribute to some specific diseases, most of them related to aging, is discussed with the proposed metabolic picture in mind. PMID:2940082

Transcranial light-emitting diode therapy for neuropsychological improvement after traumatic brain injury: a new perspective for diffuse axonal lesion management.

PubMed

Dos Santos, João Gustavo Rocha Peixoto; Paiva, Wellingson Silva; Teixeira, Manoel Jacobsen

2018-01-01

The cost of traumatic brain injury (TBI) for public health policies is undeniable today. Even patients who suffer from mild TBI may persist with cognitive symptoms weeks after the accident. Most of them show no lesion in computed tomography or conventional magnetic resonance imaging, but microstructural white matter abnormalities (diffuse axonal lesion) can be found in diffusion tensor imaging. Different brain networks work together to form an important part of the cognition process, and they can be affected by TBI. The default mode network (DMN) plays an important central role in normal brain activities, presenting greater relative deactivation during more cognitively demanding tasks. After deactivation, it allows a distinct network to activate. This network (the central executive network) acts mainly during tasks involving executive functions. The salience network is another network necessary for normal executive function, and its activation leads to deactivation of the DMN. The use of red or near-infrared (NIR) light to stimulate or regenerate tissue is known as photobiomodulation. It was discovered that NIR (wavelength 800-900 nm) and red (wavelength 600 nm) light-emitting diodes (LEDs) are able to penetrate through scalp and skull and have the potential to improve the subnormal, cellular activity of compromised brain tissue. Based on this, different experimental and clinical studies were done to test LED therapy for TBI, and promising results were found. It leads us to consider developing different approaches to maximize the positive effects of this therapy and improve the quality of life of TBI patients.

Immediate, but Not Delayed, Microsurgical Skull Reconstruction Exacerbates Brain Damage in Experimental Traumatic Brain Injury Model

PubMed Central

Lau, Tsz; Kaneko, Yuji; van Loveren, Harry; Borlongan, Cesario V.

2012-01-01

Moderate to severe traumatic brain injury (TBI) often results in malformations to the skull. Aesthetic surgical maneuvers may offer normalized skull structure, but inconsistent surgical closure of the skull area accompanies TBI. We examined whether wound closure by replacement of skull flap and bone wax would allow aesthetic reconstruction of the TBI-induced skull damage without causing any detrimental effects to the cortical tissue. Adult male Sprague-Dawley rats were subjected to TBI using the controlled cortical impact (CCI) injury model. Immediately after the TBI surgery, animals were randomly assigned to skull flap replacement with or without bone wax or no bone reconstruction, then were euthanized at five days post-TBI for pathological analyses. The skull reconstruction provided normalized gross bone architecture, but 2,3,5-triphenyltetrazolium chloride and hematoxylin and eosin staining results revealed larger cortical damage in these animals compared to those that underwent no surgical maneuver at all. Brain swelling accompanied TBI, especially the severe model, that could have relieved the intracranial pressure in those animals with no skull reconstruction. In contrast, the immediate skull reconstruction produced an upregulation of the edema marker aquaporin-4 staining, which likely prevented the therapeutic benefits of brain swelling and resulted in larger cortical infarcts. Interestingly, TBI animals introduced to a delay in skull reconstruction (i.e., 2 days post-TBI) showed significantly reduced edema and infarcts compared to those exposed to immediate skull reconstruction. That immediate, but not delayed, skull reconstruction may exacerbate TBI-induced cortical tissue damage warrants a careful consideration of aesthetic repair of the skull in TBI. PMID:22438975

Stereology techniques in radiation biology

NASA Technical Reports Server (NTRS)

Kubinova, Lucie; Mao, XiaoWen; Janacek, Jiri; Archambeau, John O.; Nelson, G. A. (Principal Investigator)

2003-01-01

Clinicians involved in conventional radiation therapy are very concerned about the dose-response relationships of normal tissues. Before proceeding to new clinical protocols, radiation biologists involved with conformal proton therapy believe it is necessary to quantify the dose response and tolerance of the organs and tissues that will be irradiated. An important focus is on the vasculature. This presentation reviews the methodology and format of using confocal microscopy and stereological methods to quantify tissue parameters, cell number, tissue volume and surface area, and vessel length using the microvasculature as a model tissue. Stereological methods and their concepts are illustrated using an ongoing study of the dose response of the microvessels in proton-irradiated hemibrain. Methods for estimating the volume of the brain and the brain cortex, the total number of endothelial cells in cortical microvessels, the length of cortical microvessels, and the total surface area of cortical microvessel walls are presented step by step in a way understandable for readers with little mathematical background. It is shown that stereological techniques, based on a sound theoretical basis, are powerful and reliable and have been used successfully.

Boron attenuates malathion-induced oxidative stress and acetylcholinesterase inhibition in rats.

PubMed

Coban, Funda Karabag; Ince, Sinan; Kucukkurt, Ismail; Demirel, Hasan Huseyin; Hazman, Omer

2015-10-01

Organophosphorus compounds cause oxidative stress and lead to alterations in antioxidant status in organisms. In this study, the effects of subchronic exposure to malathion and the protective effects of boron (B) were evaluated in 48 Wistar rats, which were divided equally into six groups. For 28 d, the control group received a normal diet and tap water, the corn oil group received a normal diet and 0.5 mL of corn oil by gastric gavage and the malathion group received a normal diet and malathion (100 mg/kg/d) by gastric gavage. During the same period, each of the three other groups received a different dosage of B (5, 10 and 20 mg/kg/d, respectively) and malathion (100 mg/kg/d) by gastric gavage. Malathion administration during the period increased malondialdehyde, nitric oxide and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, as well as markers of liver function, yet decreased acetylcholinesterase, reduced glutathione, superoxide dismutase, and catalase activities in blood, liver, kidney and brain tissues. Administration of B in a dose-dependent manner also reversed malathion-induced oxidative stress, lipid peroxidation (LPO) and antioxidant enzyme activity. Moreover, B exhibited protective action against malathion-induced histopathological changes in liver, kidney and brain tissues. These results demonstrate that, if used in a dose-dependent manner, B decreases malathion-induced oxidative stress, enhances the antioxidant defense mechanism and regenerates tissues in rats.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Buis, Dennis R.; Lagerwaard, Frank J.; Dirven, Clemens M.F.

Purpose: To assess the dosimetric consequences of brain arteriovenous malformation (bAVM) delineation on magnetic resonance angiography (MRA) for the purpose of stereotactic radiosurgery. Methods and Materials: Three observers contoured a bAVM in 20 patients, using digital subtraction angiography (V{sub DSA}) and three-dimensional time-of-flight MRA (V{sub MRA}). Displacement between contours was calculated. Agreement and differences between observers and imaging modalities were assessed. A standardized treatment plan with dynamic conformal arcs was generated and dosimetric coverage of all contours and the volume of normal brain tissue within the high dose region was determined. Results: The generalized reliability coefficient was 'fair' for targetmore » volume (0.79), but 'poor' for displacement (0.35). V{sub MRA} was larger than V{sub DSA} (5.0 vs. 4.0 mL, p = 0.001). No difference in displacement was found (2.8 vs. 2.5 mm, p = 0.156). Dosimetric coverage of V{sub MRA} was 62.9% (95% CI, 56.9-68.8) when V{sub DSA} was used as planning target volume, and coverage of V{sub DSA} was 83.5% (95% CI, 78.1-88.8) when V{sub MRA} was used for planning (p < 0.001). The mean volume of normal brain within the 80% isodose was larger when the bAVM was delineated on MRA (0.7 vs. 1.0 mL (p = 0.02) for targets {<=}3 mL and 3.7 vs. 7.0 mL (p = 0.01) for targets >3 mL). Conclusions: Brain arteriovenous malformations delineated on MRA are larger and more randomly displaced. However, for bAVMs {<=}3 mL, the difference in volume of normal brain tissue within the high-dose region does not seem to be clinically relevant. Therefore, MRA-images might be used as the sole imaging modality for the radiosurgical treatment of bAVMs {<=}3 mL when the bAVM is located in a noneloquent position.« less

Focused Ultrasound-Induced Blood–Brain Barrier Opening to Enhance Temozolomide Delivery for Glioblastoma Treatment: A Preclinical Study

PubMed Central

Wei, Kuo-Chen; Chu, Po-Chun; Wang, Hay-Yan Jack; Huang, Chiung-Yin; Chen, Pin-Yuan; Tsai, Hong-Chieh; Lu, Yu-Jen; Lee, Pei-Yun; Tseng, I-Chou; Feng, Li-Ying; Hsu, Peng-Wei; Yen, Tzu-Chen; Liu, Hao-Li

2013-01-01

The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment. PMID:23527068

Glymphatic MRI in idiopathic normal pressure hydrocephalus

PubMed Central

Ringstad, Geir; Vatnehol, Svein Are Sirirud; Eide, Per Kristian

2017-01-01

Abstract The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer’s disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging. PMID:28969373

A survey of human brain transcriptome diversity at the single cell level.

PubMed

Darmanis, Spyros; Sloan, Steven A; Zhang, Ye; Enge, Martin; Caneda, Christine; Shuer, Lawrence M; Hayden Gephart, Melanie G; Barres, Ben A; Quake, Stephen R

2015-06-09

The human brain is a tissue of vast complexity in terms of the cell types it comprises. Conventional approaches to classifying cell types in the human brain at single cell resolution have been limited to exploring relatively few markers and therefore have provided a limited molecular characterization of any given cell type. We used single cell RNA sequencing on 466 cells to capture the cellular complexity of the adult and fetal human brain at a whole transcriptome level. Healthy adult temporal lobe tissue was obtained during surgical procedures where otherwise normal tissue was removed to gain access to deeper hippocampal pathology in patients with medical refractory seizures. We were able to classify individual cells into all of the major neuronal, glial, and vascular cell types in the brain. We were able to divide neurons into individual communities and show that these communities preserve the categorization of interneuron subtypes that is typically observed with the use of classic interneuron markers. We then used single cell RNA sequencing on fetal human cortical neurons to identify genes that are differentially expressed between fetal and adult neurons and those genes that display an expression gradient that reflects the transition between replicating and quiescent fetal neuronal populations. Finally, we observed the expression of major histocompatibility complex type I genes in a subset of adult neurons, but not fetal neurons. The work presented here demonstrates the applicability of single cell RNA sequencing on the study of the adult human brain and constitutes a first step toward a comprehensive cellular atlas of the human brain.

High-Speed and Scalable Whole-Brain Imaging in Rodents and Primates.

PubMed

Seiriki, Kaoru; Kasai, Atsushi; Hashimoto, Takeshi; Schulze, Wiebke; Niu, Misaki; Yamaguchi, Shun; Nakazawa, Takanobu; Inoue, Ken-Ichi; Uezono, Shiori; Takada, Masahiko; Naka, Yuichiro; Igarashi, Hisato; Tanuma, Masato; Waschek, James A; Ago, Yukio; Tanaka, Kenji F; Hayata-Takano, Atsuko; Nagayasu, Kazuki; Shintani, Norihito; Hashimoto, Ryota; Kunii, Yasuto; Hino, Mizuki; Matsumoto, Junya; Yabe, Hirooki; Nagai, Takeharu; Fujita, Katsumasa; Matsuda, Toshio; Takuma, Kazuhiro; Baba, Akemichi; Hashimoto, Hitoshi

2017-06-21

Subcellular resolution imaging of the whole brain and subsequent image analysis are prerequisites for understanding anatomical and functional brain networks. Here, we have developed a very high-speed serial-sectioning imaging system named FAST (block-face serial microscopy tomography), which acquires high-resolution images of a whole mouse brain in a speed range comparable to that of light-sheet fluorescence microscopy. FAST enables complete visualization of the brain at a resolution sufficient to resolve all cells and their subcellular structures. FAST renders unbiased quantitative group comparisons of normal and disease model brain cells for the whole brain at a high spatial resolution. Furthermore, FAST is highly scalable to non-human primate brains and human postmortem brain tissues, and can visualize neuronal projections in a whole adult marmoset brain. Thus, FAST provides new opportunities for global approaches that will allow for a better understanding of brain systems in multiple animal models and in human diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Mapping human brain capillary water lifetime: high‐resolution metabolic neuroimaging

PubMed Central

Li, Xin; Sammi, Manoj K.; Bourdette, Dennis N.; Neuwelt, Edward A.

2015-01-01

Shutter‐speed analysis of dynamic‐contrast‐agent (CA)‐enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (τ b) and blood volume fraction (v b; capillary density–volume product (ρ † V)) in a high‐resolution 1H2O MRI voxel (40 μL) or ROI. The equilibrium water extravasation rate constant, k po (τ b −1), averages 3.2 and 2.9 s−1 in resting‐state normal white matter (NWM) and gray matter (NGM), respectively (n = 6). The results (italicized) lead to three major conclusions. (A) k po differences are dominated by capillary water permeability (P W †), not size, differences. NWM and NGM voxel k po and vb values are independent. Quantitative analyses of concomitant population‐averaged k po, vb variations in normal and normal‐appearing MS brain ROIs confirm PW † dominance. (B) P W † is dominated (>95%) by a trans(endothelial)cellular pathway, not the P CA † paracellular route. In MS lesions and GBM tumors, PCA † increases but PW † decreases. (C) k po tracks steady‐state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional k po correlates with literature MRSI ATP (positively) and Na + (negatively) tissue concentrations. This suggests that the PW † pathway is metabolically active. Excellent agreement of the relative NGM/NWM k po vb product ratio with the literature 31PMRSI‐MT CMRoxphos ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (k io) is proportional to plasma membrane P‐type ATPase turnover, likely due to active trans‐membrane water cycling. With synaptic proximities and synergistic metabolic cooperativities, polar brain endothelial, neuroglial, and neuronal cells form “gliovascular units.” We hypothesize that a chain of water cycling processes transmits brain metabolic activity to k po, letting it report neurogliovascular unit Na+,K+‐ATPase activity. Cerebral k po maps represent metabolic (functional) neuroimages. The NGM 2.9 s−1 k po means an equilibrium unidirectional water efflux of ~1015 H2O molecules s−1 per capillary (in 1 μL tissue): consistent with the known ATP consumption rate and water co‐transporting membrane symporter stoichiometries. © 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd. PMID:25914365

Brain infection with Staphylococcus aureus leads to high extracellular levels of glutamate, aspartate, γ-aminobutyric acid, and zinc.

PubMed

Hassel, Bjørnar; Dahlberg, Daniel; Mariussen, Espen; Goverud, Ingeborg Løstegaard; Antal, Ellen-Ann; Tønjum, Tone; Maehlen, Jan

2014-12-01

Staphylococcal brain infections may cause mental deterioration and epileptic seizures, suggesting interference with normal neurotransmission in the brain. We injected Staphylococcus aureus into rat striatum and found an initial 76% reduction in the extracellular level of glutamate as detected by microdialysis at 2 hr after staphylococcal infection. At 8 hr after staphylococcal infection, however, the extracellular level of glutamate had increased 12-fold, and at 20 hr it had increased >30-fold. The extracellular level of aspartate and γ-aminobutyric acid (GABA) also increased greatly. Extracellular Zn(2+) , which was estimated at ∼2.6 µmol/liter in the control situation, was increased by 330% 1-2.5 hr after staphylococcal infection and by 100% at 8 and 20 hr. The increase in extracellular glutamate, aspartate, and GABA appeared to reflect the degree of tissue damage. The area of tissue damage greatly exceeded the area of staphylococcal infiltration, pointing to soluble factors being responsible for cell death. However, the N-methyl-D-aspartate receptor antagonist MK-801 ameliorated neither tissue damage nor the increase in extracellular neuroactive amino acids, suggesting the presence of neurotoxic factors other than glutamate and aspartate. In vitro staphylococci incubated with glutamine and glucose formed glutamate, so bacteria could be an additional source of infection-related glutamate. We conclude that the dramatic increase in the extracellular concentration of neuroactive amino acids and zinc could interfere with neurotransmission in the surrounding brain tissue, contributing to mental deterioration and a predisposition to epileptic seizures, which are often seen in brain abscess patients. © 2014 Wiley Periodicals, Inc.

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

PubMed Central

Hametner, Simon; Yao, Bing; van Gelderen, Peter; Merkle, Hellmut; Cantor, Fredric K.; Lassmann, Hans; Duyn, Jeff H.

2011-01-01

Previous authors have shown that the transverse relaxivity R2* and frequency shifts that characterize gradient echo signal decay in magnetic resonance imaging are closely associated with the distribution of iron and myelin in the brain's white matter. In multiple sclerosis, iron accumulation in brain tissue may reflect a multiplicity of pathological processes. Hence, iron may have the unique potential to serve as an in vivo magnetic resonance imaging tracer of disease pathology. To investigate the ability of iron in tracking multiple sclerosis-induced pathology by magnetic resonance imaging, we performed qualitative histopathological analysis of white matter lesions and normal-appearing white matter regions with variable appearance on gradient echo magnetic resonance imaging at 7 Tesla. The samples used for this study derive from two patients with multiple sclerosis and one non-multiple sclerosis donor. Magnetic resonance images were acquired using a whole body 7 Tesla magnetic resonance imaging scanner equipped with a 24-channel receive-only array designed for tissue imaging. A 3D multi-gradient echo sequence was obtained and quantitative R2* and phase maps were reconstructed. Immunohistochemical stainings for myelin and oligodendrocytes, microglia and macrophages, ferritin and ferritin light polypeptide were performed on 3- to 5-µm thick paraffin sections. Iron was detected with Perl's staining and 3,3′-diaminobenzidine-tetrahydrochloride enhanced Turnbull blue staining. In multiple sclerosis tissue, iron presence invariably matched with an increase in R2*. Conversely, R2* increase was not always associated with the presence of iron on histochemical staining. We interpret this finding as the effect of embedding, sectioning and staining procedures. These processes likely affected the histopathological analysis results but not the magnetic resonance imaging that was obtained before tissue manipulations. Several cellular sources of iron were identified. These sources included oligodendrocytes in normal-appearing white matter and activated macrophages/microglia at the edges of white matter lesions. Additionally, in white matter lesions, iron precipitation in aggregates typical of microbleeds was shown by the Perl's staining. Our combined imaging and pathological study shows that multi-gradient echo magnetic resonance imaging is a sensitive technique for the identification of iron in the brain tissue of patients with multiple sclerosis. However, magnetic resonance imaging-identified iron does not necessarily reflect pathology and may also be seen in apparently normal tissue. Iron identification by multi-gradient echo magnetic resonance imaging in diseased tissues can shed light on the pathological processes when coupled with topographical information and patient disease history. PMID:22171355

Determinants of iron accumulation in the normal aging brain.

PubMed

Pirpamer, Lukas; Hofer, Edith; Gesierich, Benno; De Guio, François; Freudenberger, Paul; Seiler, Stephan; Duering, Marco; Jouvent, Eric; Duchesnay, Edouard; Dichgans, Martin; Ropele, Stefan; Schmidt, Reinhold

2016-07-01

In a recent postmortem study, R2* relaxometry in gray matter (GM) of the brain has been validated as a noninvasive measure for iron content in brain tissue. Iron accumulation in the normal aging brain is a common finding and relates to brain maturation and degeneration. The goal of this study was to assess the determinants of iron accumulation during brain aging. The study cohort consisted of 314 healthy community-dwelling participants of the Austrian Stroke Prevention Study. Their age ranged from 38-82 years. Quantitative magnetic resonance imaging was performed on 3T and included R2* mapping, based on a 3D multi-echo gradient echo sequence. The median of R2* values was measured in all GM regions, which were segmented automatically using FreeSurfer. We investigated 25 possible determinants for cerebral iron deposition. These included demographics, brain volume, lifestyle factors, cerebrovascular risk factors, serum levels of iron, and single nucleotide polymorphisms related to iron regulating genes (rs1800562, rs3811647, rs1799945, and rs1049296). The body mass index (BMI) was significantly related to R2* in 15/32 analyzed brain regions with the strongest correlations found in the amygdala (p = 0.0091), medial temporal lobe (p = 0.0002), and hippocampus (p ≤ 0.0001). Further associations to R2* values were found in deep GM for age and smoking. No significant associations were found for gender, GM volume, serum levels of iron, or iron-associated genetic polymorphisms. In conclusion, besides age, the BMI and smoking are the only significant determinants of brain iron accumulation in normally aging subjects. Smoking relates to iron deposition in the basal ganglia, whereas higher BMI is associated with iron content in the neocortex following an Alzheimer-like distribution. Copyright © 2016 Elsevier Inc. All rights reserved.

SU-E-T-79: Comparison of Doses Received by the Hippocampus in Patients Treated with Single Vs Multiple Isocenter Based Stereotactic Radiation Therapy to the Brain for Multiple Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Algan, O; Giem, J; Young, J

Purpose: To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiotherapy utilizing a single isocenter (SI) versus multiple isocenter (MI) in patients with multiple intracranial metastases. Methods: Seven patients imaged with MRI including SPGR sequence and diagnosed with 2–3 brain metastases were included in this retrospective study. Two sets of stereotactic IMRT treatment plans, (MI vs SI), were generated. The hippocampus was contoured on SPGR sequences and doses received by the hippocampus and whole brain were calculated. The prescribed dose was 25Gy in 5 fractions. The two groups were compared using t-testmore » analysis. Results: There were 17 lesions in 7 patients. The median tumor, right hippocampus, left hippocampus and brain volumes were: 3.37cc, 2.56cc, 3.28cc, and 1417cc respectively. In comparing the two treatment plans, there was no difference in the PTV coverage except in the tail of the DVH curve. All tumors had V95 > 99.5%. The only statistically significant parameter was the V100 (72% vs 45%, p=0.002, favoring MI). All other evaluated parameters including the V95 and V98 did not reveal any statistically significant differences. None of the evaluated dosimetric parameters for the hippocampus (V100, V80, V60, V40, V20, V10, D100, D90, D70, D50, D30, D10) revealed any statistically significant differences (all p-values > 0.31) between MI and SI plans. The total brain dose was slightly higher in the SI plans, especially in the lower dose regions, although this difference was not statistically significant. Utilizing brain-sub-PTV volumes did not change these results. Conclusion: The use of SI treatment planning for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain compared to MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.« less

Ultrasound-mediated delivery and distribution of polymeric nanoparticles in the normal brain parenchyma of a metastatic brain tumour model

PubMed Central

Baghirov, Habib; Snipstad, Sofie; Sulheim, Einar; Berg, Sigrid; Hansen, Rune; Thorsen, Frits; Mørch, Yrr; Åslund, Andreas K. O.

2018-01-01

The treatment of brain diseases is hindered by the blood-brain barrier (BBB) preventing most drugs from entering the brain. Focused ultrasound (FUS) with microbubbles can open the BBB safely and reversibly. Systemic drug injection might induce toxicity, but encapsulation into nanoparticles reduces accumulation in normal tissue. Here we used a novel platform based on poly(2-ethyl-butyl cyanoacrylate) nanoparticle-stabilized microbubbles to permeabilize the BBB in a melanoma brain metastasis model. With a dual-frequency ultrasound transducer generating FUS at 1.1 MHz and 7.8 MHz, we opened the BBB using nanoparticle-microbubbles and low-frequency FUS, and applied high-frequency FUS to generate acoustic radiation force and push nanoparticles through the extracellular matrix. Using confocal microscopy and image analysis, we quantified nanoparticle extravasation and distribution in the brain parenchyma. We also evaluated haemorrhage, as well as the expression of P-glycoprotein, a key BBB component. FUS and microbubbles distributed nanoparticles in the brain parenchyma, and the distribution depended on the extent of BBB opening. The results from acoustic radiation force were not conclusive, but in a few animals some effect could be detected. P-glycoprotein was not significantly altered immediately after sonication. In summary, FUS with our nanoparticle-stabilized microbubbles can achieve accumulation and displacement of nanoparticles in the brain parenchyma. PMID:29338016

Cholinesterase (ChE) response and related mortality among birds fed ChE inhibitors

USGS Publications Warehouse

Ludke, J.L.; Hill, E.F.; Dieter, M.P.

1975-01-01

Patterns of mortality and inhibition of brain and plasma ChE in birds treated with ChE inhibitors were studied in an attempt to determine the validity of using ChE activity as a monitoring and diagnostic technique. Analysis of brain ChE activity proved to be reliable for diagnosing and monitoring effects of selected ChE inhibitors in birds. Brain ChE inhibition exceeding 20% indicated exposure, and inhibition greater than 50% was sufficient for diagnosing cause of death. Individuals that died from dietary exposure to parathion or carbofuran had brain ChE activities below 55% of normal; although individuals could survive with brain ChE activity lower than 50%. Problems associated with collection, storage, and analysis of tissues for ChE activity are discussed.

Total and regional brain volumes in a population-based normative sample from 4 to 18 years: the NIH MRI Study of Normal Brain Development.

PubMed

2012-01-01

Using a population-based sampling strategy, the National Institutes of Health (NIH) Magnetic Resonance Imaging Study of Normal Brain Development compiled a longitudinal normative reference database of neuroimaging and correlated clinical/behavioral data from a demographically representative sample of healthy children and adolescents aged newborn through early adulthood. The present paper reports brain volume data for 325 children, ages 4.5-18 years, from the first cross-sectional time point. Measures included volumes of whole-brain gray matter (GM) and white matter (WM), left and right lateral ventricles, frontal, temporal, parietal and occipital lobe GM and WM, subcortical GM (thalamus, caudate, putamen, and globus pallidus), cerebellum, and brainstem. Associations with cross-sectional age, sex, family income, parental education, and body mass index (BMI) were evaluated. Key observations are: 1) age-related decreases in lobar GM most prominent in parietal and occipital cortex; 2) age-related increases in lobar WM, greatest in occipital, followed by the temporal lobe; 3) age-related trajectories predominantly curvilinear in females, but linear in males; and 4) small systematic associations of brain tissue volumes with BMI but not with IQ, family income, or parental education. These findings constitute a normative reference on regional brain volumes in children and adolescents.

Immunopathological Changes in the Brain of Immunosuppressed Mice Experimentally Infected with Toxocara canis

PubMed Central

Eid, Mohamed M.; El-Kowrany, Samy I.; Othman, Ahmad A.; Gendy, Dina I. El; Saied, Eman M.

2015-01-01

Toxocariasis is a soil-transmitted helminthozoonosis due to infection of humans by larvae of Toxocara canis. The disease could produce cognitive and behavioral disturbances especially in children. Meanwhile, in our modern era, the incidence of immunosuppression has been progressively increasing due to increased incidence of malignancy as well as increased use of immunosuppressive agents. The present study aimed at comparing some of the pathological and immunological alterations in the brain of normal and immunosuppressed mice experimentally infected with T. canis. Therefore, 180 Swiss albino mice were divided into 4 groups including normal (control) group, immunocompetent T. canis-infected group, immunosuppressed group (control), and immunosuppressed infected group. Infected mice were subjected to larval counts in the brain, and the brains from all mice were assessed for histopathological changes, astrogliosis, and IL-5 mRNA expression levels in brain tissues. The results showed that under immunosuppression, there were significant increase in brain larval counts, significant enhancement of reactive gliosis, and significant reduction in IL-5 mRNA expression. All these changes were maximal in the chronic stage of infection. In conclusion, the immunopathological alterations in the brains of infected animals were progressive over time, and were exaggerated under the effect of immunosuppression as did the intensity of cerebral infection. PMID:25748709

A Dual Tracer 18F-FCH/18F-FDG PET Imaging of an Orthotopic Brain Tumor Xenograft Model.

PubMed

Fu, Yilong; Ong, Lai-Chun; Ranganath, Sudhir H; Zheng, Lin; Kee, Irene; Zhan, Wenbo; Yu, Sidney; Chow, Pierce K H; Wang, Chi-Hwa

2016-01-01

Early diagnosis of low grade glioma has been a challenge to clinicians. Positron Emission Tomography (PET) using 18F-FDG as a radio-tracer has limited utility in this area because of the high background in normal brain tissue. Other radiotracers such as 18F-Fluorocholine (18F-FCH) could provide better contrast between tumor and normal brain tissue but with high incidence of false positives. In this study, the potential application of a dual tracer 18F-FCH/18F-FDG-PET is investigated in order to improve the sensitivity of PET imaging for low grade glioma diagnosis based on a mouse orthotopic xenograft model. BALB/c nude mice with and without orthotopic glioma xenografts from U87 MG-luc2 glioma cell line are used for the study. The animals are subjected to 18F-FCH and 18F-FDG PET imaging, and images acquired from two separate scans are superimposed for analysis. The 18F-FCH counts are subtracted from the merged images to identify the tumor. Micro-CT, bioluminescence imaging (BLI), histology and measurement of the tumor diameter are also conducted for comparison. Results show that there is a significant contrast in 18F-FCH uptake between tumor and normal brain tissue (2.65 ± 0.98), but with a high false positive rate of 28.6%. The difficulty of identifying the tumor by 18F-FDG only is also proved in this study. All the tumors can be detected based on the dual tracer technique of 18F-FCH/18F-FDG-PET imaging in this study, while the false-positive caused by 18F-FCH can be eliminated. Dual tracer 18F-FCH/18F-FDG PET imaging has the potential to improve the visualization of low grade glioma. 18F-FCH delineates tumor areas and the tumor can be identified by subtracting the 18F-FCH counts. The sensitivity was over 95%. Further studies are required to evaluate the possibility of applying this technique in clinical trials.

A Dual Tracer 18F-FCH/18F-FDG PET Imaging of an Orthotopic Brain Tumor Xenograft Model

PubMed Central

Ranganath, Sudhir H.; Zheng, Lin; Kee, Irene; Zhan, Wenbo; Yu, Sidney; Chow, Pierce K. H.; Wang, Chi-Hwa

2016-01-01

Early diagnosis of low grade glioma has been a challenge to clinicians. Positron Emission Tomography (PET) using 18F-FDG as a radio-tracer has limited utility in this area because of the high background in normal brain tissue. Other radiotracers such as 18F-Fluorocholine (18F-FCH) could provide better contrast between tumor and normal brain tissue but with high incidence of false positives. In this study, the potential application of a dual tracer 18F-FCH/18F-FDG-PET is investigated in order to improve the sensitivity of PET imaging for low grade glioma diagnosis based on a mouse orthotopic xenograft model. BALB/c nude mice with and without orthotopic glioma xenografts from U87 MG-luc2 glioma cell line are used for the study. The animals are subjected to 18F-FCH and 18F-FDG PET imaging, and images acquired from two separate scans are superimposed for analysis. The 18F-FCH counts are subtracted from the merged images to identify the tumor. Micro-CT, bioluminescence imaging (BLI), histology and measurement of the tumor diameter are also conducted for comparison. Results show that there is a significant contrast in 18F-FCH uptake between tumor and normal brain tissue (2.65 ± 0.98), but with a high false positive rate of 28.6%. The difficulty of identifying the tumor by 18F-FDG only is also proved in this study. All the tumors can be detected based on the dual tracer technique of 18F-FCH/ 18F-FDG-PET imaging in this study, while the false-positive caused by 18F-FCH can be eliminated. Dual tracer 18F-FCH/18F-FDG PET imaging has the potential to improve the visualization of low grade glioma. 18F-FCH delineates tumor areas and the tumor can be identified by subtracting the 18F-FCH counts. The sensitivity was over 95%. Further studies are required to evaluate the possibility of applying this technique in clinical trials. PMID:26844770

Acute coenurosis of dairy sheep from 11 flocks in Greece.

PubMed

Giadinis, N D; Psychas, V; Polizopoulou, Z; Papadopoulos, E; Papaioannou, N; Komnenou, A Th; Thomas, A-L; Petridou, E J; Kritsepi-Konstantinou, M; Lafi, S Q; Brellou, G D

2012-07-01

A syndrome of acute neurological dysfunction with increased mortality was observed in lambs of 10 dairy sheep flocks and adult animals in one flock in Central and Northern Greece. Each farmer completed a questionnaire regarding the management and feeding of their flocks. In seven of the 11 flocks the affected animals were grazing pasture, while in the remaining four flocks (5, 8, 9, 10) the animals were fed alfalfa hay (Medicago sativa) and concentrates indoors. A follow-up study of the affected flocks was conducted during the next 12 months. Of 42 sheep with acute coenurosis that were examined, the most prominent neurological abnormalities were ataxia, depression, blindness, scoliosis, coma and dysmetria. Except for the four sheep that were comatose, all other animals had normal body temperatures and their appetites remained normal or were slightly decreased. Haematological findings of 15 examined sheep were within normal limits. The affected sheep were subject to euthanasia. A histopathological examination was performed in 13 cases. Faecal samples from dogs associated with these flocks were negative for taeniid infections. During the following 12 months cases of chronic coenurosis in these flocks were observed. In the 42 animals that were necropsied, the main gross findings were cystic formations between 0.5-1 cm in diameter with translucent walls that were seen lying free on the leptomeninges or partly penetrating the brain tissue, sterile microabscecess and brain necrosis. Histopathological evaluation of tissue sections of 13 brains showed multifocal purulent or pyogranulomatous meningoencephalitis, accompanied by eosinophilic infiltrations. No bacteria were isolated following bacterial culture of brain tissue Parasitological examination of the cysts from five cases revealed whitish specks on the transparent cyst wall and germination membrane representing the scolices. Acute coenurosis was diagnosed in all cases studied. Acute coenurosis can be one of the causes of acute encephalopathy mainly in lambs, but also in adult sheep. This condition is incurable, but can be controlled by changing the feeding regime. Cases of chronic coenurosis may be seen a few months later in the same flock.

Glycoblotting method allows for rapid and efficient glycome profiling of human Alzheimer's disease brain, serum and cerebrospinal fluid towards potential biomarker discovery.

PubMed

Gizaw, Solomon T; Ohashi, Tetsu; Tanaka, Masakazu; Hinou, Hiroshi; Nishimura, Shin-Ichiro

2016-08-01

Understanding of the significance of posttranslational glycosylation in Alzheimer's disease (AD) is of growing importance for the investigation of the pathogenesis of AD as well as discovery research of the disease-specific serum biomarkers. We designed a standard protocol for the glycoblotting combined with MALDI-TOFMS to perform rapid and quantitative profiling of the glycan parts of glycoproteins (N-glycans) and glycosphingolipids (GSLs) using human AD's post-mortem samples such as brain tissues (dissected cerebral cortices such as frontal, parietal, occipital, and temporal domains), serum and cerebrospinal fluid (CSF). The structural profiles of the major N-glycans released from glycoproteins and the total expression levels of the glycans were found to be mostly similar between the brain tissues of the AD patients and those of the normal control group. In contrast, the expression levels of the serum and CSF protein N-glycans such as bisect-type and multiply branched glycoforms were increased significantly in AD patient group. In addition, the levels of some gangliosides such as GM1, GM2 and GM3 appeared to alter in the AD patient brain and serum samples when compared with the normal control groups. Alteration of the expression levels of major N- and GSL-glycans in human brain tissues, serum and CSF of AD patients can be monitored quantitatively by means of the glycoblotting-based standard protocols. The changes in the expression levels of the glycans derived from the human post-mortem samples uncovered by the standardized glycoblotting method provides potential serum biomarkers in central nervous system disorders and can contribute to the insight into the molecular mechanisms in the pathogenesis of neurodegenerative diseases and future drug discovery. Most importantly, the present preliminary trials using human post-mortem samples of AD patients suggest that large-scale serum glycomics cohort by means of various-types of human AD patients as well as the normal control sera can facilitate the discovery research of highly sensitive and reliable serum biomarkers for an early diagnosis of AD. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. Copyright © 2016 Elsevier B.V. All rights reserved.

Intraoperative monitoring of brain tissue oxygenation during arteriovenous malformation resection.

PubMed

Arikan, Fuat; Vilalta, Jordi; Noguer, Montserrat; Olive, Montserrat; Vidal-Jorge, Marian; Sahuquillo, Juan

2014-10-01

In normal perfusion pressure breakthrough (NPPB) it is assumed that following arteriovenous malformation (AVM) resection, vasoparalysis persists in the margins of the lesion and that a sudden increase in cerebral blood flow (CBF) after AVM exclusion leads to brain swelling and postsurgical complications. However, the pathophysiology NPPB remains controversial.The aim of our study was to investigate the oxygenation status in tissue surrounding AVMs and in the distant brain using intraoperative monitoring of cerebral partial pressure of oxygen (PtiO(2)) to achieve a better understanding of NPPB pathophysiology. Patients with supratentorial AVMs were monitored intraoperatively using 2 polarographic Clark-type electrodes. To establish reference values, we also studied PtiO(2) in a group of patients who underwent surgery to treat incidental aneurysms. Twenty-two patients with supratentorial AVMs and 16 patients with incidentally found aneurysms were included. Hypoxic pattern was defined as PtiO(2)≤15 mm Hg and/or PtiO(2)/PaO(2) ratio ≤0.10. Tissue hypoxia was detected in 63.6% of the catheters placed in the perinidal area and in 43.8% of catheters placed in a distant area. AVM excision significantly improved oxygenation both around the AVM and in the distant area. The PtiO(2)/PaO(2) ratio is a better indicator than absolute PtiO(2) in detecting tissue hypoxia in mechanically ventilated patients. Intraoperative monitoring showed tissue hypoxia in the margins of AVMs and in the distant ipsilateral brain as the most common finding. Surgical removal of AVMs induces a significant improvement in the oxygenation status in both areas.

Expression profiles of inhibitor of growth protein 2 in normal and cancer tissues: An immunohistochemical screening analysis.

PubMed

Zhao, Shuang; Yang, Xue-Feng; Gou, Wen-Feng; Lu, Hang; Li, Hua; Zhu, Zhi-Tu; Sun, Hong-Zhi; Zheng, Hua-Chuan

2016-02-01

Inhibitor of growth protein 2 (ING2) has an important role in the regulation of chromatin remodeling, cell proliferation, cell‑cycle arrest, senescence and apoptosis. The present study performed an immunohistochemical analysis for expression profiling of ING2 protein in an array of tissues comprising normal mouse and human tissues, as well as human hepatocellular (n=62), renal clear cell (n=62), pancreatic (n=62), esophageal squamous cell (n=45), cervical squamous cell (n=31), breast (n=144), gastric (n=196), colorectal (n=96), ovarian (n=208), endometrial (n=96) and lung (n=192) carcinoma tissues. In mouse tissues, ING2 was detected in the nuclei and cytoplasm of the glandular epithelium of breast, hepatocytes, intestine, bronchium and alveoli, as well as the squamous epithelium of skin and glomeruli, and in myocardial cells, while it was located in the cytoplasm of renal tubules and striated muscle cells. ING2 protein was scattered in the brain and spleen. In human tissues, ING2 protein was principally distributed in the cytoplasm, while in it was present in the cytoplasm and nuclei in the stomach, intestine, cervix, endometrium trachea, breast and pancreas. The nuclear location of ING2 in the stomach was more prominent than that in the cytoplasm. High ING2 immunoreactivity was detected in the tongue, stomach, skin, pancreas, cervix and breast, whereas weakly in the brain stem, thymus, thyroid, lung, striated muscle, testis, bladder and ovary. In total, 617 out of 1,194 of the tested cancer tissues (51.7%) were ING2-positive. In most cases, ING2 expression was found to be restricted to the cytoplasm of all cancer tissues, while in certain cancer types, including renal clear cell, ovarian and colorectal carcinoma, it was occasionally present in the nuclei. Among the cancer tissues examined, ING2 was most frequently expressed in breast cancer (67.4%) and gynecological cancer types, including ovarian cancer (61.5%) and endometrial cancer (57.3%). Compared with that in the respective normal tissues, ING2 expression in breast cancer tissues was decreased, while that in cervical cancer was upregulated in the nuclei as well as the cytoplasm. In endometrial cancer, expression of ING2 was increased in the nuclei and declined in the cytoplasm compared with that in the normal endometrium. ING2‑positive cases were less frequent for renal clear cell carcinoma (17.7%). The results of the present study suggested that ING2 may be involved in the repair and regeneration of organs or tissues and is associated with breast and gynecological carcinogenesis.

Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes.

PubMed

Casanova, Ramon; Espeland, Mark A; Goveas, Joseph S; Davatzikos, Christos; Gaussoin, Sarah A; Maldjian, Joseph A; Brunner, Robert L; Kuller, Lewis H; Johnson, Karen C; Mysiw, W Jerry; Wagner, Benjamin; Resnick, Susan M

2011-05-01

Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years; however, it is unknown whether this results in a broad-based characteristic pattern of effects. Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L(1) penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluation of Reference Genes for Quantitative Real-Time PCR in Songbirds

PubMed Central

Zinzow-Kramer, Wendy M.; Horton, Brent M.; Maney, Donna L.

2014-01-01

Quantitative real-time PCR (qPCR) is becoming a popular tool for the quantification of gene expression in the brain and endocrine tissues of songbirds. Accurate analysis of qPCR data relies on the selection of appropriate reference genes for normalization, yet few papers on songbirds contain evidence of reference gene validation. Here, we evaluated the expression of ten potential reference genes (18S, ACTB, GAPDH, HMBS, HPRT, PPIA, RPL4, RPL32, TFRC, and UBC) in brain, pituitary, ovary, and testis in two species of songbird: zebra finch and white-throated sparrow. We used two algorithms, geNorm and NormFinder, to assess the stability of these reference genes in our samples. We found that the suitability of some of the most popular reference genes for target gene normalization in mammals, such as 18S, depended highly on tissue type. Thus, they are not the best choices for brain and gonad in these songbirds. In contrast, we identified alternative genes, such as HPRT, RPL4 and PPIA, that were highly stable in brain, pituitary, and gonad in these species. Our results suggest that the validation of reference genes in mammals does not necessarily extrapolate to other taxonomic groups. For researchers wishing to identify and evaluate suitable reference genes for qPCR songbirds, our results should serve as a starting point and should help increase the power and utility of songbird models in behavioral neuroendocrinology. PMID:24780145

Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes

PubMed Central

Casanova, Ramon; Espeland, Mark A.; Goveas, Joseph S.; Davatzikos, Christos; Gaussoin, Sarah A.; Maldjian, Joseph A.; Brunner, Robert L.; Kuller, Lewis H.; Johnson, Karen C.; Mysiw, W. Jerry; Wagner, Benjamin; Resnick, Susan M.

2011-01-01

Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years, however it is unknown whether this results in a broad-based characteristic pattern of effects. Structural MRI was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L1 penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and non-users. PMID:21292420

Cerebral blood perfusion after treatment with zolpidem and flumazenil in the baboon.

PubMed

Clauss, Ralf P; Dormehl, Irene C; Kilian, Elmaré; Louw, Werner K A; Nel, Wally H; Oliver, Douglas W

2002-01-01

Previous studies have shown that zolpidem (CAS 82626-48-0) can lead to improved perfusion in damaged brain tissue. Zolpidem belongs to the imidazopyridine chemical class and it illicits its pharmacological action via the gamma-aminobutyric acid (GABA) receptor system through stimulation of particularly the omega 1 receptors and to a lesser extent omega 2 receptors. Previously it was reported that no cerebral blood flow effects were observed in normal baboons after treatment with zolpidem, whereas an asymmetric regional increase in cerebral blood flow was observed in a neurologically abnormal baboon. In this study, the effect of a combination of the benzodiazepine receptor antagonist flumazenil (CAS 78755-81-4) and zolpidem on brain perfusion was examined by the 99mTc-hexamethyl-propylene amine oxime (99mTc-HMPAO) split dose brain single photon emission computed tomography (SPECT). Four normal baboons and the neurologically abnormal baboon from the previous zolpidem study were examined. In the current study the asymmetric changes observed after zolpidem--only treatment in the abnormal baboon was attenuated by flumazenil intervention. A decreased brain blood flow was observed after combination treatment of zolpidem and flumazenil in the normal baboons. The involvement of the omega receptors is suggested by these results. Up- or down-regulation of omega receptors may also contribute to the observed responses in the abnormal baboon and a brain injured patient.

Quantitative imaging of magnesium distribution at single-cell resolution in brain tumors and infiltrating tumor cells with secondary ion mass spectrometry (SIMS)

PubMed Central

Chandra, Subhash; Parker, Dylan J.; Barth, Rolf F.; Pannullo, Susan C.

2016-01-01

Glioblastoma multiforme (GBM) is one of the deadliest forms of human brain tumors. The infiltrative pattern of growth of these tumors includes the spread of individual and/or clusters of tumor cells at some distance from the main tumor mass in parts of the brain protected by an intact blood-brain-barrier. Pathophysiological studies of GBM could be greatly enhanced by analytical techniques capable of in situ single-cell resolution measurements of infiltrating tumor cells. Magnesium homeostasis is an area of active investigation in high grade gliomas. In the present study, we have used the F98 rat glioma as a model of human GBM and an elemental/isotopic imaging technique of secondary ion mass spectrometry (SIMS), a CAMECA IMS-3f ion microscope, for studying Mg distributions with single-cell resolution in freeze-dried brain tissue cryosections. Quantitative observations were made on tumor cells in the main tumor mass, contiguous brain tissue, and infiltrating tumor cells in adjacent normal brain. The brain tissue contained a significantly lower total Mg concentration of 4.70 ± 0.93 mmol/Kg wet weight (mean ± SD) in comparison to 11.64 ± 1.96 mmol/Kg wet weight in tumor cells of the main tumor mass and 10.72 ± 1.76 mmol/Kg wet weight in infiltrating tumor cells (p<0.05). The nucleus of individual tumor cells contained elevated levels of bound Mg. These observations demonstrate enhanced Mg-influx and increased binding of Mg in tumor cells and provide strong support for further investigation of GBMs for altered Mg homeostasis and activation of Mg-transporting channels as possible therapeutic targets. PMID:26703785

In silico predicted reproductive endocrine transcriptional regulatory networks during zebrafish (Danio rerio) development.

PubMed

Hala, D

2017-03-21

The interconnected topology of transcriptional regulatory networks (TRNs) readily lends to mathematical (or in silico) representation and analysis as a stoichiometric matrix. Such a matrix can be 'solved' using the mathematical method of extreme pathway (ExPa) analysis, which identifies uniquely activated genes subject to transcription factor (TF) availability. In this manuscript, in silico multi-tissue TRN models of brain, liver and gonad were used to study reproductive endocrine developmental programming in zebrafish (Danio rerio) from 0.25h post fertilization (hpf; zygote) to 90 days post fertilization (dpf; adult life stage). First, properties of TRN models were studied by sequentially activating all genes in multi-tissue models. This analysis showed the brain to exhibit lowest proportion of co-regulated genes (19%) relative to liver (23%) and gonad (32%). This was surprising given that the brain comprised 75% and 25% more TFs than liver and gonad respectively. Such 'hierarchy' of co-regulatory capability (brain

Intraoperative Magnetic Resonance Imaging of Cerebral Oxygen Metabolism During Resection of Brain Lesions.

PubMed

Stadlbauer, Andreas; Merkel, Andreas; Zimmermann, Max; Sommer, Björn; Buchfelder, Michael; Meyer-Bäse, Anke; Rössler, Karl

2017-04-01

Tissue oxygen tension is an important parameter for brain tissue viability and its noninvasive intraoperative monitoring in the whole brain is of highly clinical relevance. The purpose of this study was the introduction of a multiparametric quantitative blood oxygenation dependent magnetic resonance imaging (MRI) approach for intraoperative examination of oxygen metabolism during the resection of brain lesions. Sixteen patients suffering from brain lesions were examined intraoperatively twice (before craniotomy and after gross-total resection) via the quantitative blood oxygenation dependent technique and a 1.5-Tesla MRI scanner, which is installed in an operating room. The MRI protocol included T2*- and T2 mapping and dynamic susceptibility weighted perfusion. Data analysis was performed with a custom-made, in-house MatLab software for calculation of maps of oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO 2 ) as well as of cerebral blood volume and cerebral blood flow. Perilesional edema showed a significant increase in both perfusion (cerebral blood volume +21%, cerebral blood flow +13%) and oxygen metabolism (OEF +32%, CMRO 2  +16%) after resection of the lesions. In perilesional nonedematous tissue only, however, oxygen metabolism (OEF +19%, CMRO 2  +11%) was significantly increased, but not perfusion. No changes were found in normal brain. Fortunately, no neurovascular adverse events were observed. This approach for intraoperative examination of oxygen metabolism in the whole brain is a new application of intraoperative MRI additionally to resection control (residual tumor detection) and updating of neuronavigation (brain shift detection). It may help to detect neurovascular adverse events early during surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

Products of cells from gliomas: VIII. Multiple-well immunoperoxidase assay of immunoreactivity of primary hybridoma supernatants with human glioma and brain tissue and cultured glioma cells.

PubMed

McKeever, P E; Wahl, R L; Shakui, P; Jackson, G A; Letica, L H; Liebert, M; Taren, J A; Beierwaltes, W H; Hoff, J T

1990-06-01

To test the feasibility of primary screening of hybridoma supernatants against human glioma tissue, over 5000 combinations of hybridoma supernatants with glioma tissue, cultured glioma cells, and normal central neural tissue were screened with a new multiple-well (M-well) screening system. This is an immunoperoxidase assay system with visual endpoints for screening 20-30 hybridoma supernatants per single microscope slide. There were extensive differences between specificities to tissue and to cultured glioma cells when both were screened with M-wells and when cultured cells were screened with standard semi-automated fluorescence. Primary M-well screening with glioma tissue detected seven hybridoma supernatants that specifically identified parenchymal cells of glioma tissue and that were not detected with cultured cells. Immunoreactivities of individual supernatants for vascular components (nine supernatants), necrosis (five supernatants), and nuclei (three supernatants) were detected. Other supernatants bound multiple sites on glioma tissue and/or subpopulations of neurons and glia of normal tissue. The results show that primary screening with glioma tissue detects a number of different specificities of hybridoma supernatants to gliomas not detected by conventional screening with cultured cells. These are potentially applicable to diagnosis and therapy.

Cerebral Microcirculation and Oxygen Tension in the Human Secondary Cortex

PubMed Central

Linninger, A. A.; Gould, I. G.; Marinnan, T.; Hsu, C.-Y.; Chojecki, M.; Alaraj, A.

2013-01-01

The three-dimensional spatial arrangement of the cortical microcirculatory system is critical for understanding oxygen exchange between blood vessels and brain cells. A three-dimensional computer model of a 3 × 3 × 3 mm3 subsection of the human secondary cortex was constructed to quantify oxygen advection in the microcirculation, tissue oxygen perfusion, and consumption in the human cortex. This computer model accounts for all arterial, capillary and venous blood vessels of the cerebral microvascular bed as well as brain tissue occupying the extravascular space. Microvessels were assembled with optimization algorithms emulating angiogenic growth; a realistic capillary bed was built with space filling procedures. The extravascular tissue was modeled as a porous medium supplied with oxygen by advection–diffusion to match normal metabolic oxygen demand. The resulting synthetic computer generated network matches prior measured morphometrics and fractal patterns of the cortical microvasculature. This morphologically accurate, physiologically consistent, multi-scale computer network of the cerebral microcirculation predicts the oxygen exchange of cortical blood vessels with the surrounding gray matter. Oxygen tension subject to blood pressure and flow conditions were computed and validated for the blood as well as brain tissue. Oxygen gradients along arterioles, capillaries and veins agreed with in vivo trends observed recently in imaging studies within experimental tolerances and uncertainty. PMID:23842693

43 CFR 11.62 - Injury determination phase-injury definition.

Code of Federal Regulations, 2014 CFR

2014-10-01

... normal brain ChE activity of the wildlife species. These enzymes are in the nervous system of vertebrate... are in the nervous systems of vertebrate organisms and the rate of ChE activity is associated with the... other organs, as well as soft tissues of the gastrointestinal tract and vascular system, when comparing...

43 CFR 11.62 - Injury determination phase-injury definition.

Code of Federal Regulations, 2010 CFR

2010-10-01

... normal brain ChE activity of the wildlife species. These enzymes are in the nervous system of vertebrate... are in the nervous systems of vertebrate organisms and the rate of ChE activity is associated with the... other organs, as well as soft tissues of the gastrointestinal tract and vascular system, when comparing...

43 CFR 11.62 - Injury determination phase-injury definition.

Code of Federal Regulations, 2013 CFR

2013-10-01

... normal brain ChE activity of the wildlife species. These enzymes are in the nervous system of vertebrate... are in the nervous systems of vertebrate organisms and the rate of ChE activity is associated with the... other organs, as well as soft tissues of the gastrointestinal tract and vascular system, when comparing...

43 CFR 11.62 - Injury determination phase-injury definition.

Code of Federal Regulations, 2011 CFR

2011-10-01

... normal brain ChE activity of the wildlife species. These enzymes are in the nervous system of vertebrate... are in the nervous systems of vertebrate organisms and the rate of ChE activity is associated with the... other organs, as well as soft tissues of the gastrointestinal tract and vascular system, when comparing...

Circular RNA hsa_circ_0008344 regulates glioblastoma cell proliferation, migration, invasion, and apoptosis.

PubMed

Zhou, Jinxu; Wang, Hongxiang; Chu, Junsheng; Huang, Qilin; Li, Guangxu; Yan, Yong; Xu, Tao; Chen, Juxiang; Wang, Yuhai

2018-04-24

Recent studies have found circular RNAs (circRNAs) involved in the biological process of cancers. However, little is known about their functional roles in glioblastoma. Human circRNA microarray analysis was performed to screen the expression profile of circRNAs in IDH1 wild-type glioblastoma tissue. The expression of hsa_circ_0008344 in glioblastoma and normal brain samples was quantified by qRT-PCR. Functional experiments were performed to investigate the biological functions of hsa_circ_0008344, including MTT assay, colony formation assay, transwell assay, and cell apoptosis assay. CircRNA microarray revealed a total of 417 abnormally expressed circRNAs (>1.5-fold, P < .05) in glioblastoma tissue compared with the adjacent normal brain. Hsa_circ_0008344, among the top differentially expressed circRNAs, was significantly upregulated in IDH1 wild-type glioblastoma. Further in vitro studies showed that knockdown of hsa_circ_0008344 suppressed glioblastoma cell proliferation, colony formation, migration, and invasion, but increased cell apoptotic rate. Hsa_circ_0008344 is upregulated in glioblastoma and may contribute to the progression of this malignancy. © 2018 Wiley Periodicals, Inc.

A Unique Procedure to Identify Cell Surface Markers Through a Spherical Self-Organizing Map Applied to DNA Microarray Analysis.

PubMed

Sugii, Yuh; Kasai, Tomonari; Ikeda, Masashi; Vaidyanath, Arun; Kumon, Kazuki; Mizutani, Akifumi; Seno, Akimasa; Tokutaka, Heizo; Kudoh, Takayuki; Seno, Masaharu

2016-01-01

To identify cell-specific markers, we designed a DNA microarray platform with oligonucleotide probes for human membrane-anchored proteins. Human glioma cell lines were analyzed using microarray and compared with normal and fetal brain tissues. For the microarray analysis, we employed a spherical self-organizing map, which is a clustering method suitable for the conversion of multidimensional data into two-dimensional data and displays the relationship on a spherical surface. Based on the gene expression profile, the cell surface characteristics were successfully mirrored onto the spherical surface, thereby distinguishing normal brain tissue from the disease model based on the strength of gene expression. The clustered glioma-specific genes were further analyzed by polymerase chain reaction procedure and immunocytochemical staining of glioma cells. Our platform and the following procedure were successfully demonstrated to categorize the genes coding for cell surface proteins that are specific to glioma cells. Our assessment demonstrates that a spherical self-organizing map is a valuable tool for distinguishing cell surface markers and can be employed in marker discovery studies for the treatment of cancer.

Transfer of Minibeam Radiation Therapy into a cost-effective equipment for radiobiological studies: a proof of concept.

PubMed

Prezado, Y; Dos Santos, M; Gonzalez, W; Jouvion, G; Guardiola, C; Heinrich, S; Labiod, D; Juchaux, M; Jourdain, L; Sebrie, C; Pouzoulet, F

2017-12-11

Minibeam radiation therapy (MBRT) is an innovative synchrotron radiotherapy technique able to shift the normal tissue complication probability curves to significantly higher doses. However, its exploration was hindered due to the limited and expensive beamtime at synchrotrons. The aim of this work was to develop a cost-effective equipment to perform systematic radiobiological studies in view of MBRT. Tumor control for various tumor entities will be addressable as well as studies to unravel the distinct biological mechanisms involved in normal and tumor tissues responses when applying MBRT. With that aim, a series of modifications of a small animal irradiator were performed to make it suitable for MBRT experiments. In addition, the brains of two groups of rats were irradiated. Half of the animals received a standard irradiation, the other half, MBRT. The animals were followed-up for 6.5 months. Substantial brain damage was observed in the group receiving standard RT, in contrast to the MBRT group, where no significant lesions were observed. This work proves the feasibility of the transfer of MBRT outside synchrotron sources towards a small animal irradiator.

Molecular networks and the evolution of human cognitive specializations.

PubMed

Fontenot, Miles; Konopka, Genevieve

2014-12-01

Inroads into elucidating the origins of human cognitive specializations have taken many forms, including genetic, genomic, anatomical, and behavioral assays that typically compare humans to non-human primates. While the integration of all of these approaches is essential for ultimately understanding human cognition, here, we review the usefulness of coexpression network analysis for specifically addressing this question. An increasing number of studies have incorporated coexpression networks into brain expression studies comparing species, disease versus control tissue, brain regions, or developmental time periods. A clearer picture has emerged of the key genes driving brain evolution, as well as the developmental and regional contributions of gene expression patterns important for normal brain development and those misregulated in cognitive diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparison of doses received by the hippocampus in patients treated with single isocenter– vs multiple isocenter–based stereotactic radiation therapy to the brain for multiple brain metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Algan, Ozer, E-mail: oalgan@ouhsc.edu; Giem, Jared; Young, Julie

To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiation therapy using a single isocenter (SI)–based or multiple isocenter (MI)–based treatment planning in patients with less than 4 brain metastases. In total, 10 patients with magnetic resonance imaging (MRI) demonstrating 2-3 brain metastases were included in this retrospective study, and 2 sets of stereotactic intensity-modulated radiation therapy (IMRT) treatment plans (SI vs MI) were generated. The hippocampus was contoured on SPGR sequences, and doses received by the hippocampus and the brain were calculated and compared between the 2 treatment techniques. A totalmore » of 23 lesions in 10 patients were evaluated. The median tumor volume, the right hippocampus volume, and the left hippocampus volume were 3.15, 3.24, and 2.63 mL, respectively. In comparing the 2 treatment plans, there was no difference in the planning target volume (PTV) coverage except in the tail for the dose-volume histogram (DVH) curve. The only statistically significant dosimetric parameter was the V{sub 100}. All of the other measured dosimetric parameters including the V{sub 95}, V{sub 99}, and D{sub 100} were not significantly different between the 2 treatment planning techniques. None of the dosimetric parameters evaluated for the hippocampus revealed any statistically significant difference between the MI and SI plans. The total brain doses were slightly higher in the SI plans, especially in the lower dose region, although this difference was not statistically different. The use of SI-based treatment plan resulted in a 35% reduction in beam-on time. The use of SI treatments for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain when compared with MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.« less

Comparison of doses received by the hippocampus in patients treated with single isocenter- vs multiple isocenter-based stereotactic radiation therapy to the brain for multiple brain metastases.

PubMed

Algan, Ozer; Giem, Jared; Young, Julie; Ali, Imad; Ahmad, Salahuddin; Hossain, Sabbir

2015-01-01

To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiation therapy using a single isocenter (SI)-based or multiple isocenter (MI)-based treatment planning in patients with less than 4 brain metastases. In total, 10 patients with magnetic resonance imaging (MRI) demonstrating 2-3 brain metastases were included in this retrospective study, and 2 sets of stereotactic intensity-modulated radiation therapy (IMRT) treatment plans (SI vs MI) were generated. The hippocampus was contoured on SPGR sequences, and doses received by the hippocampus and the brain were calculated and compared between the 2 treatment techniques. A total of 23 lesions in 10 patients were evaluated. The median tumor volume, the right hippocampus volume, and the left hippocampus volume were 3.15, 3.24, and 2.63mL, respectively. In comparing the 2 treatment plans, there was no difference in the planning target volume (PTV) coverage except in the tail for the dose-volume histogram (DVH) curve. The only statistically significant dosimetric parameter was the V100. All of the other measured dosimetric parameters including the V95, V99, and D100 were not significantly different between the 2 treatment planning techniques. None of the dosimetric parameters evaluated for the hippocampus revealed any statistically significant difference between the MI and SI plans. The total brain doses were slightly higher in the SI plans, especially in the lower dose region, although this difference was not statistically different. The use of SI-based treatment plan resulted in a 35% reduction in beam-on time. The use of SI treatments for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain when compared with MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment. Copyright © 2015 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

Optimized statistical parametric mapping for partial-volume-corrected amyloid positron emission tomography in patients with Alzheimer's disease and Lewy body dementia

NASA Astrophysics Data System (ADS)

Oh, Jungsu S.; Kim, Jae Seung; Chae, Sun Young; Oh, Minyoung; Oh, Seung Jun; Cha, Seung Nam; Chang, Ho-Jong; Lee, Chong Sik; Lee, Jae Hong

2017-03-01

We present an optimized voxelwise statistical parametric mapping (SPM) of partial-volume (PV)-corrected positron emission tomography (PET) of 11C Pittsburgh Compound B (PiB), incorporating the anatomical precision of magnetic resonance image (MRI) and amyloid β (A β) burden-specificity of PiB PET. First, we applied region-based partial-volume correction (PVC), termed the geometric transfer matrix (GTM) method, to PiB PET, creating MRI-based lobar parcels filled with mean PiB uptakes. Then, we conducted a voxelwise PVC by multiplying the original PET by the ratio of a GTM-based PV-corrected PET to a 6-mm-smoothed PV-corrected PET. Finally, we conducted spatial normalizations of the PV-corrected PETs onto the study-specific template. As such, we increased the accuracy of the SPM normalization and the tissue specificity of SPM results. Moreover, lobar smoothing (instead of whole-brain smoothing) was applied to increase the signal-to-noise ratio in the image without degrading the tissue specificity. Thereby, we could optimize a voxelwise group comparison between subjects with high and normal A β burdens (from 10 patients with Alzheimer's disease, 30 patients with Lewy body dementia, and 9 normal controls). Our SPM framework outperformed than the conventional one in terms of the accuracy of the spatial normalization (85% of maximum likelihood tissue classification volume) and the tissue specificity (larger gray matter, and smaller cerebrospinal fluid volume fraction from the SPM results). Our SPM framework optimized the SPM of a PV-corrected A β PET in terms of anatomical precision, normalization accuracy, and tissue specificity, resulting in better detection and localization of A β burdens in patients with Alzheimer's disease and Lewy body dementia.

Cortisol Excess and the Brain.

PubMed

Resmini, Eugenia; Santos, Alicia; Webb, Susan M

2016-01-01

Until the last decade, little was known about the effects of chronic hypercortisolism on the brain. In the last few years, new data have arisen thanks to advances in imaging techniques; therefore, it is now possible to investigate brain activity in vivo. Memory impairments are present in patients with Cushing's syndrome (CS) and are related to hippocampal damage; functional dysfunctions would precede structural abnormalities as detected by brain imaging. Earlier diagnosis and rapid normalization of hypercortisolism could stop the progression of hippocampal damage and memory impairments. Impairments of executive functions (including decision-making) and other functions such as visuoconstructive skills, language, motor functions and information processing speed are also present in CS patients. There is controversy concerning the reversibility of brain impairment. It seems that longer disease duration and older age are associated with less recovery of brain functioning. Conversely, earlier diagnosis and rapid normalization of hypercortisolism appear to stop progression of brain damage and functional impairments. Moreover, brain tissue functioning and neuroplasticity can be influenced by many factors. Currently available studies appear to be complementary, evaluating the same phenomenon from different points of view, but are often not directly comparable. Finally, CS patients have a high prevalence of psychopathology, such as depression and anxiety which do not completely revert after cure. Thus, psychological or psychiatric evaluation could be recommended in CS patients, so that treatment may be prescribed if required. © 2016 S. Karger AG, Basel.

Reference tissue normalization in longitudinal (18)F-florbetapir positron emission tomography of late mild cognitive impairment.

PubMed

Shokouhi, Sepideh; Mckay, John W; Baker, Suzanne L; Kang, Hakmook; Brill, Aaron B; Gwirtsman, Harry E; Riddle, William R; Claassen, Daniel O; Rogers, Baxter P

2016-01-15

Semiquantitative methods such as the standardized uptake value ratio (SUVR) require normalization of the radiotracer activity to a reference tissue to monitor changes in the accumulation of amyloid-β (Aβ) plaques measured with positron emission tomography (PET). The objective of this study was to evaluate the effect of reference tissue normalization in a test-retest (18)F-florbetapir SUVR study using cerebellar gray matter, white matter (two different segmentation masks), brainstem, and corpus callosum as reference regions. We calculated the correlation between (18)F-florbetapir PET and concurrent cerebrospinal fluid (CSF) Aβ1-42 levels in a late mild cognitive impairment cohort with longitudinal PET and CSF data over the course of 2 years. In addition to conventional SUVR analysis using mean and median values of normalized brain radiotracer activity, we investigated a new image analysis technique-the weighted two-point correlation function (wS2)-to capture potentially more subtle changes in Aβ-PET data. Compared with the SUVRs normalized to cerebellar gray matter, all cerebral-to-white matter normalization schemes resulted in a higher inverse correlation between PET and CSF Aβ1-42, while the brainstem normalization gave the best results (high and most stable correlation). Compared with the SUVR mean and median values, the wS2 values were associated with the lowest coefficient of variation and highest inverse correlation to CSF Aβ1-42 levels across all time points and reference regions, including the cerebellar gray matter. The selection of reference tissue for normalization and the choice of image analysis method can affect changes in cortical (18)F-florbetapir uptake in longitudinal studies.

Normative biometry of the fetal brain using magnetic resonance imaging.

PubMed

Kyriakopoulou, Vanessa; Vatansever, Deniz; Davidson, Alice; Patkee, Prachi; Elkommos, Samia; Chew, Andrew; Martinez-Biarge, Miriam; Hagberg, Bibbi; Damodaram, Mellisa; Allsop, Joanna; Fox, Matt; Hajnal, Joseph V; Rutherford, Mary A

2017-07-01

The fetal brain shows accelerated growth in the latter half of gestation, and these changes can be captured by 2D and 3D biometry measurements. The aim of this study was to quantify brain growth in normal fetuses using Magnetic Resonance Imaging (MRI) and to produce reference biometry data and a freely available centile calculator ( https://www.developingbrain.co.uk/fetalcentiles/ ). A total of 127 MRI examinations (1.5 T) of fetuses with a normal brain appearance (21-38 gestational weeks) were included in this study. 2D and 3D biometric parameters were measured from slice-to-volume reconstructed images, including 3D measurements of supratentorial brain tissue, lateral ventricles, cortex, cerebellum and extra-cerebral CSF and 2D measurements of brain biparietal diameter and fronto-occipital length, skull biparietal diameter and occipitofrontal diameter, head circumference, transverse cerebellar diameter, extra-cerebral CSF, ventricular atrial diameter, and vermis height, width, and area. Centiles were constructed for each measurement. All participants were invited for developmental follow-up. All 2D and 3D measurements, except for atrial diameter, showed a significant positive correlation with gestational age. There was a sex effect on left and total lateral ventricular volumes and the degree of ventricular asymmetry. The 5th, 50th, and 95th centiles and a centile calculator were produced. Developmental follow-up was available for 73.1% of cases [mean chronological age 27.4 (±10.2) months]. We present normative reference charts for fetal brain MRI biometry at 21-38 gestational weeks. Developing growth trajectories will aid in the better understanding of normal fetal brain growth and subsequently of deviations from typical development in high-risk pregnancies or following premature delivery.

Genomic characterization of brain metastases reveals branched evolution and potential therapeutic targets

PubMed Central

Santagata, Sandro; Cahill, Daniel P.; Taylor-Weiner, Amaro; Jones, Robert T.; Van Allen, Eliezer M.; Lawrence, Michael S.; Horowitz, Peleg M.; Cibulskis, Kristian; Ligon, Keith L.; Tabernero, Josep; Seoane, Joan; Martinez-Saez, Elena; Curry, William T.; Dunn, Ian F.; Paek, Sun Ha; Park, Sung-Hye; McKenna, Aaron; Chevalier, Aaron; Rosenberg, Mara; Barker, Frederick G.; Gill, Corey M.; Van Hummelen, Paul; Thorner, Aaron R.; Johnson, Bruce E.; Hoang, Mai P.; Choueiri, Toni K.; Signoretti, Sabina; Sougnez, Carrie; Rabin, Michael S.; Lin, Nancy U.; Winer, Eric P.; Stemmer-Rachamimov, Anat; Meyerson, Matthew; Garraway, Levi; Gabriel, Stacey; Lander, Eric S.; Beroukhim, Rameen; Batchelor, Tracy T.; Baselga, Jose; Louis, David N.

2016-01-01

Brain metastases are associated with a dismal prognosis. Whether brain metastases harbor distinct genetic alterations beyond those observed in primary tumors is unknown. We performed whole-exome sequencing of 86 matched brain metastases, primary tumors and normal tissue. In all clonally related cancer samples, we observed branched evolution, where all metastatic and primary sites shared a common ancestor yet continued to evolve independently. In 53% of cases, we found potentially clinically informative alterations in the brain metastases not detected in the matched primary-tumor sample. In contrast, spatially and temporally separated brain metastasis sites were genetically homogenous. Distal extracranial and regional lymph node metastases were highly divergent from brain metastases. We detected alterations associated with sensitivity to PI3K/AKT/mTOR, CDK, and HER2/EGFR inhibitors in the brain metastases. Genomic analysis of brain metastases provides an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors, regional lymph nodes, or extracranial metastases. PMID:26410082

Sensitive and specific detection of classical scrapie prions in the brains of goats by real-time quaking-induced conversion.

PubMed

Dassanayake, Rohana P; Orrú, Christina D; Hughson, Andrew G; Caughey, Byron; Graça, Telmo; Zhuang, Dongyue; Madsen-Bouterse, Sally A; Knowles, Donald P; Schneider, David A

2016-03-01

Real-time quaking-induced conversion (RT-QuIC) is a rapid, specific and highly sensitive prion seeding activity detection assay that uses recombinant prion protein (rPrPSen) to detect subinfectious levels of the abnormal isoforms of the prion protein (PrPSc). Although RT-QuIC has been successfully used to detect PrPSc in various tissues from humans and animals, including sheep, tissues from goats infected with classical scrapie have not yet been tested. Therefore, the aims of the present study were to (1) evaluate whether prion seeding activity could be detected in the brain tissues of goats with scrapie using RT-QuIC, (2) optimize reaction conditions to improve scrapie detection in goats, and (3) compare the performance of RT-QuIC for the detection of PrPSc with the more commonly used ELISA and Western blot assays. We further optimized RT-QuIC conditions for sensitive and specific detection of goat scrapie seeding activity in brain tissue from clinical animals. When used with 200  mM sodium chloride, both full-length sheep rPrPSen substrates (PrP genotypes A136R154Q171 and V136R154Q171) provided good discrimination between scrapie-infected and normal goat brain samples at 10(- )3 dilution within 15  h. Our findings indicate that RT-QuIC was at least 10,000-fold more sensitive than ELISA and Western blot assays for the detection of scrapie seeding activity in goat brain samples. In addition to PRNP WT samples, positive RT-QuIC reactions were also observed with three PRNP polymorphic goat brain samples (G/S127, I/M142 and H/R143) tested. Taken together, these findings demonstrate that RT-QuIC sensitively detects prion seeding activity in classical scrapie-infected goat brain samples.

Sensitive and specific detection of classical scrapie prions in the brains of goats by real-time quaking-induced conversion

PubMed Central

Dassanayake, Rohana P.; Orrú, Christina D.; Hughson, Andrew G.; Caughey, Byron; Graça, Telmo; Zhuang, Dongyue; Madsen-Bouterse, Sally A.; Knowles, Donald P.; Schneider, David A.

2016-01-01

Real-time quaking-induced conversion (RT-QuIC) is a rapid, specific and highly sensitive prion seeding activity detection assay that uses recombinant prion protein (rPrPSen) to detect subinfectious levels of the abnormal isoforms of the prion protein (PrPSc). Although RT-QuIC has been successfully used to detect PrPSc in various tissues from humans and animals, including sheep, tissues from goats infected with classical scrapie have not yet been tested. Therefore, the aims of the present study were to (1) evaluate whether prion seeding activity could be detected in the brain tissues of goats with scrapie using RT-QuIC, (2) optimize reaction conditions to improve scrapie detection in goats, and (3) compare the performance of RT-QuIC for the detection of PrPSc with the more commonly used ELISA and Western blot assays. We further optimized RT-QuIC conditions for sensitive and specific detection of goat scrapie seeding activity in brain tissue from clinical animals. When used with 200 mM sodium chloride, both full-length sheep rPrPSen substrates (PrP genotypes A136R154Q171 and V136R154Q171) provided good discrimination between scrapie-infected and normal goat brain samples at 10− 3 dilution within 15 h. Our findings indicate that RT-QuIC was at least 10 000-fold more sensitive than ELISA and Western blot assays for the detection of scrapie seeding activity in goat brain samples. In addition to PRNP WT samples, positive RT-QuIC reactions were also observed with three PRNP polymorphic goat brain samples (G/S127, I/M142 and H/R143) tested. Taken together, these findings demonstrate that RT-QuIC sensitively detects prion seeding activity in classical scrapie-infected goat brain samples. PMID:26653410

Transient cerebral hypoperfusion assisted intraarterial cationic liposome delivery to brain tissue

PubMed Central

Joshi, Shailendra; Singh-Moon, Rajinder P.; Wang, Mei; Chaudhuri, Durba B.; Holcomb, Mark; Straubinger, Ninfa L.; Bruce, Jeffrey N.; Bigio, Irving J.; Straubinger, Robert M.

2014-01-01

Object Transient cerebral hypoperfusion (TCH) has empirically been used to assist intraarterial (IA) drug delivery to brain tumors. Transient (< 3 min) reduction of cerebral blood flow (CBF) occurs during many neuro- and cardiovascular interventions and has recently been used to better target IA drugs to brain tumors. In the present experiments, we assessed whether the effectiveness of IA delivery of cationic liposomes could be improved by TCH. Methods Cationic liposomes composed of 1:1 DOTAP:PC (dioleoyl-trimethylammonium-propane:phosphatidylcholine) were administered to three groups of Sprague Dawley rats. In the first group, we tested the effect of blood flow reduction on IA delivery of cationic liposomes. In the second group, we compared TCH-assisted IA liposomal delivery vs. intravenous (IV) administration of the same dose. In the third group, we assessed retention of cationic liposomes in brain four hours after TCH assisted delivery. The liposomes contained a near infrared dye, DilC18(7), whose concentration could be measured in vivo by diffuse reflectance spectroscopy. Results IA injections of cationic liposomes during TCH increased their delivery approximately four-fold compared to injections during normal blood flow. Optical pharmacokinetic measurements revealed that relative to IV injections, IA injection of cationic liposomes during TCH produced tissue concentrations that were 100-fold greater. The cationic liposomes were retained in the brain tissue four hours after a single IA injection. There was no gross impairment of neurological functions in surviving animals. Conclusions Transient reduction in CBF significantly increased IA delivery of cationic liposomes in the brain. High concentrations of liposomes could be delivered to brain tissue after IA injections with concurrent TCH while none could be detected after IV injection. IA-TCH injections were well tolerated and cationic liposomes were retained for at least 4 hours after IA administration. These results should encourage development of cationic liposomal formulations of chemotherapeutic drugs and their IA delivery during TCH. PMID:24664370

The effects of ethanol on insulin-like growth factor-I immunoreactive neurons in the central nervous system.

PubMed

Dalcik, Cannur; Yildirim, Guler K; Dalcik, Hakki

2009-08-01

To evaluate the effect of chronically ethanol treatment on insulin-like growth factor-I (IGF-I) synthesis in various adult brain regions using immunocytochemistry. We performed this study at the Faculty of Medicine, Kocaeli University, Kocaeli, Turkey from March 2006 to October 2007. The vascular perfusion was utilized to fix the adult rat brains (10 for each group). After applying the routine histological techniques, the tissues were embedded in the paraffin. The immunohistochemical protocol was applied to the 10 um thick sections and the expression of IGF-I positive cells were observed in the neuro-anatomic areas. The distribution of IGF-I immunoreactive cells differed between the layers of the normal cerebral cortex and in the thalamic areas. In the alcoholic brain, the amount of IGF-I immunoreactive cells were decreased compared to the similar neuro-anatomical areas examined in the normal brains. The presence of IGF-I immunoreactivity in the neurons of the various neuro-anatomic areas demonstrates clearly that, these particular neurons are active in IGF-I synthesis. The decrease in the immunoreactivity of IGF-I in the chronically ethanol treated adult rat brain areas, show clearly that, ethanol effects negatively on the IGF-I synthesis.

Cyanide poisoning of a Cooper’s hawk (Accipiter cooperii)

USGS Publications Warehouse

Franson, J. Christian

2017-01-01

A Cooper’s hawk (Accipiter cooperii) was found dead in a ditch leading from a heap leach pad at a gold mine in Nevada. Observations at autopsy included an absence of external lesions, traces of subcutaneous and coronary fat, no food in the upper gastrointestinal tract, and no lesions in the viscera. Cyanide concentrations (µg/g ww) were 5.04 in blood, 3.88 in liver, and 1.79 in brain. No bacteria or viruses were isolated from tissues, and brain cholinesterase activity was within the normal range for a Cooper’s hawk.

Methylation of the TERT promoter and risk stratification of childhood brain tumours: an integrative genomic and molecular study.

PubMed

Castelo-Branco, Pedro; Choufani, Sanaa; Mack, Stephen; Gallagher, Denis; Zhang, Cindy; Lipman, Tatiana; Zhukova, Nataliya; Walker, Erin J; Martin, Dianna; Merino, Diana; Wasserman, Jonathan D; Elizabeth, Cynthia; Alon, Noa; Zhang, Libo; Hovestadt, Volker; Kool, Marcel; Jones, David T W; Zadeh, Gelareh; Croul, Sidney; Hawkins, Cynthia; Hitzler, Johann; Wang, Jean C Y; Baruchel, Sylvain; Dirks, Peter B; Malkin, David; Pfister, Stefan; Taylor, Michael D; Weksberg, Rosanna; Tabori, Uri

2013-05-01

Identification of robust biomarkers of malignancy and methods to establish disease progression is a major goal in paediatric neuro-oncology. We investigated whether methylation of the TERT promoter can be a biomarker for malignancy and patient outcome in paediatric brain tumours. For the discovery cohort, we used samples obtained from patients with paediatric brain tumours and individuals with normal brain tissues stored at the German Cancer Research Center (Heidelberg, Germany). We used methylation arrays for genome-wide assessment of DNA. For the validation cohort, we used samples obtained from several tissues for which full clinical and follow-up data were available from two hospitals in Toronto (ON, Canada). We did methylation analysis using quantitative Sequenom and pyrosequencing of an identified region of the TERT promoter. We assessed TERT expression by real-time PCR. To establish whether the biomarker could be used to assess and predict progression, we analysed methylation in paired samples of tumours that transformed from low to high grade and from localised to metastatic, and in choroid plexus tumours of different grades. Finally, we investigated overall survival in patients with posterior fossa ependymomas in which the identified region was hypermethylated or not. All individuals responsible for assays were masked to the outcome of the patients. Analysis of 280 samples in the discovery cohort identified one CpG site (cg11625005) in which 78 (99%) of 79 samples from normal brain tissues and low-grade tumours were not hypermethylated, but 145 (72%) of 201 samples from malignant tumours were hypermethylated (>15% methylated; p<0.0001). Analysis of 68 samples in the validation cohort identified a subset of five CpG sites (henceforth, upstream of the transcription start site [UTSS]) that was hypermethylated in all malignant paediatric brain tumours that expressed TERT but not in normal tissues that did not express TERT (p<0.0001). UTSS had a positive predictive value of 1.00 (95% CI 0.95-1.00) and a negative predictive value of 0.95 (0.87-0.99). In two paired samples of paediatric gliomas, UTSS methylation increased during transformation from low to high grade; it also increased in two paired samples that progressed from localised to metastatic disease. Two of eight atypical papillomas that had high UTSS methylation progressed to carcinomas, while the other six assessed did not progress or require additional treatment. 5-year overall survival was 51% (95% CI 31-71) for 25 patients with hypermethylated UTSS posterior fossa ependymomas and 95% (86-100) for 20 with non-hypermethylated tumours (p=0.0008). 5-year progression-free survival was 86% (68-100) for the 25 patients with non-hypermethylated UTSS tumours and 30% (10-50) for those with hypermethylated tumours (p=0.0008). Hypermethylation of the UTSS region in the TERT promoter is associated with TERT expression in cancers. In paediatric brain tumours, UTSS hypermethylation is associated with tumour progression and poor prognosis. This region is easy to amplify, and the assay to establish hypermethylation can be done on most tissues in most clinical laboratories. Therefore the UTSS region is a potentially accessible biomarker for various cancers. The Canadian Institute of Health Research and the Terry Fox Foundation. Copyright © 2013 Elsevier Ltd. All rights reserved.

Tissue distribution of oral vitamin B12 is influenced by B12 status and B12 form: an experimental study in rats.

PubMed

Kornerup, Linda S; Fedosov, Sergey N; Juul, Christian B; Greibe, Eva; Heegaard, Christian W; Nexo, Ebba

2018-06-01

Hydroxocobalamin (HOCbl) is the dominating Cbl form in food, whereas cyanocobalamin (CNCbl) is common in vitamin pills and oral supplements. This study compares single-dose absorption and distribution of oral HO[ 57 Co]Cbl and CN[ 57 Co]Cbl in Cbl-deficient and normal rats. Male Wistar rats (7 weeks) were fed a 14-day diet with (n = 15) or without (n = 15) Cbl. We compared the uptakes of HO[ 57 Co]Cbl (free or bound to bovine transcobalamin) and free CN[ 57 Co]Cbl administered by gastric gavage (n = 5 in each diet group). Rats were sacrificed after 24 h. Blood, liver, kidney, brain, heart, spleen, intestines, skeletal muscle, 24-h urine and faeces were collected, and the content of [ 57 Co]Cbl was measured. Endogenous Cbl in tissues and plasma was analysed by routine methods. Mean endogenous plasma-Cbl was sevenfold lower in deficient vs. normal rats (190 vs. 1330 pmol/L, p < 0.0001). Cbl depletion increased endogenous Cbl ratios (tissue/plasma = k in /k out ) in all organs except for the kidney, where the ratio decreased considerably. Twenty-four-hour accumulation of labelled Cbl showed that HOCbl > CNCbl (liver) and CNCbl > HOCbl (brain, muscle and plasma). The Cbl status of rats and the administered Cbl form influence 24-h Cbl accumulation in tissues and plasma.

A Postmortem Study of Frontal and Temporal Gyri Thickness and Cell Number in Human Obesity.

PubMed

Gómez-Apo, Erick; García-Sierra, Adrián; Silva-Pereyra, Juan; Soto-Abraham, Virgilia; Mondragón-Maya, Alejandra; Velasco-Vales, Verónica; Pescatello, Linda S

2018-01-01

This study aimed to compare cortex thickness and neuronal cell density in postmortem brain tissue from people with overweight or obesity and normal weight. The cortex thickness and neuron density of eight donors with overweight or obesity (mean = 31.6 kg/m 2 ; SD = 4.35; n = 8; 6 male) and eight donors with normal weight (mean = 21.8 kg/m 2 ; SD = 1.5; n = 8; 5 male) were compared. All participants were Mexican and lived in Mexico City. Randomly selected thickness measures of different cortex areas from the frontal and temporal lobes were analyzed based on high-resolution real-size photographs. A histological analysis of systematic-random fields was used to quantify the number of neurons in postmortem left and right of the first, second, and third gyri of frontal and temporal lobe brain samples. No statistical difference was found in cortical thickness between donors with overweight or obesity and individuals with normal weight. A smaller number of neurons was found among the donors with overweight or obesity than the donors with normal weight at different frontal and temporal areas. A lower density of neurons is associated with overweight or obesity. The morphological basis for structural brain changes in obesity requires further investigation. © 2017 The Obesity Society.

Subcortical heterotopia appearing as huge midline mass in the newborn brain.

PubMed

Fukumura, Shinobu; Watanabe, Toshihide; Kimura, Sachiko; Ochi, Satoko; Yoshifuji, Kazuhisa; Tsutsumi, Hiroyuki

2016-02-01

We report the case of a 2-year-old boy who showed a huge midline mass in the brain at prenatal assessment. After birth, magnetic resonance imaging (MRI) revealed a conglomerate mass with an infolded microgyrus at the midline, which was suspected as a midline brain-in-brain malformation. MRI also showed incomplete cleavage of his frontal cortex and thalamus, consistent with lobar holoprosencephaly. The patient underwent an incisional biopsy of the mass on the second day of life. The mass consisted of normal central nervous tissue with gray and white matter, representing a heterotopic brain. The malformation was considered to be a subcortical heterotopia. With maturity, focal signal changes and decreased cerebral perfusion became clear on brain imaging, suggesting secondary glial degeneration. Coincident with these MRI abnormalities, the child developed psychomotor retardation and severe epilepsy focused on the side of the intracranial mass.

Peri-tumoral leakage during intra-tumoral convection-enhanced delivery has implications for efficacy of peri-tumoral infusion before removal of tumor.

PubMed

Yang, Xiaoliang; Saito, Ryuta; Nakamura, Taigen; Zhang, Rong; Sonoda, Yukihiko; Kumabe, Toshihiro; Forsayeth, John; Bankiewicz, Krystof; Tominaga, Teiji

2016-01-01

In cases of malignant brain tumors, infiltrating tumor cells that exist at the tumor-surrounding brain tissue always escape from cytoreductive surgery and, protected by blood-brain barrier (BBB), survive the adjuvant chemoradiotherapy, eventually leading to tumor recurrence. Local interstitial delivery of chemotherapeutic agents is a promising strategy to target these cells. During our effort to develop effective drug delivery methods by intra-tumoral infusion of chemotherapeutic agents, we found consistent pattern of leakage from the tumor. Here we describe our findings and propose promising strategy to cover the brain tissue surrounding the tumor with therapeutic agents by means of convection-enhanced delivery. First, the intracranial tumor isograft model was used to define patterns of leakage from tumor mass after intra-tumoral infusion of the chemotherapeutic agents. Liposomal doxorubicin, although first distributed inside the tumor, distributed diffusely into the surrounding normal brain once the leakage happen. Trypan blue dye was used to evaluate the distribution pattern of peri-tumoral infusions. When infused intra- or peri-tumorally, infusates distributed robustly into the tumor border. Subsequently, volume of distributions with different infusion scheduling; including intra-tumoral infusion, peri-tumoral infusion after tumor resection, peri-tumoral infusion without tumor removal with or without systemic infusion of steroids, were compared with Evans-blue dye. Peri-tumoral infusion without tumor removal resulted in maximum volume of distribution. Prior use of steroids further increased the volume of distribution. Local interstitial drug delivery targeting tumor surrounding brain tissue before tumor removal should be more effective when targeting the invading cells.

Diffuse traumatic axonal injury in mice induces complex behavioural alterations that are normalized by neutralization of interleukin-1β.

PubMed

Ekmark-Lewén, Sara; Flygt, Johanna; Fridgeirsdottir, Gudrun A; Kiwanuka, Olivia; Hånell, Anders; Meyerson, Bengt J; Mir, Anis K; Gram, Hermann; Lewén, Anders; Clausen, Fredrik; Hillered, Lars; Marklund, Niklas

2016-04-01

Widespread traumatic axonal injury (TAI) results in brain network dysfunction, which commonly leads to persisting cognitive and behavioural impairments following traumatic brain injury (TBI). TBI induces a complex neuroinflammatory response, frequently located at sites of axonal pathology. The role of the pro-inflammatory cytokine interleukin (IL)-1β has not been established in TAI. An IL-1β-neutralizing or a control antibody was administered intraperitoneally at 30 min following central fluid percussion injury (cFPI), a mouse model of widespread TAI. Mice subjected to moderate cFPI (n = 41) were compared with sham-injured controls (n = 20) and untreated, naive mice (n = 9). The anti-IL-1β antibody reached the target brain regions in adequate therapeutic concentrations (up to ~30 μg/brain tissue) at 24 h post-injury in both cFPI (n = 5) and sham-injured (n = 3) mice, with lower concentrations at 72 h post-injury (up to ~18 μg/g brain tissue in three cFPI mice). Functional outcome was analysed with the multivariate concentric square field (MCSF) test at 2 and 9 days post-injury, and the Morris water maze (MWM) at 14-21 days post-injury. Following TAI, the IL-1β-neutralizing antibody resulted in an improved behavioural outcome, including normalized behavioural profiles in the MCSF test. The performance in the MWM probe (memory) trial was improved, although not in the learning trials. The IL-1β-neutralizing treatment did not influence cerebral ventricle size or the number of microglia/macrophages. These findings support the hypothesis that IL-1β is an important contributor to the processes causing complex cognitive and behavioural disturbances following TAI. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Stem cells for brain repair in neonatal hypoxia-ischemia.

PubMed

Chicha, L; Smith, T; Guzman, R

2014-01-01

Neonatal hypoxic-ischemic insults are a significant cause of pediatric encephalopathy, developmental delays, and spastic cerebral palsy. Although the developing brain's plasticity allows for remarkable self-repair, severe disruption of normal myelination and cortical development upon neonatal brain injury are likely to generate life-persisting sensory-motor and cognitive deficits in the growing child. Currently, no treatments are available that can address the long-term consequences. Thus, regenerative medicine appears as a promising avenue to help restore normal developmental processes in affected infants. Stem cell therapy has proven effective in promoting functional recovery in animal models of neonatal hypoxic-ischemic injury and therefore represents a hopeful therapy for this unmet medical condition. Neural stem cells derived from pluripotent stem cells or fetal tissues as well as umbilical cord blood and mesenchymal stem cells have all shown initial success in improving functional outcomes. However, much still remains to be understood about how those stem cells can safely be administered to infants and what their repair mechanisms in the brain are. In this review, we discuss updated research into pathophysiological mechanisms of neonatal brain injury, the types of stem cell therapies currently being tested in this context, and the potential mechanisms through which exogenous stem cells might interact with and influence the developing brain.

Yellow fever 17-D vaccine is neurotropic and produces encephalitis in immunosuppressed hamsters.

PubMed

Mateo, Rosa I; Xiao, Shu-Yuan; Travassos da Rosa, Amelia P A; Lei, Hao; Guzman, Hilda; Lu, Liang; Tesh, Robert B

2007-11-01

Immunosuppressed (cyclophosphamide) adult golden hamsters inoculated intraperitoneally (i.p.) with wild-type Asibi yellow fever virus (YFV) developed a rapidly fatal illness. Histopathologic and immunohistochemical studies of tissues from these animals showed typical hepatic changes of severe yellow fever (inflammation, hepatocyte necrosis, and steatosis) without brain involvement. In contrast, 50% of immunosuppressed hamsters receiving the YFV-17D-attenuated vaccine developed a slowly progressive encephalitic-type illness. Brain tissue from these latter animals revealed focal neuronal changes, inflammation, and YFV antigen-positive neurons; however, the liver and spleen appeared normal. YFV was isolated from brain cultures of many of these animals. Immunocompetent (non-immunosuppressed) hamsters inoculated with both viruses developed a subclinical infection. Results of this study indicate that wild-type YFV is hepatotropic in immunosuppressed hamsters, whereas the attenuated YFV-17 is primarily neurotropic. These findings support current recommendations against yellow fever vaccination of immunosuppressed/immunocompromised people and suggest that this hamster model might be useful for monitoring the safety of other live-attenuated YFV vaccines.

Mechanisms that Underlie Co-variation of the Brain and Face

PubMed Central

Marcucio, Ralph S.; Young, Nathan M.; Hu, Diane; Hallgrimsson, Benedikt

2011-01-01

The effect of the brain on the morphology of the face has long been recognized in both evolutionary biology and clinical medicine. In this paper we describe factors that are active between development of the brain and face and how these might impact craniofacial variation. First, there is the physical influence of the brain, which contributes to overall growth and morphology of the face through direct structural interactions. Second, there is the molecular influence of the brain, which signals to facial tissues to establish signaling centers that regulate patterned growth. Importantly, subtle alterations to these physical or molecular interactions may contribute to both normal and abnormal variation. These interactions are therefore critical to our understanding of how a diversity of facial morphologies can be generated both within species and across evolutionary time. PMID:21381182

Anti-oxidative effects of curcumin on immobilization-induced oxidative stress in rat brain, liver and kidney.

PubMed

Samarghandian, Saeed; Azimi-Nezhad, Mohsen; Farkhondeh, Tahereh; Samini, Fariborz

2017-03-01

Restraint stress has been indicated to induce oxidative damage in tissues. Several investigations have reported that curcumin (CUR) may have a protective effect against oxidative stress. The present study was designed to investigate the protective effects of CUR on restraint stress induced oxidative stress damage in the brain, liver and kidneys. For chronic restraint stress, rats were kept in the restrainers for 1h every day, for 21 consecutive days. The animals received systemic administrations of CUR daily for 21days. In order to evaluate the changes of the oxidative stress parameters following restraint stress, the levels of malondialdehyde (MDA), reduced glutathione (GSH), as well as antioxidant enzyme activities superoxide dismutase (SOD) glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) were measured in the brain, liver and kidney of rats after the end of restraint stress. The restraint stress significantly increased MDA level, but decreased the level of GSH and activists of SOD, GPx, GR, and CAT the brain, liver and kidney of rats in comparison to the normal rats (P<0.001). Intraperitoneal administration of CUR significantly attenuated oxidative stress and lipid peroxidation, prevented apoptosis, and increased antioxidant defense mechanism activity in the tissues versus the control group (P<0.05). This study shows that CUR can prevent restraint stress-induced oxidative damage in the brain, liver and kidney of rats and propose that CUR may be useful agents against oxidative stress in the tissues. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Individualized model predicts brain current flow during transcranial direct-current stimulation treatment in responsive stroke patient.

PubMed

Datta, Abhishek; Baker, Julie M; Bikson, Marom; Fridriksson, Julius

2011-07-01

Although numerous published reports have demonstrated the beneficial effects of transcranial direct-current stimulation (tDCS) on task performance, fundamental questions remain regarding the optimal electrode configuration on the scalp. Moreover, it is expected that lesioned brain tissue will influence current flow and should therefore be considered (and perhaps leveraged) in the design of individualized tDCS therapies for stroke. The current report demonstrates how different electrode configurations influence the flow of electrical current through brain tissue in a patient who responded positively to a tDCS treatment targeting aphasia. The patient, a 60-year-old man, sustained a left hemisphere ischemic stroke (lesion size = 87.42 mL) 64 months before his participation. In this study, we present results from the first high-resolution (1 mm(3)) model of tDCS in a brain with considerable stroke-related damage; the model was individualized for the patient who received anodal tDCS to his left frontal cortex with the reference cathode electrode placed on his right shoulder. We modeled the resulting brain current flow and also considered three additional reference electrode positions: right mastoid, right orbitofrontal cortex, and a "mirror" configuration with the anode over the undamaged right cortex. Our results demonstrate the profound effect of lesioned tissue on resulting current flow and the ability to modulate current pattern through the brain, including perilesional regions, through electrode montage design. The complexity of brain current flow modulation by detailed normal and pathologic anatomy suggest: (1) That computational models are critical for the rational interpretation and design of individualized tDCS stroke-therapy; and (2) These models must accurately reproduce head anatomy as shown here. Copyright © 2011 Elsevier Inc. All rights reserved.

HELICoiD project: a new use of hyperspectral imaging for brain cancer detection in real-time during neurosurgical operations

NASA Astrophysics Data System (ADS)

Fabelo, Himar; Ortega, Samuel; Kabwama, Silvester; Callico, Gustavo M.; Bulters, Diederik; Szolna, Adam; Pineiro, Juan F.; Sarmiento, Roberto

2016-05-01

Hyperspectral images allow obtaining large amounts of information about the surface of the scene that is captured by the sensor. Using this information and a set of complex classification algorithms is possible to determine which material or substance is located in each pixel. The HELICoiD (HypErspectraL Imaging Cancer Detection) project is a European FET project that has the goal to develop a demonstrator capable to discriminate, with high precision, between normal and tumour tissues, operating in real-time, during neurosurgical operations. This demonstrator could help the neurosurgeons in the process of brain tumour resection, avoiding the excessive extraction of normal tissue and unintentionally leaving small remnants of tumour. Such precise delimitation of the tumour boundaries will improve the results of the surgery. The HELICoiD demonstrator is composed of two hyperspectral cameras obtained from Headwall. The first one in the spectral range from 400 to 1000 nm (visible and near infrared) and the second one in the spectral range from 900 to 1700 nm (near infrared). The demonstrator also includes an illumination system that covers the spectral range from 400 nm to 2200 nm. A data processing unit is in charge of managing all the parts of the demonstrator, and a high performance platform aims to accelerate the hyperspectral image classification process. Each one of these elements is installed in a customized structure specially designed for surgical environments. Preliminary results of the classification algorithms offer high accuracy (over 95%) in the discrimination between normal and tumour tissues.

A different regional response by mouse oligodendrocyte progenitor cells (OPCs) to high-dose X-irradiation has consequences for repopulating OPC-depleted normal tissue.

PubMed

Irvine, Karen-Amanda; Blakemore, William F

2007-01-01

This study was designed to investigate whether the residual, dysfunctional oligodendrocyte progenitor cells (OPCs) observed following X-irradiation of the mouse spinal cord [D. M. Chari et al. (2003) Exp. Neurol., 198, 145-153], the presence of which prevented the endogenous repopulation of these areas from normal tissue, reflects a general response of OPCs in the mouse central nervous system (CNS) to X-irradiation. The brains of adult mice were exposed to 40 Gy of X-irradiation and the effect of X-irradiation on the OPCs was assessed up to 4 weeks post-irradiation using anti-NG2 antibodies. X-irradiation resulted in almost complete depletion of OPCs within the telencephalon (cortex, corpus callosum and hippocampus) by 7 days post-irradiation, which was followed by progressive repopulation of OPCs from non-irradiated areas of the cortex. By contrast, within the lower brain centres (the diencephalon and mesencephalon) OPC loss occurred much more slowly so that 26% of the OPCs still remained 4 weeks after X-irradiation. The consequence of this heterogeneous response to X-irradiation was that whereas transplanted and endogenous OPCs rapidly established themselves in the OPC-depleted telencephalon this did not occur in the areas where there was incomplete depletion of endogenous OPCs. Our findings confirm not only the requirement for almost complete OPC depletion in order to establish transplanted OPCs in normal tissue but also highlight a heterogeneity of progenitor populations in different areas of the mouse CNS.

Estrogen and progesterone signalling in the normal breast and its implications for cancer development.

PubMed

Hilton, Heidi N; Clarke, Christine L; Graham, J Dinny

2018-05-05

The ovarian hormones estrogen and progesterone are master regulators of the development and function of a broad spectrum of human tissues, including the breast, reproductive and cardiovascular systems, brain and bone. Acting through the nuclear estrogen (ER) and progesterone receptors (PR), both play complex and essential coordinated roles in the extensive development of the lobular alveolar epithelial structures of the normal breast during puberty, the normal menstrual cycle and pregnancy. The past decade has seen major advances in understanding the mechanisms of action of estrogen and progesterone in the normal breast and in the delineation of the complex hierarchy of cell types regulated by ovarian hormones in this tissue. There is evidence for a role for both ER and PR in driving breast cancer, and both are favourable prognostic markers with respect to outcome. In this review, we summarize current knowledge of the mechanisms of action of ER and PR in the normal breast, and implications for the development and management of breast cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Regional Brain Tissue Changes and Associations with Disease Severity in Children with Sleep Disordered Breathing.

PubMed

Horne, Rosemary S C; Roy, Bhaswati; Walter, Lisa M; Biggs, Sarah N; Tamanyan, Knarik; Weichard, Aidan; Nixon, Gillian M; Davey, Margot J; Ditchfield, Michael; Harper, Ronald M; Kumar, Rajesh

2017-12-15

Children with sleep-disordered breathing (SDB) exhibit behavioral, cognitive, and autonomic deficits, suggestive of neural injury. We assessed whether the tissue alterations resulted from acute or chronic processes, and if alterations correlated with disease severity. Brain tissue integrity was examined with mean diffusivity (MD) (3.0-Tesla scanner) in 20 non-snoring controls (mean age±sem, 12.2±0.6y; 10 male) and 18 children with SDB (12.3±0.7y; 11 male). Sleep, cognitive, and behavioral measures were compared between groups following overnight polysomnography using Student's t-tests. Whole-brain MD maps were realigned and averaged, normalized, smoothed, and compared between groups using ANCOVA (covariates; age, gender, and socioeconomic status). Partial correlations were calculated between whole-brain smoothed MD maps and obstructive apnea hypopnea indices (OAHI). Age, gender, and sleep variables did not differ between groups. The SDB group showed higher OAHI, body mass indices, and systolic blood pressure. Significantly reduced MD values (acute changes) appeared in the hippocampus, insula, thalamus, temporal and occipital cortices, and cerebellum, but were increased (chronic damage) in the frontal and prefrontal cortices in the SDB group over controls. Both positive and negative correlations appeared with extent of tissue changes and disease severity. Externalizing and Total Problem Behaviors were significantly higher in SDB children. Verbal, performance and total IQ scores trended lower, and behavioral scores trended higher. Pediatric SDB is accompanied by predominantly acute brain changes in areas that regulate autonomic, cognitive, and mood functions, and chronic changes in frontal cortices essential for behavioral control. Interventions need to be keyed to address acute vs chronic injury. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Effects of microbeam radiation therapy on normal and tumoral blood vessels.

PubMed

Bouchet, Audrey; Serduc, Raphäel; Laissue, Jean Albert; Djonov, Valentin

2015-09-01

Microbeam radiation therapy (MRT) is a new form of preclinical radiotherapy using quasi-parallel arrays of synchrotron X-ray microbeams. While the deposition of several hundred Grays in the microbeam paths, the normal brain tissues presents a high tolerance which is accompanied by the permanence of apparently normal vessels. Conversely, the efficiency of MRT on tumor growth control is thought to be related to a preferential damaging of tumor blood vessels. The high resistance of the healthy vascular network was demonstrated in different animal models by in vivo biphoton microscopy, magnetic resonance imaging, and histological studies. While a transient increase in permeability was shown, the structure of the vessels remained intact. The use of a chick chorioallantoic membrane at different stages of development showed that the damages induced by microbeams depend on vessel maturation. In vivo and ultrastructural observations showed negligible effects of microbeams on the mature vasculature at late stages of development; nevertheless a complete destruction of the immature capillary plexus was found in the microbeam paths. The use of MRT in rodent models revealed a preferential effect on tumor vessels. Although no major modification was observed in the vasculature of normal brain tissue, tumors showed a denudation of capillaries accompanied by transient increased permeability followed by reduced tumor perfusion and finally, a decrease in number of tumor vessels. Thus, MRT is a very promising treatment strategy with pronounced tumor control effects most likely based on the anti-vascular effects of MRT. Copyright © 2015. Published by Elsevier Ltd.

Far-red to near infrared emission and scattering spectroscopy for biomedical applications

NASA Astrophysics Data System (ADS)

Zhang, Gang

2001-06-01

The thesis investigates the far-red and near infrared (NIR) spectral region from biomedical tissue samples for monitoring the state of tissues. The NIR emission wing intensity is weak in comparison to the emission in the visible spectral region. The wing emission from biomedical samples has revealed meaningful information about the state of the tissues. A model is presented to explain the shape of the spectral wing based on a continuum of energy levels. The wing can be used to classify different kinds of tissues; especially it can be used to differentiate cancer part from normal human breast tissues. The research work of the far-red emission from thermal damaged tissue samples shows that the emission intensity in this spectral region is proportional to the extent of the thermal damage of the tissue. Near infrared spectral absorption method is used to investigate blood hemodynamics (perfusion and oxygenation) in brain during sleep-wake transition. The result of the research demonstrates that the continuous wave (CW) type near infrared spectroscopy (NIRS) device can be used to investigate brain blood perfusion and oxygenation with a similar precision with frequency domain (FD) type device. The human subject sleep and wake transition, has been monitored by CW type NIRS instrument with traditional electroencephalograph (EEG) method. Parallel change in oxy-Hb and deoxy-Hb is a discrete event that occurs in the transition from both sleep to wakefulness and wakefulness to sleep. These hemodynamic switches are generally about few seconds delayed from the human decided transition point between sleep and wake on the polygraph EEG recording paper. The combination of NIRS and EEG methods monitor the brain activity, gives more information about the brain activity. The sleep apnea investigation was associated with recurrent apneas, insufficient nasal continuous positive airway pressure (CPAP) and the different response of the peripheral and central compartments to breathing events. The different results with finger pulse oximetry and NIRS suggest that optical monitoring of the brain may have advantages that may help clarify the morbidity of obstructive sleep apnea (OSA) Syndrome.

A model-constrained Monte Carlo method for blind arterial input function estimation in dynamic contrast-enhanced MRI: II. In vivo results

NASA Astrophysics Data System (ADS)

Schabel, Matthias C.; DiBella, Edward V. R.; Jensen, Randy L.; Salzman, Karen L.

2010-08-01

Accurate quantification of pharmacokinetic model parameters in tracer kinetic imaging experiments requires correspondingly accurate determination of the arterial input function (AIF). Despite significant effort expended on methods of directly measuring patient-specific AIFs in modalities as diverse as dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), dynamic positron emission tomography (PET), and perfusion computed tomography (CT), fundamental and technical difficulties have made consistent and reliable achievement of that goal elusive. Here, we validate a new algorithm for AIF determination, the Monte Carlo blind estimation (MCBE) method (which is described in detail and characterized by extensive simulations in a companion paper), by comparing AIFs measured in DCE-MRI studies of eight brain tumor patients with results of blind estimation. Blind AIFs calculated with the MCBE method using a pool of concentration-time curves from a region of normal brain tissue were found to be quite similar to the measured AIFs, with statistically significant decreases in fit residuals observed in six of eight patients. Biases between the blind and measured pharmacokinetic parameters were the dominant source of error. Averaged over all eight patients, the mean biases were +7% in K trans, 0% in kep, -11% in vp and +10% in ve. Corresponding uncertainties (median absolute deviation from the best fit line) were 0.0043 min-1 in K trans, 0.0491 min-1 in kep, 0.29% in vp and 0.45% in ve. The use of a published population-averaged AIF resulted in larger mean biases in three of the four parameters (-23% in K trans, -22% in kep, -63% in vp), with the bias in ve unchanged, and led to larger uncertainties in all four parameters (0.0083 min-1 in K trans, 0.1038 min-1 in kep, 0.31% in vp and 0.95% in ve). When blind AIFs were calculated from a region of tumor tissue, statistically significant decreases in fit residuals were observed in all eight patients despite larger deviations of these blind AIFs from the measured AIFs. The observed decrease in root-mean-square fit residuals between the normal brain and tumor tissue blind AIFs suggests that the local blood supply in tumors is measurably different from that in normal brain tissue and that the proposed method is able to discriminate between the two. We have shown the feasibility of applying the MCBE algorithm to DCE-MRI data acquired in brain, finding generally good agreement with measured AIFs and decreased biases and uncertainties relative to the use of a population-averaged AIF. These results demonstrate that the MCBE algorithm is a useful alternative to direct AIF measurement in cases where acquisition of high-quality arterial input function data is difficult or impossible.

A rapid approach to high-resolution fluorescence imaging in semi-thick brain slices.

PubMed

Selever, Jennifer; Kong, Jian-Qiang; Arenkiel, Benjamin R

2011-07-26

A fundamental goal to both basic and clinical neuroscience is to better understand the identities, molecular makeup, and patterns of connectivity that are characteristic to neurons in both normal and diseased brain. Towards this, a great deal of effort has been placed on building high-resolution neuroanatomical maps(1-3). With the expansion of molecular genetics and advances in light microscopy has come the ability to query not only neuronal morphologies, but also the molecular and cellular makeup of individual neurons and their associated networks(4). Major advances in the ability to mark and manipulate neurons through transgenic and gene targeting technologies in the rodent now allow investigators to 'program' neuronal subsets at will(5-6). Arguably, one of the most influential contributions to contemporary neuroscience has been the discovery and cloning of genes encoding fluorescent proteins (FPs) in marine invertebrates(7-8), alongside their subsequent engineering to yield an ever-expanding toolbox of vital reporters(9). Exploiting cell type-specific promoter activity to drive targeted FP expression in discrete neuronal populations now affords neuroanatomical investigation with genetic precision. Engineering FP expression in neurons has vastly improved our understanding of brain structure and function. However, imaging individual neurons and their associated networks in deep brain tissues, or in three dimensions, has remained a challenge. Due to high lipid content, nervous tissue is rather opaque and exhibits auto fluorescence. These inherent biophysical properties make it difficult to visualize and image fluorescently labelled neurons at high resolution using standard epifluorescent or confocal microscopy beyond depths of tens of microns. To circumvent this challenge investigators often employ serial thin-section imaging and reconstruction methods(10), or 2-photon laser scanning microscopy(11). Current drawbacks to these approaches are the associated labor-intensive tissue preparation, or cost-prohibitive instrumentation respectively. Here, we present a relatively rapid and simple method to visualize fluorescently labelled cells in fixed semi-thick mouse brain slices by optical clearing and imaging. In the attached protocol we describe the methods of: 1) fixing brain tissue in situ via intracardial perfusion, 2) dissection and removal of whole brain, 3) stationary brain embedding in agarose, 4) precision semi-thick slice preparation using new vibratome instrumentation, 5) clearing brain tissue through a glycerol gradient, and 6) mounting on glass slides for light microscopy and z-stack reconstruction (Figure 1). For preparing brain slices we implemented a relatively new piece of instrumentation called the 'Compresstome' VF-200 (http://www.precisionary.com/products_vf200.html). This instrument is a semi-automated microtome equipped with a motorized advance and blade vibration system with features similar in function to other vibratomes. Unlike other vibratomes, the tissue to be sliced is mounted in an agarose plug within a stainless steel cylinder. The tissue is extruded at desired thicknesses from the cylinder, and cut by the forward advancing vibrating blade. The agarose plug/cylinder system allows for reproducible tissue mounting, alignment, and precision cutting. In our hands, the 'Compresstome' yields high quality tissue slices for electrophysiology, immunohistochemistry, and direct fixed-tissue mounting and imaging. Combined with optical clearing, here we demonstrate the preparation of semi-thick fixed brain slices for high-resolution fluorescent imaging.

Effect of Brain Tumor Presence During Radiation on Tissue Toxicity: Transcriptomic and Metabolic Changes.

PubMed

Zawaski, Janice A; Sabek, Omaima M; Voicu, Horatiu; Eastwood Leung, Hon-Chiu; Gaber, M Waleed

2017-11-15

Radiation therapy (RT) causes functional and transcriptomic changes in the brain; however, most studies have been carried out in normal rodent brains. Here, the long-term effect of irradiation and tumor presence during radiation was investigated. Male Wistar rats ∼7 weeks old were divided into 3 groups: sham implant, RT+sham implant, and RT+tumor implant (C6 glioma). Hypofractionated irradiation (8 or 6 Gy/day for 5 days) was localized to a 1-cm strip of cranium starting 5 days after implantation, resulting in complete tumor regression and prolonged survival. Biopsy of tissue was performed in the implant area 65 days after implantation. RNA was hybridized to GeneChip Rat Exon 1.0 ST array. Data were analyzed using significant analysis of microarrays and ingenuity pathway analysis. 1 H magnetic resonance spectroscopy ( 1 H-MRS) imaging was performed in the implantation site 65 to 70 days after implantation using a 9.4 T Biospec magnetic resonance imaging scanner with a quadrature rat brain array. Immunohistochemical staining for astrogliosis, HMG-CoA synthase 2, γ-aminobutyric acid (GABA) and taurine was performed at ∼65 days after implantation. Eighty-four genes had a false discovery rate <3.5%. We compared RT+tumor implant with RT+sham implant animals. The tumor presence affected networks associated with cancer/cell morphology/tissue morphology. 1 H-MRS showed significant reduction in taurine levels (P<.04) at the implantation site in both groups. However, the RT+tumor group also showed significant increase in levels of neurotransmitter GABA (P=.02). Hippocampal taurine levels were only significantly reduced in the RT+tumor group (P=.03). HMG-CoA synthase 2, GABA and taurine levels were confirmed using staining. Glial fibrillary acidic protein staining demonstrated a significant increase in inflammation that was heightened in the RT+tumor group. Our data indicate that tumor presence during radiation significantly affects long-term functional transcriptomics landscape and neurotransmitter levels at the tumor implantation site/normal tissue, accompanied by increased inflammation (astrogliosis). Copyright © 2017 Elsevier Inc. All rights reserved.

Microtubule actin cross-linking factor 1, a novel target in glioblastoma.

PubMed

Afghani, Najlaa; Mehta, Toral; Wang, Jialiang; Tang, Nan; Skalli, Omar; Quick, Quincy A

2017-01-01

Genetic heterogeneity is recognized as a major contributing factor of glioblastoma resistance to clinical treatment modalities and consequently low overall survival rates. This genetic diversity results in variations in protein expression, both intratumorally and between individual glioblastoma patients. In this regard, the spectraplakin protein, microtubule actin cross-linking factor 1 (MACF1), was examined in glioblastoma. An expression analysis of MACF1 in various types of brain tumor tissue revealed that MACF1 was predominately present in grade III-IV astroctyomas and grade IV glioblastoma, but not in normal brain tissue, normal human astrocytes and lower grade brain tumors. Subsequent genetic inhibition experiments showed that suppression of MACF1 selectively inhibited glioblastoma cell proliferation and migration in cell lines established from patient derived xenograft mouse models and immortalized glioblastoma cell lines that were associated with downregulation of the Wnt-signaling mediators, Axin1 and β-catenin. Additionally, concomitant MACF1 silencing with the chemotherapeutic agent temozolomide (TMZ) used for the clinical treatment of glioblastomas cooperatively reduced the proliferative capacity of glioblastoma cells. In conclusion, the present study represents the first investigation on the functional role of MACF1 in tumor cell biology, as well as demonstrates its potential as a unique biomarker that can be targeted synergistically with TMZ as part of a combinatorial therapeutic approach for the treatment of genetically multifarious glioblastomas.

Antitumor effect of fibrin glue containing temozolomide against malignant glioma

PubMed Central

Anai, Shigeo; Hide, Takuichiro; Takezaki, Tatsuya; Kuroda, Jun-ichiro; Shinojima, Naoki; Makino, Keishi; Nakamura, Hideo; Yano, Shigetoshi; Kuratsu, Jun-ichi

2014-01-01

Temozolomide (TMZ), used to treat glioblastoma and malignant glioma, induces autophagy, apoptosis and senescence in cancer cells. We investigated fibrin glue (FG) as a drug delivery system for the local administration of high-concentration TMZ aimed at preventing glioma recurrence. Our high-power liquid chromatography studies indicated that FG containing TMZ (TMZ-FG) manifested a sustained drug release potential. We prepared a subcutaneous tumor model by injecting groups of mice with three malignant glioma cell lines and examined the antitumor effect of TMZ-FG. We estimated the tumor volume and performed immunostaining and immunoblotting using antibodies to Ki-67, cleaved caspase 3, LC3 and p16. When FG sheets containing TMZ (TMZ-FGS) were inserted beneath the tumors, their growth was significantly suppressed. In mice treated with peroral TMZ plus TMZ-FGS the tumors tended to be smaller than in mice whose tumors were treated with TMZ-FGS or peroral TMZ alone. The TMZ-FGS induced autophagy, apoptosis and senescence in subcutaneous glioma tumor cells. To assess the safety of TMZ-FG for normal brain, we placed it directly on the brain of living mice and stained tissue sections obtained in the acute and chronic phase immunohistochemically. In both phases, TMZ-FG failed to severely damage normal brain tissue. TMZ-FG may represent a safe new drug delivery system with sustained drug release potential to treat malignant glioma. PMID:24673719

The Meninges: New Therapeutic Targets For Multiple Sclerosis

PubMed Central

Russi, Abigail E.; Brown, Melissa A.

2014-01-01

The CNS is largely comprised of non-regenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an “immune specialized” status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data has established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood barrier integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting of the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the blood brain barrier. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments. PMID:25241937

"Facilitated" amino acid transport is upregulated in brain tumors.

PubMed

Miyagawa, T; Oku, T; Uehara, H; Desai, R; Beattie, B; Tjuvajev, J; Blasberg, R

1998-05-01

The goal of this study was to determine the magnitude of "facilitated" amino acid transport across tumor and brain capillaries and to evaluate whether amino acid transporter expression is "upregulated" in tumor vessels compared to capillaries in contralateral brain tissue. Aminocyclopentane carboxylic acid (ACPC), a non-metabolized [14C]-labeled amino acid, and a reference molecule for passive vascular permeability, [67Ga]-gallium-diethylenetriaminepentaacetic acid (Ga-DTPA), were used in these studies. Two experimental rat gliomas were studied (C6 and RG2). Brain tissue was rapidly processed for double label quantitative autoradiography 10 minutes after intravenous injection of ACPC and Ga-DTPA. Parametric images of blood-to-brain transport (K1ACPC and K1Ga-DTPA, microL/min/g) produced from the autoradiograms and the histology were obtained from the same tissue section. These three images were registered in an image array processor; regions of interest in tumor and contralateral brain were defined on morphologic criteria (histology) and were transferred to the autoradiographic images to obtain mean values. The facilitated component of ACPC transport (deltaK1ACPC) was calculated from the K1ACPC and K1Ga-DTPA data, and paired comparisons between tumor and contralateral brain were performed. ACPC flux, K1ACPC, across normal brain capillaries (22.6 +/- 8.1 microL/g/min) was >200-fold greater than that of Ga-DTPA (0.09 +/- 0.04 microL/g/min), and this difference was largely (approximately 90%) due to facilitated ACPC transport. Substantially higher K1ACPC values compared to corresponding K1DTPA values were also measured in C6 and RG2 gliomas. The deltaK1ACPC values for C6 glioma were more than twice that of contralateral brain cortex. K1ACPC and deltaK1ACPC values for RG2 gliomas was not significantly higher than that of contralateral cortex, although a approximately 2-fold difference in facilitated transport is obtained after normalization for differences in capillary surface area between RG2 tumors and contralateral cortex. K1ACPC, deltaK1ACPC, and K DTPA were directly related to tumor cell density, were higher in regions of "impending" necrosis, and the tumor/contralateral brain ACPC radio-activity ratios (0 to 10 minutes) were very similar to that obtained with 0 to 60 minutes experiments. These results indicate that facilitated transport of ACPC is upregulated across C6 and RG2 glioma capillaries, and that tumors can induce upregulation of amino acid transporter expression in their supporting vasculature. They also suggest that early imaging (e.g., 0 to 20 minutes) with radiolabeled amino acids in a clinical setting may be optimal for defining brain tumors.

Hemorrhage detection in MRI brain images using images features

NASA Astrophysics Data System (ADS)

Moraru, Luminita; Moldovanu, Simona; Bibicu, Dorin; Stratulat (Visan), Mirela

2013-11-01

The abnormalities appear frequently on Magnetic Resonance Images (MRI) of brain in elderly patients presenting either stroke or cognitive impairment. Detection of brain hemorrhage lesions in MRI is an important but very time-consuming task. This research aims to develop a method to extract brain tissue features from T2-weighted MR images of the brain using a selection of the most valuable texture features in order to discriminate between normal and affected areas of the brain. Due to textural similarity between normal and affected areas in brain MR images these operation are very challenging. A trauma may cause microstructural changes, which are not necessarily perceptible by visual inspection, but they could be detected by using a texture analysis. The proposed analysis is developed in five steps: i) in the pre-processing step: the de-noising operation is performed using the Daubechies wavelets; ii) the original images were transformed in image features using the first order descriptors; iii) the regions of interest (ROIs) were cropped from images feature following up the axial symmetry properties with respect to the mid - sagittal plan; iv) the variation in the measurement of features was quantified using the two descriptors of the co-occurrence matrix, namely energy and homogeneity; v) finally, the meaningful of the image features is analyzed by using the t-test method. P-value has been applied to the pair of features in order to measure they efficacy.

Two-photon high-resolution measurement of partial pressure of oxygen in cerebral vasculature and tissue.

PubMed

Sakadzić, Sava; Roussakis, Emmanuel; Yaseen, Mohammad A; Mandeville, Emiri T; Srinivasan, Vivek J; Arai, Ken; Ruvinskaya, Svetlana; Devor, Anna; Lo, Eng H; Vinogradov, Sergei A; Boas, David A

2010-09-01

Measurements of oxygen partial pressure (pO(2)) with high temporal and spatial resolution in three dimensions is crucial for understanding oxygen delivery and consumption in normal and diseased brain. Among existing pO(2) measurement methods, phosphorescence quenching is optimally suited for the task. However, previous attempts to couple phosphorescence with two-photon laser scanning microscopy have faced substantial difficulties because of extremely low two-photon absorption cross-sections of conventional phosphorescent probes. Here we report to our knowledge the first practical in vivo two-photon high-resolution pO(2) measurements in small rodents' cortical microvasculature and tissue, made possible by combining an optimized imaging system with a two-photon-enhanced phosphorescent nanoprobe. The method features a measurement depth of up to 250 microm, sub-second temporal resolution and requires low probe concentration. The properties of the probe allowed for direct high-resolution measurement of cortical extravascular (tissue) pO(2), opening many possibilities for functional metabolic brain studies.

Multi-scale spectrally resolved quantitative fluorescence imaging system: towards neurosurgical guidance in glioma resection

NASA Astrophysics Data System (ADS)

Xie, Yijing; Thom, Maria; Miserocchi, Anna; McEvoy, Andrew W.; Desjardins, Adrien; Ourselin, Sebastien; Vercauteren, Tom

2017-02-01

In glioma resection surgery, the detection of tumour is often guided by using intraoperative fluorescence imaging notably with 5-ALA-PpIX, providing fluorescent contrast between normal brain tissue and the gliomas tissue to achieve improved tumour delineation and prolonged patient survival compared with the conventional white-light guided resection. However, the commercially available fluorescence imaging system relies on surgeon's eyes to visualise and distinguish the fluorescence signals, which unfortunately makes the resection subjective. In this study, we developed a novel multi-scale spectrally-resolved fluorescence imaging system and a computational model for quantification of PpIX concentration. The system consisted of a wide-field spectrally-resolved quantitative imaging device and a fluorescence endomicroscopic imaging system enabling optical biopsy. Ex vivo animal tissue experiments as well as human tumour sample studies demonstrated that the system was capable of specifically detecting the PpIX fluorescent signal and estimate the true concentration of PpIX in brain specimen.

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio.

PubMed

Ross, Jaime M; Öberg, Johanna; Brené, Stefan; Coppotelli, Giuseppe; Terzioglu, Mügen; Pernold, Karin; Goiny, Michel; Sitnikov, Rouslan; Kehr, Jan; Trifunovic, Aleksandra; Larsson, Nils-Göran; Hoffer, Barry J; Olson, Lars

2010-11-16

At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes.

T1ρ-weighted Dynamic Glucose-enhanced MR Imaging in the Human Brain.

PubMed

Paech, Daniel; Schuenke, Patrick; Koehler, Christina; Windschuh, Johannes; Mundiyanapurath, Sibu; Bickelhaupt, Sebastian; Bonekamp, David; Bäumer, Philipp; Bachert, Peter; Ladd, Mark E; Bendszus, Martin; Wick, Wolfgang; Unterberg, Andreas; Schlemmer, Heinz-Peter; Zaiss, Moritz; Radbruch, Alexander

2017-12-01

Purpose To evaluate the ability to detect intracerebral regions of increased glucose concentration at T1ρ-weighted dynamic glucose-enhanced (DGE) magnetic resonance (MR) imaging at 7.0 T. Materials and Methods This prospective study was approved by the institutional review board. Nine patients with newly diagnosed glioblastoma and four healthy volunteers were included in this study from October 2015 to July 2016. Adiabatically prepared chemical exchange-sensitive spin-lock imaging was performed with a 7.0-T whole-body unit with a temporal resolution of approximately 7 seconds, yielding the time-resolved DGE contrast. T1ρ-weighted DGE MR imaging was performed with injection of 100 mL of 20% d-glucose via the cubital vein. Glucose enhancement, given by the relative signal intensity change at T1ρ-weighted MR imaging (DGEρ), was quantitatively investigated in brain gray matter versus white matter of healthy volunteers and in tumor tissue versus normal-appearing white matter of patients with glioblastoma. The median signal intensities of the assessed brain regions were compared by using the Wilcoxon rank-sum test. Results In healthy volunteers, the median signal intensity in basal ganglia gray matter (DGEρ = 4.59%) was significantly increased compared with that in white matter tissue (DGEρ = 0.65%) (P = .028). In patients, the median signal intensity in the glucose-enhanced tumor region as displayed on T1ρ-weighted DGE images (DGEρ = 2.02%) was significantly higher than that in contralateral normal-appearing white matter (DGEρ = 0.08%) (P < .0001). Conclusion T1ρ-weighted DGE MR imaging in healthy volunteers and patients with newly diagnosed, untreated glioblastoma enabled visualization of brain glucose physiology and pathophysiologically increased glucose uptake and may have the potential to provide information about glucose metabolism in tumor tissue. © RSNA, 2017 Online supplemental material is available for this article.

Subject-specific bone attenuation correction for brain PET/MR: can ZTE-MRI substitute CT scan accurately?

PubMed

Khalifé, Maya; Fernandez, Brice; Jaubert, Olivier; Soussan, Michael; Brulon, Vincent; Buvat, Irène; Comtat, Claude

2017-09-21

In brain PET/MR applications, accurate attenuation maps are required for accurate PET image quantification. An implemented attenuation correction (AC) method for brain imaging is the single-atlas approach that estimates an AC map from an averaged CT template. As an alternative, we propose to use a zero echo time (ZTE) pulse sequence to segment bone, air and soft tissue. A linear relationship between histogram normalized ZTE intensity and measured CT density in Hounsfield units ([Formula: see text]) in bone has been established thanks to a CT-MR database of 16 patients. Continuous AC maps were computed based on the segmented ZTE by setting a fixed linear attenuation coefficient (LAC) to air and soft tissue and by using the linear relationship to generate continuous μ values for the bone. Additionally, for the purpose of comparison, four other AC maps were generated: a ZTE derived AC map with a fixed LAC for the bone, an AC map based on the single-atlas approach as provided by the PET/MR manufacturer, a soft-tissue only AC map and, finally, the CT derived attenuation map used as the gold standard (CTAC). All these AC maps were used with different levels of smoothing for PET image reconstruction with and without time-of-flight (TOF). The subject-specific AC map generated by combining ZTE-based segmentation and linear scaling of the normalized ZTE signal into [Formula: see text] was found to be a good substitute for the measured CTAC map in brain PET/MR when used with a Gaussian smoothing kernel of [Formula: see text] corresponding to the PET scanner intrinsic resolution. As expected TOF reduces AC error regardless of the AC method. The continuous ZTE-AC performed better than the other alternative MR derived AC methods, reducing the quantification error between the MRAC corrected PET image and the reference CTAC corrected PET image.

Subject-specific bone attenuation correction for brain PET/MR: can ZTE-MRI substitute CT scan accurately?

NASA Astrophysics Data System (ADS)

Khalifé, Maya; Fernandez, Brice; Jaubert, Olivier; Soussan, Michael; Brulon, Vincent; Buvat, Irène; Comtat, Claude

2017-10-01

In brain PET/MR applications, accurate attenuation maps are required for accurate PET image quantification. An implemented attenuation correction (AC) method for brain imaging is the single-atlas approach that estimates an AC map from an averaged CT template. As an alternative, we propose to use a zero echo time (ZTE) pulse sequence to segment bone, air and soft tissue. A linear relationship between histogram normalized ZTE intensity and measured CT density in Hounsfield units (HU ) in bone has been established thanks to a CT-MR database of 16 patients. Continuous AC maps were computed based on the segmented ZTE by setting a fixed linear attenuation coefficient (LAC) to air and soft tissue and by using the linear relationship to generate continuous μ values for the bone. Additionally, for the purpose of comparison, four other AC maps were generated: a ZTE derived AC map with a fixed LAC for the bone, an AC map based on the single-atlas approach as provided by the PET/MR manufacturer, a soft-tissue only AC map and, finally, the CT derived attenuation map used as the gold standard (CTAC). All these AC maps were used with different levels of smoothing for PET image reconstruction with and without time-of-flight (TOF). The subject-specific AC map generated by combining ZTE-based segmentation and linear scaling of the normalized ZTE signal into HU was found to be a good substitute for the measured CTAC map in brain PET/MR when used with a Gaussian smoothing kernel of 4~mm corresponding to the PET scanner intrinsic resolution. As expected TOF reduces AC error regardless of the AC method. The continuous ZTE-AC performed better than the other alternative MR derived AC methods, reducing the quantification error between the MRAC corrected PET image and the reference CTAC corrected PET image.

Fisher statistics for analysis of diffusion tensor directional information.

PubMed

Hutchinson, Elizabeth B; Rutecki, Paul A; Alexander, Andrew L; Sutula, Thomas P

2012-04-30

A statistical approach is presented for the quantitative analysis of diffusion tensor imaging (DTI) directional information using Fisher statistics, which were originally developed for the analysis of vectors in the field of paleomagnetism. In this framework, descriptive and inferential statistics have been formulated based on the Fisher probability density function, a spherical analogue of the normal distribution. The Fisher approach was evaluated for investigation of rat brain DTI maps to characterize tissue orientation in the corpus callosum, fornix, and hilus of the dorsal hippocampal dentate gyrus, and to compare directional properties in these regions following status epilepticus (SE) or traumatic brain injury (TBI) with values in healthy brains. Direction vectors were determined for each region of interest (ROI) for each brain sample and Fisher statistics were applied to calculate the mean direction vector and variance parameters in the corpus callosum, fornix, and dentate gyrus of normal rats and rats that experienced TBI or SE. Hypothesis testing was performed by calculation of Watson's F-statistic and associated p-value giving the likelihood that grouped observations were from the same directional distribution. In the fornix and midline corpus callosum, no directional differences were detected between groups, however in the hilus, significant (p<0.0005) differences were found that robustly confirmed observations that were suggested by visual inspection of directionally encoded color DTI maps. The Fisher approach is a potentially useful analysis tool that may extend the current capabilities of DTI investigation by providing a means of statistical comparison of tissue structural orientation. Copyright © 2012 Elsevier B.V. All rights reserved.

Distinction of brain tissue, low grade and high grade glioma with time-resolved fluorescence spectroscopy

PubMed Central

Yong, William H.; Butte, Pramod V.; Pikul, Brian K.; Jo, Javier A.; Fang, Qiyin; Papaioannou, Thanassis; Black, Keith L.; Marcu, Laura

2010-01-01

Neuropathology frozen section diagnoses are difficult in part because of the small tissue samples and the paucity of adjunctive rapid intraoperative stains. This study aims to explore the use of time-resolved laser-induced fluorescence spectroscopy as a rapid adjunctive tool for the diagnosis of glioma specimens and for distinction of glioma from normal tissues intraoperatively. Ten low grade gliomas, 15 high grade gliomas without necrosis, 6 high grade gliomas with necrosis and/or radiation effect, and 14 histologically uninvolved “normal” brain specimens are spectroscopicaly analyzed and contrasted. Tissue autofluorescence was induced with a pulsed Nitrogen laser (337 nm, 1.2 ns) and the transient intensity decay profiles were recorded in the 370-500 nm spectral range with a fast digitized (0.2 ns time resolution). Spectral intensities and time-dependent parameters derived from the time-resolved spectra of each site were used for tissue characterization. A linear discriminant analysis diagnostic algorithm was used for tissue classification. Both low and high grade gliomas can be distinguished from histologically uninvolved cerebral cortex and white matter with high accuracy (above 90%). In addition, the presence or absence of treatment effect and/or necrosis can be identified in high grade gliomas. Taking advantage of tissue autofluorescence, this technique facilitates a direct and rapid investigation of surgically obtained tissue. PMID:16368511

Effects of Nd:YAG and CO2 lasers on cerebral microvasculature. Study in normal rabbit brain.

PubMed

Kuroiwa, T; Tsuyumu, M; Takei, H; Inaba, Y

1986-01-01

The effect of Nd:YAG and CO2 laser beams on cerebral microvasculature was examined in experimental animals. Soft x-ray microangiography and histological examination of the brain after Nd:YAG laser exposure revealed broad avascular or oligovascular zones in the irradiated and the surrounding edematous tissue, in which the surviving vessels were narrowed and tapered without significant leakage of blood. After CO2 laser exposure, a wedge-shaped tissue defect surrounded by layers of charring, coagulation, and edema was observed. The main finding in the surrounding coagulation and edematous layers was dilatation of the vessels. Hemorrhage was sometimes observed, mainly in the edematous layer. These findings seem to explain the effective hemostatic capability of the Nd:YAG laser and the occasional hemorrhage following CO2 laser exposure, especially at high energy output.

Proficiency performance benchmarks for removal of simulated brain tumors using a virtual reality simulator NeuroTouch.

PubMed

AlZhrani, Gmaan; Alotaibi, Fahad; Azarnoush, Hamed; Winkler-Schwartz, Alexander; Sabbagh, Abdulrahman; Bajunaid, Khalid; Lajoie, Susanne P; Del Maestro, Rolando F

2015-01-01

Assessment of neurosurgical technical skills involved in the resection of cerebral tumors in operative environments is complex. Educators emphasize the need to develop and use objective and meaningful assessment tools that are reliable and valid for assessing trainees' progress in acquiring surgical skills. The purpose of this study was to develop proficiency performance benchmarks for a newly proposed set of objective measures (metrics) of neurosurgical technical skills performance during simulated brain tumor resection using a new virtual reality simulator (NeuroTouch). Each participant performed the resection of 18 simulated brain tumors of different complexity using the NeuroTouch platform. Surgical performance was computed using Tier 1 and Tier 2 metrics derived from NeuroTouch simulator data consisting of (1) safety metrics, including (a) volume of surrounding simulated normal brain tissue removed, (b) sum of forces utilized, and (c) maximum force applied during tumor resection; (2) quality of operation metric, which involved the percentage of tumor removed; and (3) efficiency metrics, including (a) instrument total tip path lengths and (b) frequency of pedal activation. All studies were conducted in the Neurosurgical Simulation Research Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, Canada. A total of 33 participants were recruited, including 17 experts (board-certified neurosurgeons) and 16 novices (7 senior and 9 junior neurosurgery residents). The results demonstrated that "expert" neurosurgeons resected less surrounding simulated normal brain tissue and less tumor tissue than residents. These data are consistent with the concept that "experts" focused more on safety of the surgical procedure compared with novices. By analyzing experts' neurosurgical technical skills performance on these different metrics, we were able to establish benchmarks for goal proficiency performance training of neurosurgery residents. This study furthers our understanding of expert neurosurgical performance during the resection of simulated virtual reality tumors and provides neurosurgical trainees with predefined proficiency performance benchmarks designed to maximize the learning of specific surgical technical skills. Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

Use of Synchrotron X-ray Fluorescence to Measure Trace Metal Distribution in the Brain

NASA Astrophysics Data System (ADS)

Linkous, D.; Flinn, J. M.; Lanzirotti, A.; Frederickson, C.; Jones, B. F.; Bertsch, P. M.

2002-12-01

X26A, National Synchrotron Light Source, was used to quantitatively evaluate the spatial distribution of trace metals, such as Zn and Cu, in brain tissue. X-ray microprobe techniques offer distinct advantages over other analytical methods by allowing analyses to be done in-situ with little or no chemical pretreatment and low detection limits (about 1 ppm). In the context of neuroscience, SXRF can provide non-destructive measurements of specific metal concentrations and distribution within nerve (brain) tissue. Neuronal tissue from organisms having undergone different normal or experimental conditions may be compared, with analytical capacities not limited by binding states of the metal (i.e., vesicular or enzymatic), as is the case with staining techniques.. Whole regions of tissue may be scanned for detectable trace metals at spatial resolutions of 10um or less using focused monochromatic x-ray beams. Here special attention has been given to zinc because it is the most common trace metal in the brain, and levels have been increasing in the environment. In this investigation, zinc concentrations present within the hilus of a rat hippocampus, and to a lesser extent in the cortex, have been shown to increase following long-term ingestion of zinc-enhanced drinking water that was associated with deficits in spatial memory. Concomitantly, copper concentrations in the internal capsule were comparatively lower. Other first order transition metals, Cr, V, Mn, and Co were not detected. In contrast, elevated levels of Zn, Cu, and Fe have been seen in amyloid plaques associated with Alzheimer's disease.

Advances in Raman spectroscopy for the diagnosis of Alzheimer's disease

NASA Astrophysics Data System (ADS)

Sudworth, Caroline D.; Archer, John K. J.; Black, Richard A.; Mann, David

2006-02-01

Within the next 50 years Alzheimer's disease is expected to affect 100 million people worldwide. The progressive decline in the mental health of the patient is caused by severe brain atrophy generated by the breakdown and aggregation of proteins, resulting in β-amyloid plaques and neurofibrillary tangles. The greatest challenge to Alzheimer's disease lies in the pursuit of an early and definitive diagnosis, in order that suitable treatment can be administered. At the present time, definitive diagnosis is restricted to post-mortem examination. Alzheimer's disease also remains without a long-term cure. This research demonstrates the potential role of Raman spectroscopy, combined with principle components analysis (PCA), as a diagnostic method. Analyses of ethically approved ex vivo post-mortem brain tissues (originating from frontal and occipital lobes) from control (3 normal elderly subjects and 3 Huntingdon's disease subjects) and Alzheimer's disease (12 subjects) brain sections, and a further set of 12 blinded samples are presented. Spectra originating from these tissues are highly reproducible, and initial results indicate a vital difference in protein content and conformation, relating to the abnormally high levels of aggregated proteins in the diseased tissues. Further examination of these spectra using PCA allows for the separation of control from diseased tissues. The validation of the PCA models using blinded samples also displays promise for the identification of Alzheimer's disease, in conjunction with secondary information regarding other brain diseases and dementias. These results provide a route for Raman spectroscopy as a possible non-invasive, non-destructive tool for the early diagnosis of Alzheimer's disease.

Association of metallothionein-III with oligodendroglial cytoplasmic inclusions in multiple system atrophy.

PubMed

Pountney, D L; Dickson, T C; Power, J H T; Vickers, J C; West, A J; Gai, W P

2011-01-01

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterised by Parkinsonian and autonomic symptoms and by widespread intracytoplasmic inclusion bodies in oligodendrocytes. These glial cytoplasmic inclusions (GCIs) are comprised of 9-10 nm filaments rich in the protein alpha-synuclein, also found in neuronal inclusion bodies associated with Parkinson's disease. Metallothioneins (MTs) are a class of low-molecular weight (6-7 kDa), cysteine-rich metal-binding proteins the expression of which is induced by heavy metals, glucocorticoids, cytokines and oxidative stress. Recent studies have shown a role for the ubiquitously expressed MT-I/II isoforms in the brain following a variety of stresses, whereas, the function of the brain-specific MT isoform, MT-III, is less clear. MT-III and MT-I/II immunostaining of post-mortem tissue in MSA and normal control human brains showed that the number of MT-III-positive cells is significantly increased in MSA in visual cortex, whereas MT-I/II isoforms showed no significant difference in the distribution of immunopositive cells in MSA compared to normal tissue. GCIs were immunopositive for MT-III, but were immunonegative for the MT-I/II isoforms. Immunofluorescence double labelling showed the co-localisation of alpha-synuclein and MT-III in GCIs in MSA tissue. In isolated GCIs, transmission electron microscopy demonstrated MT-III immunogold labelling of the amorphous material surrounding alpha-synuclein filaments in GCIs. High-molecular weight MT-III species in addition to MT-III monomer were detected in GCIs by Western analysis of the detergent-solubilised proteins of purified GCIs. These results show that MT-III, but not MT-I/II, is a specific component of GCIs, present in abnormal aggregated forms external to the alpha-synuclein filaments.

[Brain metastases: Focal treatment (surgery and radiation therapy) and cognitive consequences].

PubMed

Reygagne, Emmanuelle; Du Boisgueheneuc, Foucaud; Berger, Antoine

2017-04-01

Brain metastases represent the first cause of malignant brain tumor. Without radiation therapy, prognosis was poor with fast neurological deterioration, and a median overall survival of one month. Nowadays, therapeutic options depend on brain metastases presentation, extra brain disease, performance status and estimated prognostic (DS GPA). Therefore, for oligometastatic brain patients with a better prognosis, this therapeutic modality is controversial. In fact, whole-brain radiation therapy improves neurological outcomes, but it can also induce late neuro-cognitive sequelae for long-term survivors of brain metastases. Thus, in this strategy for preserving good cognitive functions, stereotactic radiation therapy is a promising treatment. Delivering precisely targeted radiation in few high-doses in one to four brain metastases, allows to reduce radiation damage to normal tissues and it should allow to decrease radiation-induced cognitive decline. In this paper, we will discuss about therapeutic strategies (radiation therapy and surgery) with their neuro-cognitive consequences for brain metastases patients and future concerning preservation of cognitive functions. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

A model for optimizing delivery of targeted radionuclide therapies into resection cavity margins for the treatment of primary brain cancers.

PubMed

Raghavan, Raghu; Howell, Roger W; Zalutsky, Michael R

2017-06-01

Radionuclides conjugated to molecules that bind specifically to cancer cells are of great interest as a means to increase the specificity of radiotherapy. Currently, the methods to disseminate these targeted radiotherapeutics have been either systemic delivery or by bolus injection into the tumor or tumor resection cavity. Herein we model a potentially more efficient method of delivery, namely pressure-driven fluid flow, called convection-enhanced delivery (CED), where a device infuses the molecules in solution (or suspension) directly into the tissue of interest. In particular, we focus on the setting of primary brain cancer after debulking surgery, where the tissue margins surrounding the surgical resection cavity are infiltrated with tumor cells and the most frequent sites of tumor recurrence. We develop the combination of fluid flow, chemical kinetics, and radiation dose models needed to examine such protocols. We focus on Auger electron-emitting radionuclides (e.g. 67 Ga, 77 Br, 111 In, 125 I, 123 I, 193m Pt, 195m Pt) whose short range makes them ideal for targeted therapy in this setting of small foci of tumor spread within normal tissue. By solving these model equations, we confirm that a CED protocol is promising in allowing sufficient absorbed dose to destroy cancer cells with minimal absorbed dose to normal cells at clinically feasible activity levels. We also show that Auger emitters are ideal for this purpose while the longer range alpha particle emitters fail to meet criteria for effective therapy (as neither would energetic beta particle emitters). The model is used with simplified assumptions on the geometry and homogeneity of brain tissue to allow semi-analytic solutions to be displayed, and with the purpose of a first examination of this new delivery protocol proposed for radionuclide therapy. However, we emphasize that it is immediately extensible to personalized therapy treatment planning as we have previously shown for conventional CED, at the price of requiring a fully numerical computerized approach.

Synthesis and Characterization of a Hydrogel with Controllable Electroosmosis: A Potential Brain Tissue Surrogate for Electrokinetic Transport

PubMed Central

Faraji, Amir H.; Cui, Jonathan J.; Guy, Yifat; Li, Ling; Weber, Stephen G.

2011-01-01

Electroosmosis is the bulk fluid flow initiated by application of an electric field to an electrolyte solution in contact with immobile objects with a non-zero ζ-potential such as the surface of a porous medium. Electroosmosis may be used to assist analytical separations. Several gel-based systems with varying electroosmotic mobilities have been made in this context. A method was recently developed to determine the ζ-potential of organotypic hippocampal slice cultures (OHSC) as a representative model for normal brain tissue. The ζ-potential of the tissue is significant. However, determining the role of the ζ-potential in solute transport in tissue in an electric field is difficult because the tissue's ζ-potential cannot be altered. We hypothesized that mass transport properties, namely the ζ-potential and tortuosity, could be modulated by controlling the composition of a set of hydrogels. Thus, poly(acrylamide-co-acrylic acid) gels were prepared with three compositions (by monomer weight percent): acrylamide/acrylic acid 100/0, 90/10, and 75/25. The ζ-potentials of these gels at pH 7.4 are distinctly different, and in fact vary approximately linearly with the weight percent of acrylic acid. We discovered that the 25% acrylic acid gel is a respectable model for brain tissue, as its ζ-potential is comparable to the OHSC. This series of gels permits the experimental determination of the importance of electrokinetic properties in a particular experiment or protocol. Additionally, tortuosities were measured electrokinetically and by evaluating diffusion coefficients. Hydrogels with well-defined ζ-potential and tortuosity may find utility in biomaterials, analytical separations, and as a surrogate model for OHSC and living biological tissues. PMID:21905710

Detection of Chronic Wasting Disease Prions in Salivary, Urinary, and Intestinal Tissues of Deer: Potential Mechanisms of Prion Shedding and Transmission▿

PubMed Central

Haley, Nicholas J.; Mathiason, Candace K.; Carver, Scott; Zabel, Mark; Telling, Glenn C.; Hoover, Edward A.

2011-01-01

Efficient horizontal transmission is a signature trait of chronic wasting disease (CWD) in cervids. Infectious prions shed into excreta appear to play a key role in this facile transmission, as has been demonstrated by bioassays of cervid and transgenic species and serial protein misfolding cyclic amplification (sPMCA). However, the source(s) of infectious prions in these body fluids has yet to be identified. In the present study, we analyzed tissues proximate to saliva, urine, and fecal production by sPMCA in an attempt to elucidate this unique aspect of CWD pathogenesis. Oropharyngeal, urogenital, and gastrointestinal tissues along with blood and obex from CWD-exposed cervids (comprising 27 animals and >350 individual samples) were analyzed and scored based on the apparent relative CWD burden. PrPCWD-generating activity was detected in a range of tissues and was highest in the salivary gland, urinary bladder, and distal intestinal tract. In the same assays, blood from the same animals and unseeded normal brain homogenate controls (n = 116 of 117) remained negative. The PrP-converting activity in peripheral tissues varied from 10−11- to 100-fold of that found in brain of the same animal. Deer with highest levels of PrPCWD amplification in the brain had higher and more widely disseminated prion amplification in excretory tissues. Interestingly, PrPCWD was not demonstrable in these excretory tissues by conventional Western blotting, suggesting a low prion burden or the presence of protease-sensitive infectious prions destroyed by harsh proteolytic treatments. These findings offer unique insights into the transmission of CWD in particular and prion infection and trafficking overall. PMID:21525361

Arizona Study of Aging and Neurodegenerative Disorders and Brain and Body Donation Program

PubMed Central

Beach, Thomas G.; Adler, Charles H.; Sue, Lucia I.; Serrano, Geidy; Shill, Holly A.; Walker, Douglas G.; Lue, LihFen; Roher, Alex E.; Dugger, Brittany N.; Maarouf, Chera; Birdsill, Alex C.; Intorcia, Anthony; Saxon-Labelle, Megan; Pullen, Joel; Scroggins, Alexander; Filon, Jessica; Scott, Sarah; Hoffman, Brittany; Garcia, Angelica; Caviness, John N.; Hentz, Joseph G.; Driver-Dunckley, Erika; Jacobson, Sandra A.; Davis, Kathryn J.; Belden, Christine M.; Long, Kathy E.; Malek-Ahmadi, Michael; Powell, Jessica J.; Gale, Lisa D.; Nicholson, Lisa R.; Caselli, Richard J.; Woodruff, Bryan K.; Rapscak, Steven Z.; Ahern, Geoffrey L.; Shi, Jiong; Burke, Anna D.; Reiman, Eric M.; Sabbagh, Marwan N.

2015-01-01

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer’s disease, Parkinson’s disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer’s Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson’s Research. The Program has made rapid autopsy a priority, with a 3.0-hour median postmortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects. PMID:25619230

Molecular and histological changes in cerebral cortex and lung tissues under the effect of tramadol treatment.

PubMed

Awadalla, Eatemad A; Salah-Eldin, Alaa-Eldin

2016-08-01

Tramadol abuse is one of the most frequent health problems in Egypt and worldwide. In most cases, tramadol abused by men face a problem with premature ejaculation. Tramadol like other opioids induces a decrease in plasma antioxidant levels, which may reflect a failure of the antioxidant defense mechanism against oxidative damage. The present work aimed to study the possible deleterious effects of oral administration of tramadol on brain and lung tissues in rats. Twenty adult male albino rats were divided into two groups; a control administered with normal saline and tramadol-treated (40mg/kg b.w.) group for 20 successive days. At the end of experimental period, blood was collected and specimens from brains and lungs were taken for histopathological and molecular studies. Malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) activities were measured in serum of control and tramadol-treated groups. Brain and lung specimens were histopathological evaluated using light microscopy. The expression levels of apoptotic related genes; Bcl-2, Bax and Caspase-3 were study in brain and lung tissues using RT-PCR analysis. We recorded a significant increase MDA level, while antioxidant enzymes; GSH, SOD and CAT were significantly decreased after tramadol-treatment. The obtained results revealed that tramadol induced a remarkable histomorphological changes in rats' brains (cerebral cortex and hippocampus) and severe histopathological changes in rats' lung when compared to that of control. On molecular level, the expression of the pro-apoptotic Bax and Caspase-3 showed a significant increase whereas the anti-apoptotic Bcl-2 decreased markedly indicating that tramadol is harmful at cellular level and can induce apoptotic changes in brain tissues. Our data confirmed the risk of increased oxidative stress, neuronal and pulmonary damage due to tramadol abuse. Although tramadol is reported to be effective in pain management, its toxicity should be kept in mind. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The muscle protein dysferlin accumulates in the Alzheimer brain

PubMed Central

Palamand, Divya; Strider, Jeff; Milone, Margherita; Pestronk, Alan

2006-01-01

Dysferlin is a transmembrane protein that is highly expressed in muscle. Dysferlin mutations cause limb-girdle dystrophy type 2B, Miyoshi myopathy and distal anterior compartment myopathy. Dysferlin has also been described in neural tissue. We studied dysferlin distribution in the brains of patients with Alzheimer disease (AD) and controls. Twelve brains, staged using the Clinical Dementia Rating were examined: 9 AD cases (mean age: 85.9 years and mean disease duration: 8.9 years), and 3 age-matched controls (mean age: 87.5 years). Dysferlin is a cytoplasmic protein in the pyramidal neurons of normal and AD brains. In addition, there were dysferlin-positive dystrophic neurites within Aβ plaques in the AD brain, distinct from tau-positive neurites. Western blots of total brain protein (RIPA) and sequential extraction buffers (high salt, high salt/Triton X-100, SDS and formic acid) of increasing protein extraction strength were performed to examine solubility state. In RIPA fractions, dysferlin was seen as 230–272 kDa bands in normal and AD brains. In serial extractions, there was a shift of dysferlin from soluble phase in high salt/Triton X-100 to the more insoluble SDS fraction in AD. Dysferlin is a new protein described in the AD brain that accumulates in association with neuritic plaques. In muscle, dysferlin plays a role in the repair of muscle membrane damage. The accumulation of dysferlin in the AD brain may be related to the inability of neurons to repair damage due to Aβ deposits accumulating in the AD brain. PMID:17024495

MR imaging of a novel NOE-mediated magnetization transfer with water in rat brain at 9.4 T.

PubMed

Zhang, Xiao-Yong; Wang, Feng; Jin, Tao; Xu, Junzhong; Xie, Jingping; Gochberg, Daniel F; Gore, John C; Zu, Zhongliang

2017-08-01

To detect, map, and quantify a novel nuclear Overhauser enhancement (NOE)-mediated magnetization transfer (MT) with water at approximately -1.6 ppm [NOE(-1.6)] in rat brain using MRI. Continuous wave MT sequences with a variety of radiofrequency irradiation powers were optimized to achieve the maximum contrast of this NOE(-1.6) effect at 9.4 T. The distribution of effect magnitudes, resonance frequency offsets, and line widths in healthy rat brains and the differences of the effect between tumors and contralateral normal brains were imaged and quantified using a multi-Lorentzian fitting method. MR measurements on reconstituted model phospholipids as well as two cell lines (HEK293 and 9L) were also performed to investigate the possible molecular origin of this NOE. Our results suggest that the NOE(-1.6) effect can be detected reliably in rat brain. Pixel-wise fittings demonstrated the regional variations of the effect. Measurements in a rodent tumor model showed that the amplitude of NOE(-1.6) in brain tumor was significantly diminished compared with that in normal brain tissue. Measurements of reconstituted phospholipids suggest that this effect may originate from choline phospholipids. NOE(-1.6) could be used as a new biomarker for the detection of brain tumor. Magn Reson Med 78:588-597, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

Accurate and robust brain image alignment using boundary-based registration.

PubMed

Greve, Douglas N; Fischl, Bruce

2009-10-15

The fine spatial scales of the structures in the human brain represent an enormous challenge to the successful integration of information from different images for both within- and between-subject analysis. While many algorithms to register image pairs from the same subject exist, visual inspection shows that their accuracy and robustness to be suspect, particularly when there are strong intensity gradients and/or only part of the brain is imaged. This paper introduces a new algorithm called Boundary-Based Registration, or BBR. The novelty of BBR is that it treats the two images very differently. The reference image must be of sufficient resolution and quality to extract surfaces that separate tissue types. The input image is then aligned to the reference by maximizing the intensity gradient across tissue boundaries. Several lower quality images can be aligned through their alignment with the reference. Visual inspection and fMRI results show that BBR is more accurate than correlation ratio or normalized mutual information and is considerably more robust to even strong intensity inhomogeneities. BBR also excels at aligning partial-brain images to whole-brain images, a domain in which existing registration algorithms frequently fail. Even in the limit of registering a single slice, we show the BBR results to be robust and accurate.

Using Electronic Noses to Detect Tumors During Neurosurgery

NASA Technical Reports Server (NTRS)

Homer, Margie L.; Ryan, Margaret A.; Lara, Liana M.; Kateb, Babak; Chen, Mike

2008-01-01

It has been proposed to develop special-purpose electronic noses and algorithms for processing the digitized outputs of the electronic noses for determining whether tissue exposed during neurosurgery is cancerous. At present, visual inspection by a surgeon is the only available intraoperative technique for detecting cancerous tissue. Implementation of the proposal would help to satisfy a desire, expressed by some neurosurgeons, for an intraoperative technique for determining whether all of a brain tumor has been removed. The electronic-nose technique could complement multimodal imaging techniques, which have also been proposed as means of detecting cancerous tissue. There are also other potential applications of the electronic-nose technique in general diagnosis of abnormal tissue. In preliminary experiments performed to assess the viability of the proposal, the problem of distinguishing between different types of cultured cells was substituted for the problem of distinguishing between normal and abnormal specimens of the same type of tissue. The figure presents data from one experiment, illustrating differences between patterns that could be used to distinguish between two types of cultured cancer cells. Further development can be expected to include studies directed toward answering questions concerning not only the possibility of distinguishing among various types of normal and abnormal tissue but also distinguishing between tissues of interest and other odorous substances that may be present in medical settings.

Astrogliosis and impaired aquaporin-4 and dystrophin systems in idiopathic normal pressure hydrocephalus.

PubMed

Eide, P K; Hansson, H-A

2017-06-19

Idiopathic normal pressure hydrocephalus (iNPH) is one subtype of dementia that may improve following drainage of cerebrospinal fluid (CSF). This prospective observational study explored whether expression of the water channel aquaporin-4 (AQP4) and the anchoring molecule dystrophin 71 (Dp71) are altered at astrocytic perivascular endfeet and in adjacent neuropil of iNPH patient. Observations were related to measurements of pulsatile and static intracranial pressure (ICP). The study included iNPH patients undergoing overnight monitoring of the pulsatile/static ICP in whom a biopsy was taken from the frontal cerebral cortex during placement of the ICP sensor. Reference (Ref) biopsies were sampled from 13 patients who underwent brain surgery for epilepsy, tumours or cerebral aneurysms. The brain tissue specimens were examined by light microscopy, immunohistochemistry, densitometry and morphometry. iNPH patients responding to surgery (n = 44) had elevated pulsatile ICP, indicative of impaired intracranial compliance. As compared to the Ref patients, the cortical biopsies of iNPH patients revealed prominent astrogliosis and reduced expression of AQP4 and Dp71 immunoreactivities in the astrocytic perivascular endfeet and in parts of the adjacent neuropil. There was a significant correlation between degree of astrogliosis and reduction of AQP4 and Dp71 at astrocytic perivascular endfeet. Idiopathic normal pressure hydrocephalus patients responding to CSF diversion present with abnormal pulsatile ICP, indicative of impaired intracranial compliance. A main histopathological finding was astrogliosis and reduction of AQP4 and of Dp71 in astrocytic perivascular endfeet. We propose that the altered AQP4 and Dp71 complex contributes to the subischaemia prevalent in the brain tissue of iNPH. © 2017 British Neuropathological Society.

Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors.

PubMed

Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar

2014-02-01

F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.

Effects of levothyroxine on learning and memory deficits in a rat model of Alzheimer's disease: the role of BDNF and oxidative stress.

PubMed

Bavarsad, Kowsar; Hadjzadeh, Mousa-Al-Reza; Hosseini, Mahmoud; Pakdel, Roghayeh; Beheshti, Farimah; Bafadam, Soleyman; Ashaari, Zeinab

2018-06-21

The effect of levothyroxine (L-T4) on the learning and memory impairment induced by streptozotocin (STZ) and brain tissue oxidative damage in rats was evaluated. An animal model of the Alzheimer's disease (AD) was established by intracerebroventricular injection of STZ (3 mg/kg) in male Wistar rats (250 ± 50 g). After that, the rats were treated for 3 weeks with L-T4 (10, 100 μg/kg) or normal saline. Passive avoidance (PA) learning and spatial memory were evaluated using shuttle box and Morris water maze (MWM), respectively. Finally, the rats were euthanized, their blood samples were collected for further thyroxine assessment and their brains were removed after decapitation in order to measure the oxidative stress parameters and brain-derived neurotrophic factor (BDNF). In the MWM, latency (s) increased in the AD rats compared with the normal control group while it decreased in the 10 μg/kg L-T4 injected AD rats compared with the AD group. In the PA, the latency for entering the dark compartment was lower in the AD group than in the normal control group and it decreased in the 10 μg/kg L-T4 injected AD rats. The low dose of L-T4 (10 μg/kg) reduced malondialdehyde concentration but increased thiols concentration, superoxide dismutase, catalase activities and BDNF level in hippocampal tissues of the AD rats. Injection of L-T4 (10 μg/kg) alleviated memory deficits and also improved factors of oxidative stress and BDNF level in the STZ-induced AD rats.

Intensity non-uniformity correction using N3 on 3-T scanners with multichannel phased array coils

PubMed Central

Boyes, Richard G.; Gunter, Jeff L.; Frost, Chris; Janke, Andrew L.; Yeatman, Thomas; Hill, Derek L.G.; Bernstein, Matt A.; Thompson, Paul M.; Weiner, Michael W.; Schuff, Norbert; Alexander, Gene E.; Killiany, Ronald J.; DeCarli, Charles; Jack, Clifford R.; Fox, Nick C.

2008-01-01

Measures of structural brain change based on longitudinal MR imaging are increasingly important but can be degraded by intensity non-uniformity. This non-uniformity can be more pronounced at higher field strengths, or when using multichannel receiver coils. We assessed the ability of the non-parametric non-uniform intensity normalization (N3) technique to correct non-uniformity in 72 volumetric brain MR scans from the preparatory phase of the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Normal elderly subjects (n = 18) were scanned on different 3-T scanners with a multichannel phased array receiver coil at baseline, using magnetization prepared rapid gradient echo (MP-RAGE) and spoiled gradient echo (SPGR) pulse sequences, and again 2 weeks later. When applying N3, we used five brain masks of varying accuracy and four spline smoothing distances (d = 50, 100, 150 and 200 mm) to ascertain which combination of parameters optimally reduces the non-uniformity. We used the normalized white matter intensity variance (standard deviation/mean) to ascertain quantitatively the correction for a single scan; we used the variance of the normalized difference image to assess quantitatively the consistency of the correction over time from registered scan pairs. Our results showed statistically significant (p < 0.01) improvement in uniformity for individual scans and reduction in the normalized difference image variance when using masks that identified distinct brain tissue classes, and when using smaller spline smoothing distances (e.g., 50-100 mm) for both MP-RAGE and SPGR pulse sequences. These optimized settings may assist future large-scale studies where 3-T scanners and phased array receiver coils are used, such as ADNI, so that intensity non-uniformity does not influence the power of MR imaging to detect disease progression and the factors that influence it. PMID:18063391

Quantitative assessment of Cerenkov luminescence for radioguided brain tumor resection surgery

NASA Astrophysics Data System (ADS)

Klein, Justin S.; Mitchell, Gregory S.; Cherry, Simon R.

2017-05-01

Cerenkov luminescence imaging (CLI) is a developing imaging modality that detects radiolabeled molecules via visible light emitted during the radioactive decay process. We used a Monte Carlo based computer simulation to quantitatively investigate CLI compared to direct detection of the ionizing radiation itself as an intraoperative imaging tool for assessment of brain tumor margins. Our brain tumor model consisted of a 1 mm spherical tumor remnant embedded up to 5 mm in depth below the surface of normal brain tissue. Tumor to background contrast ranging from 2:1 to 10:1 were considered. We quantified all decay signals (e±, gamma photon, Cerenkov photons) reaching the brain volume surface. CLI proved to be the most sensitive method for detecting the tumor volume in both imaging and non-imaging strategies as assessed by contrast-to-noise ratio and by receiver operating characteristic output of a channelized Hotelling observer.

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

PubMed Central

Stankiewicz, James; Panter, Scott S; Neema, Mohit; Arora, Ashish; Batt, Courtney; Bakshi, Rohit

2007-01-01

Summary Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurologic disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathologic processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development. PMID:17599703

Normal brain tissue volumes after long-term recovery in anorexia and bulimia nervosa.

PubMed

Wagner, Angela; Greer, Phil; Bailer, Ursula F; Frank, Guido K; Henry, Shannan E; Putnam, Karen; Meltzer, Carolyn C; Ziolko, Scott K; Hoge, Jessica; McConaha, Claire; Kaye, Walter H

2006-02-01

Individuals who are ill with anorexia (AN) and bulimia nervosa (BN) often have increased cerebrospinal fluid (CSF) volumes and decreased total gray and white matter volumes. It is unclear whether such disturbances persist after recovery from an eating disorder. Magnetic resonance imaging was performed on 40 women who were long-term recovered (>1 year no binging, purging, or restricting behaviors, normal weight, and menstrual cycles, not on medication) from restricting or binge/purging type AN or BN and 31 healthy control women (CW). Voxel-based morphometry (VBM) was used for data analysis. Recovered AN and BN subgroups were similar to CW in terms of cerebrospinal fluid (CSF) volume as well as total or regional gray or white matter volume. These findings suggest that structural brain abnormalities are reversible in individuals with eating disorders after long-term recovery.

Brain tissue partial pressure of oxygen predicts the outcome of severe traumatic brain injury under mild hypothermia treatment.

PubMed

Sun, Hongtao; Zheng, Maohua; Wang, Yanmin; Diao, Yunfeng; Zhao, Wanyong; Wei, Zhengjun

2016-01-01

The aim of this study was to investigate the clinical significance and changes of brain tissue partial pressure of oxygen (PbtO2) in the course of mild hypothermia treatment (MHT) for treating severe traumatic brain injury (sTBI). There were 68 cases with sTBI undergoing MHT. PbtO2, intracranial pressure (ICP), jugular venous oxygen saturation (SjvO2), and cerebral perfusion pressure (CPP) were continuously monitored, and clinical outcomes were evaluated using the Glasgow Outcome Scale score. Of 68 patients with sTBI, PbtO2, SjvO2, and CPP were obviously increased, but decreased ICP level was observed throughout the MHT. PbtO2 and ICP were negatively linearly correlated, while there was a positive linear correlation between PbtO2 and SjvO2. Monitoring CPP and SjvO2 was performed under normal circumstances, and a large proportion of patients were detected with low PbtO2. Decreased PbtO2 was also found after MHT. Continuous PbtO2 monitoring could be introduced to evaluate the condition of regional cerebral oxygen metabolism, thereby guiding the clinical treatment and predicting the outcome.

Quantitative Susceptibility Mapping by Inversion of a Perturbation Field Model: Correlation with Brain Iron in Normal Aging

PubMed Central

Poynton, Clare; Jenkinson, Mark; Adalsteinsson, Elfar; Sullivan, Edith V.; Pfefferbaum, Adolf; Wells, William

2015-01-01

There is increasing evidence that iron deposition occurs in specific regions of the brain in normal aging and neurodegenerative disorders such as Parkinson's, Huntington's, and Alzheimer's disease. Iron deposition changes the magnetic susceptibility of tissue, which alters the MR signal phase, and allows estimation of susceptibility differences using quantitative susceptibility mapping (QSM). We present a method for quantifying susceptibility by inversion of a perturbation model, or ‘QSIP’. The perturbation model relates phase to susceptibility using a kernel calculated in the spatial domain, in contrast to previous Fourier-based techniques. A tissue/air susceptibility atlas is used to estimate B0 inhomogeneity. QSIP estimates in young and elderly subjects are compared to postmortem iron estimates, maps of the Field-Dependent Relaxation Rate Increase (FDRI), and the L1-QSM method. Results for both groups showed excellent agreement with published postmortem data and in-vivo FDRI: statistically significant Spearman correlations ranging from Rho = 0.905 to Rho = 1.00 were obtained. QSIP also showed improvement over FDRI and L1-QSM: reduced variance in susceptibility estimates and statistically significant group differences were detected in striatal and brainstem nuclei, consistent with age-dependent iron accumulation in these regions. PMID:25248179

Automated Spatial Brain Normalization and Hindbrain White Matter Reference Tissue Give Improved [(18)F]-Florbetaben PET Quantitation in Alzheimer's Model Mice.

PubMed

Overhoff, Felix; Brendel, Matthias; Jaworska, Anna; Korzhova, Viktoria; Delker, Andreas; Probst, Federico; Focke, Carola; Gildehaus, Franz-Josef; Carlsen, Janette; Baumann, Karlheinz; Haass, Christian; Bartenstein, Peter; Herms, Jochen; Rominger, Axel

2016-01-01

Preclinical PET studies of β-amyloid (Aβ) accumulation are of growing importance, but comparisons between research sites require standardized and optimized methods for quantitation. Therefore, we aimed to evaluate systematically the (1) impact of an automated algorithm for spatial brain normalization, and (2) intensity scaling methods of different reference regions for Aβ-PET in a large dataset of transgenic mice. PS2APP mice in a 6 week longitudinal setting (N = 37) and another set of PS2APP mice at a histologically assessed narrow range of Aβ burden (N = 40) were investigated by [(18)F]-florbetaben PET. Manual spatial normalization by three readers at different training levels was performed prior to application of an automated brain spatial normalization and inter-reader agreement was assessed by Fleiss Kappa (κ). For this method the impact of templates at different pathology stages was investigated. Four different reference regions on brain uptake normalization were used to calculate frontal cortical standardized uptake value ratios (SUVRCTX∕REF), relative to raw SUVCTX. Results were compared on the basis of longitudinal stability (Cohen's d), and in reference to gold standard histopathological quantitation (Pearson's R). Application of an automated brain spatial normalization resulted in nearly perfect agreement (all κ≥0.99) between different readers, with constant or improved correlation with histology. Templates based on inappropriate pathology stage resulted in up to 2.9% systematic bias for SUVRCTX∕REF. All SUVRCTX∕REF methods performed better than SUVCTX both with regard to longitudinal stability (d≥1.21 vs. d = 0.23) and histological gold standard agreement (R≥0.66 vs. R≥0.31). Voxel-wise analysis suggested a physiologically implausible longitudinal decrease by global mean scaling. The hindbrain white matter reference (R mean = 0.75) was slightly superior to the brainstem (R mean = 0.74) and the cerebellum (R mean = 0.73). Automated brain normalization with reference region templates presents an excellent method to avoid the inter-reader variability in preclinical Aβ-PET scans. Intracerebral reference regions lacking Aβ pathology serve for precise longitudinal in vivo quantification of [(18)F]-florbetaben PET. Hindbrain white matter reference performed best when considering the composite of quality criteria.

[Effect of phospholipids containing omega-3 fatty acids on structural changes of microsomal lipids in cell membranes of functionally different cells].

PubMed

Datsenko, Z M; Volkov, H L; Kryvenko, O M; Nechytaĭlo, L O; Shovkun, S A; Khmel', T O; Perederiĭ, O F

2002-01-01

As a result of the experimental researches conducted it has been shown that administration of some normal animal marine phospholipids (PL) including in their structure omega-3 polyunsaturated fatty acids (PUFA) provides for quantitative changes of individual PL, fatty acids (FA) content and quantity in general and individual PL of liver, heart, brain and gonads microsomes. While estimating general microsomal PL fraction FA content under the action of PL omega-3 PUFA FA concentration change, unsaturation index (omega 6/omega 3) and relation of arachidonic acid to docosahexenic (AA/DHA) decrease have been identified. The decrease of AA/DHA relationship occurs due to AA and DHA quantitative changes. In the case of AA increase in some tissues there is observed the decrease of docosapentaenic acid and increase of DHA and eucosapentaenic (EPA) acidds. As a result of studying FA content in the individual PL composition it has been identified that certain PL classes characteristic for some tissues respond by changes of some certain FA. The relationship omega 6/omega 3 has been shown as decreasing in phosphatidilcholine (PC) all tissues microsomes (liver, gonads, heart, brain), in phosphatidilethanolamine (PEA) of liver and cardiac microsomes, in phosphatidilserine (PS) this relationship relationship decreases in the liver, brain and heart, for phosphatidilinositole (PI) the changes take place in liver, gonads, brain. Simultaneously, the decrease of AA/DHA relationship in the individual PL decrease of AA and increase of EPA and DHA depend on the tested tissues. The marine phospholipids might be supposed to render their effect on AA metabolism resulting in AA/DHA relationship in PEA and PS relationship displays itself as specific and depends on the tissues functions. The preference of PEA and PS use by certain tissues microsomes could be explained by their membrane protective capability.

Estimated maximal and current brain volume predict cognitive ability in old age

PubMed Central

Royle, Natalie A.; Booth, Tom; Valdés Hernández, Maria C.; Penke, Lars; Murray, Catherine; Gow, Alan J.; Maniega, Susana Muñoz; Starr, John; Bastin, Mark E.; Deary, Ian J.; Wardlaw, Joanna M.

2013-01-01

Brain tissue deterioration is a significant contributor to lower cognitive ability in later life; however, few studies have appropriate data to establish how much influence prior brain volume and prior cognitive performance have on this association. We investigated the associations between structural brain imaging biomarkers, including an estimate of maximal brain volume, and detailed measures of cognitive ability at age 73 years in a large (N = 620), generally healthy, community-dwelling population. Cognitive ability data were available from age 11 years. We found positive associations (r) between general cognitive ability and estimated brain volume in youth (male, 0.28; females, 0.12), and in measured brain volume in later life (males, 0.27; females, 0.26). Our findings show that cognitive ability in youth is a strong predictor of estimated prior and measured current brain volume in old age but that these effects were the same for both white and gray matter. As 1 of the largest studies of associations between brain volume and cognitive ability with normal aging, this work contributes to the wider understanding of how some early-life factors influence cognitive aging. PMID:23850342

Brain abnormalities in cognition, anxiety, and depression regulatory regions in adolescents with single ventricle heart disease.

PubMed

Pike, Nancy A; Roy, Bhaswati; Gupta, Ritika; Singh, Sadhana; Woo, Mary A; Halnon, Nancy J; Lewis, Alan B; Kumar, Rajesh

2018-06-01

Single ventricle heart disease (SVHD) adolescents show cognitive impairments and anxiety and depressive symptoms, indicating the possibility of brain injury in regions that control these functions. However, brain tissue integrity in cognition, anxiety, and depression regulatory sites in SVHD remains unclear. We examined brain tissue changes in SVHD compared to controls using T2-relaxometry procedures, which measure free water content and show tissue injury. Proton-density and T2-weighted images, using a 3.0-Tesla MRI, as well as anxiety (Beck anxiety inventory [BAI]), depressive symptoms (patient health questionnaire-9 [PHQ-9]), and cognition (wide range assessment of memory and learning 2 [WRAML2] and Montreal cognitive assessment [MoCA]) data were collected from 20 SVHD (age: 15.8 ± 1.1 years, male/female: 11/9) and 36 controls (age: 16.0 ± 1.1 years, male/female: 19/17). Whole-brain T2-relaxation maps were calculated, normalized to a common space, smoothed, and compared between groups and sexes (analysis of covariance; covariates: age, sex; p < 0.001). SVHD subjects showed significantly increased BAI and PHQ-9 and reduced MoCA and WRAML2 scores over controls. Several brain regions in SVHD showed increased T2-relaxation values (chronic injury), including the cingulate, and insula, hippocampus/para-hippocampal gyrus, thalamus, hypothalamus, amygdala, frontal white matter, corpus callosum, brainstem, and cerebellar areas. Decreased T2-relaxation values (acute injury) emerged in a few regions, including the prefrontal and cerebellar cortices in SVHD over controls. In addition, male SVHD showed more brain changes over female SVHD. Adolescents with SVHD showed significant brain injury with variable male-female differences in areas that control cognition, anxiety, and depression, which may contribute to functional deficits found in the condition. © 2018 Wiley Periodicals, Inc.

Presence of claudins mRNA in the brain. Selective modulation of expression by kindling epilepsy.

PubMed

Lamas, Mónica; González-Mariscal, Lorenza; Gutiérrez, Rafael

2002-08-15

In the central nervous system, the junctional types that establish and maintain tissue architecture include gap junctions, for cytoplasmic connectivity, and tight junctions, for paracellular and/or cell polarity barriers. Connexins are the integral membrane proteins of gap junctions, whereas occludin and members of the multigene family of claudins form tight junctions. In the brain, there are no transendothelial pathways, as continuous tight junctions are present between the endothelial cells. Thus, they provide a continuous cellular barrier between the blood and the insterstitial fluid. However, several brain pathologies, including epilepsy, are known to alter the permeability of the blood-brain barrier and to cause edema. Therefore, since claudins, as constitutive proteins of tight junctions are likely candidates for modulation under pathological states, we explored their normal pattern of expression in the brain and its modulation by seizures. We found that several members of this family are normally expressed in the hippocampus and cortex. Interestingly, claudin-7 is expressed in the hippocampus but not in the cortex. On the other hand, the expression of claudin-8 is selectively down-regulated in the hippocampus as kindling evolves. These results link for the first time the modulation of expression of a tight junction protein to abnormal neuronal synchronization that could probably be reflected in permeability changes of the blood-brain barrier or edema.

Concentration change of DA, DOPAC, Glu and GABA in brain tissues in schizophrenia developmental model rats induced by MK-801.

PubMed

Liu, Yong; Tang, Yamei; Pu, Weidan; Zhang, Xianghui; Zhao, Jingping

2011-08-01

To explore the related neurobiochemical mechanism by comparing the concentration change of dopamine (DA), dihydroxy-phenyl acetic acid (DOPAC), glutamate (Glu), and γ-aminobutyric acid (GABA) in the brain tissues in schizophrenia (SZ) developmental model rats and chronic medication model rats. A total of 60 neonatal male Spragur-Dawley (SD) rats were randomly assigned to 3 groups at the postnatal day 6: an SZ developmental rat model group (subcutaneous injection with MK-801 at the postnatal day 7-10, 0.1 mg/kg, Bid), a chronic medication model group (intraperitoneal injection at the postnatal day 47-60, 0.2 mg/kg,Qd), and a normal control group (injection with 0.9% normal saline during the corresponding periods). DA, DOPAC, Glu, and GABA of the tissue homogenate from the medial prefrontal cortex (mPFC) and hippocampus were examined with Coularray electrochemic detection by high performance liquid chromatogram technique. The utilization rate of DA and Glu was calculated. Compared with the normal control group, the concentration of DA and DOPAC in the mPFC and the hippocampus in the SZ developmental model group significantly decreased (P<0.05), and the GABA concentration and Glu utilization rate in the mPFC also decreased (P<0.05). Compared with the chronic medication model group, the DA concentration of the mPFC in the SZ developmental group decreased (P<0.05), and the DOPAC concentration and the utility rate of DA in the hippocampus also decreased (P<0.01, P<0.05, respectively). The activities of DA, Glu and GABA system decrease in the mPFC and the DA system function reduces in the hippocampus of SZ developmental rats.

Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells.

PubMed

Calgani, Alessia; Vignaroli, Giulia; Zamperini, Claudio; Coniglio, Federica; Festuccia, Claudio; Di Cesare, Ernesto; Gravina, Giovanni Luca; Mattei, Claudia; Vitale, Flora; Schenone, Silvia; Botta, Maurizio; Angelucci, Adriano

2016-07-01

Glioblastoma cells efficiently interact with and infiltrate the surrounding normal tissue, rendering surgical resection and adjuvant chemo/radiotherapy ineffective. New therapeutic targets, able to interfere with glioblastoma's capacity to synergize with normal brain tissue, are currently under investigation. The compound Si306, a pyrazolo[3,4-d]pyrimidine derivative, selected for its favorable activity against SRC, was tested in vitro and in vivo on glioblastoma cell lines. In vivo, combination treatment with Si306 and radiotherapy was strongly active in reducing U-87 xenograft growth with respect to control and single treatments. The histology revealed a significant difference in the stromal compartment of tumoral tissue derived from control or radiotherapy-treated samples with respect to Si306-treated samples, showing in the latter a reduced presence of collagen and α-SMA-positive cells. This effect was paralleled in vitro by the capacity of Si306 to interfere with myofibroblastic differentiation of normal fibroblasts induced by U-87 cells. In the presence of Si306, TGF-β released by U-87 cells, mainly in hypoxia, was ineffective in upregulating α-SMA and β-PDGFR in fibroblasts. Si306 efficiently reached the brain and significantly prolonged the survival of mice orthotopically injected with U-87 cells. Drugs that target SRC could represent an effective therapeutic strategy in glioblastoma, able to block positive paracrine loop with stromal cells based on the β-PDGFR axis and the formation of a tumor-promoting microenvironment. This approach could be important in combination with conventional treatments in the effort to reduce tumor resistance to therapy. Mol Cancer Ther; 15(7); 1535-44. ©2016 AACR. ©2016 American Association for Cancer Research.

Impaired growth and neurological abnormalities in branched-chain α-keto acid dehydrogenase kinase-deficient mice

PubMed Central

Joshi, Mandar A.; Jeoung, Nam Ho; Obayashi, Mariko; Hattab, Eyas M.; Brocken, Eric G.; Liechty, Edward A.; Kubek, Michael J.; Vattem, Krishna M.; Wek, Ronald C.; Harris, Robert A.

2006-01-01

The BCKDH (branched-chain α-keto acid dehydrogenase complex) catalyses the rate-limiting step in the oxidation of BCAAs (branched-chain amino acids). Activity of the complex is regulated by a specific kinase, BDK (BCKDH kinase), which causes inactivation, and a phosphatase, BDP (BCKDH phosphatase), which causes activation. In the present study, the effect of the disruption of the BDK gene on growth and development of mice was investigated. BCKDH activity was much greater in most tissues of BDK−/− mice. This occurred in part because the E1 component of the complex cannot be phosphorylated due to the absence of BDK and also because greater than normal amounts of the E1 component were present in tissues of BDK−/− mice. Lack of control of BCKDH activity resulted in markedly lower blood and tissue levels of the BCAAs in BDK−/− mice. At 12 weeks of age, BDK−/− mice were 15% smaller than wild-type mice and their fur lacked normal lustre. Brain, muscle and adipose tissue weights were reduced, whereas weights of the liver and kidney were greater. Neurological abnormalities were apparent by hind limb flexion throughout life and epileptic seizures after 6–7 months of age. Inhibition of protein synthesis in the brain due to hyperphosphorylation of eIF2α (eukaryotic translation initiation factor 2α) might contribute to the neurological abnormalities seen in BDK−/− mice. BDK−/− mice show significant improvement in growth and appearance when fed a high protein diet, suggesting that higher amounts of dietary BCAA can partially compensate for increased oxidation in BDK−/− mice. Disruption of the BDK gene establishes that regulation of BCKDH by phosphorylation is critically important for the regulation of oxidative disposal of BCAAs. The phenotype of the BDK−/− mice demonstrates the importance of tight regulation of oxidative disposal of BCAAs for normal growth and neurological function. PMID:16875466

The dynamic genome: transposons and environmental adaptation in the nervous system.

PubMed

Lapp, Hannah E; Hunter, Richard G

2016-02-01

Classically thought as genomic clutter, the functional significance of transposable elements (TEs) has only recently become a focus of attention in neuroscience. Increasingly, studies have demonstrated that the brain seems to have more retrotransposition and TE transcription relative to other somatic tissues, suggesting a unique role for TEs in the central nervous system. TE expression and transposition also appear to vary by brain region and change in response to environmental stimuli such as stress. TEs appear to serve a number of adaptive roles in the nervous system. The regulation of TE expression by steroid, epigenetic and other mechanisms in interplay with the environment represents a significant and novel avenue to understanding both normal brain function and disease.

Laser applications in neurosurgery

NASA Astrophysics Data System (ADS)

Cerullo, Leonard J.

1985-09-01

The "false start" of the laser in neurosurgery should not be misconstrued as a denial of the inherent advantages of precision and gentleness in dealing with neural tissue. Rather, early investigators were frustrated by unrealistic expectations, cumbersome equipment, and a general ignorance of microtechnique. By the early 70s, microneurosurgery was well established, surgical laser equipment for free hand and microlinked application had been developed, and a more realistic view of the limitations of the laser had been established. Consequently, the late 70s really heralded the renaissance of the laser in neurosurgery. Since then, there has been an overwhelming acceptance of the tool in a variety of clinical situations, broadly categorized in five groups. 1)|Perhaps the most generally accepted area is in the removal of extra-axial tumors of the brain and spinal cord. These tumors, benign by histology but treacherous by location, do not present until a significant amount of neurological compensation has already occurred. The application of additional trauma to the neural tissue, whether by further tumor growth or surgical manipulation, frequently results in irreversible damage. Here, the ability of the laser to vaporize tissue, in a fairly hemostatic fashion, without mechanical or thermal damage to sensitive surrounding tissues, is essential. 2)|The ability to incise delicate neural tissue with minimal spread of thermal destruction to adjacent functioning tissue makes the laser the ideal instrument when tumors deep under the surface are encountered in the brain or spinal cord. Thus, the second group of applications is in the transgression of normal neural structures to arrive at deeper pathological tissue. 3)|The third area of benefit for the laser in neurosurgery has been in the performance of neuroablative procedures, calling for deliberate destruction of functioning neural tissue in a controlled fashion. Again, the precision and shape confinement of the destructive beam makes the laser superior to all conventional destructive instruments. 4)|The coagulative properties of certain chromophoric lasers has allowed a new attack on certain vascular tumors and malformations of the brain and spinal cord which had been operated only with trepidation or not at all. Early reports are sobering but encouraging. 5)|Finally, the use of the laser with tissue photosensitization, albeit it in its infancy, offers great promise. This is particularly true in the case of primary brain cancer, where the infiltration of tumorous tissue among normal pathways precludes the classical oncologic surgery practice of resection of a "safe margin". The ability to track and destroy these cells, without affecting adjacent cells, may be the greatest single contribution of the laser to neurosurgery in the future. The present applications of the laser are relatively crude by comparison with what is expected. Endoscopic laser surgery, both vascular and subarachnoid, will diminish morbidity and improve results. From the exotic treatment of aneurysms and arteriovenous malformations of the brain to the mundane care of herniated disks of the spine, it is anticipated that the laser will play an important role. The use of a laser, coupled with computerized imagining devices, will allow increasing precision in arrival to and treatment of deep seated lesions of the brain, brainstem, and spinal cord. The use of different wavelengths, perhaps in the X-ray and ultraviolet spectra, will allow increasing precision with decreasing invasion. Manipulation of wavelength, time, and treatment area will allow subcellular surgery, perhaps in the treatment of personality disorders and movement disorders as well as epilepsy. Tissue welding will allow heightened regenerative and recuperative powers to be exploited. The possibility of laser biostimulation must also be considered. In short, it appears that the future of the laser in neurosurgery is limited only by the imagination of the surgeons. Certainly, the opportunity to exploit new wavelengths offered by the FEL is the key to the future.

Banking brain tissue for research.

PubMed

Klioueva, Natasja; Bovenberg, Jasper; Huitinga, Inge

2017-01-01

Well-characterized human brain tissue is crucial for scientific breakthroughs in research of the human brain and brain diseases. However, the collection, characterization, management, and accessibility of brain human tissue are rather complex. Well-characterized human brain tissue is often provided from private, sometimes small, brain tissue collections by (neuro)pathologic experts. However, to meet the increasing demand for human brain tissue from the scientific community, many professional brain-banking activities aiming at both neurologic and psychiatric diseases as well as healthy controls are currently being initiated worldwide. Professional biobanks are open-access and in many cases run donor programs. They are therefore costly and need effective business plans to guarantee long-term sustainability. Here we discuss the ethical, legal, managerial, and financial aspects of professional brain banks. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of an Agaricus blazei aqueous extract pretreatment on paracetamol-induced brain and liver injury in rats.

PubMed

Soares, Andréia A; de Oliveira, Andrea L; Sá-Nakanishi, Anacharis B; Comar, Jurandir F; Rampazzo, Ana P S; Vicentini, Fernando A; Natali, Maria R M; Gomes da Costa, Sandra M; Bracht, Adelar; Peralta, Rosane M

2013-01-01

The action of an Agaricus blazei aqueous extract pretreatment on paracetamol injury in rats was examined not only in terms of the classical indicators (e.g., levels of hepatic enzymes in the plasma) but also in terms of functional and metabolic parameters (e.g., gluconeogenesis). Considering solely the classical indicators for tissue damage, the results can be regarded as an indication that the A. blazei extract is able to provide a reasonable degree of protection against the paracetamol injury in both the hepatic and brain tissues. The A. blazei pretreatment largely prevented the increased levels of hepatic enzymes in the plasma (ASP, ALT, LDH, and ALP) and practically normalized the TBARS levels in both liver and brain tissues. With respect to the functional and metabolic parameters of the liver, however, the extract provided little or no protection. This includes morphological signs of inflammation and the especially important functional parameter gluconeogenesis, which was impaired by paracetamol. Considering these results and the long list of extracts and substances that are said to have hepatoprotective effects, it would be useful to incorporate evaluations of functional parameters into the experimental protocols of studies aiming to attribute or refute effective hepatoprotective actions to natural products.

Effects of an Agaricus blazei Aqueous Extract Pretreatment on Paracetamol-Induced Brain and Liver Injury in Rats

PubMed Central

Soares, Andréia A.; de Oliveira, Andrea L.; Sá-Nakanishi, Anacharis B.; Comar, Jurandir F.; Rampazzo, Ana P. S.; Vicentini, Fernando A.; Natali, Maria R. M.; Gomes da Costa, Sandra M.; Peralta, Rosane M.

2013-01-01

The action of an Agaricus blazei aqueous extract pretreatment on paracetamol injury in rats was examined not only in terms of the classical indicators (e.g., levels of hepatic enzymes in the plasma) but also in terms of functional and metabolic parameters (e.g., gluconeogenesis). Considering solely the classical indicators for tissue damage, the results can be regarded as an indication that the A. blazei extract is able to provide a reasonable degree of protection against the paracetamol injury in both the hepatic and brain tissues. The A. blazei pretreatment largely prevented the increased levels of hepatic enzymes in the plasma (ASP, ALT, LDH, and ALP) and practically normalized the TBARS levels in both liver and brain tissues. With respect to the functional and metabolic parameters of the liver, however, the extract provided little or no protection. This includes morphological signs of inflammation and the especially important functional parameter gluconeogenesis, which was impaired by paracetamol. Considering these results and the long list of extracts and substances that are said to have hepatoprotective effects, it would be useful to incorporate evaluations of functional parameters into the experimental protocols of studies aiming to attribute or refute effective hepatoprotective actions to natural products. PMID:23984368

The roles of cerebral blood flow, capillary transit time heterogeneity, and oxygen tension in brain oxygenation and metabolism

PubMed Central

Jespersen, Sune N; Østergaard, Leif

2012-01-01

Normal brain function depends critically on moment-to-moment regulation of oxygen supply by the bloodstream to meet changing metabolic needs. Neurovascular coupling, a range of mechanisms that converge on arterioles to adjust local cerebral blood flow (CBF), represents our current framework for understanding this regulation. We modeled the combined effects of CBF and capillary transit time heterogeneity (CTTH) on the maximum oxygen extraction fraction (OEFmax) and metabolic rate of oxygen that can biophysically be supported, for a given tissue oxygen tension. Red blood cell velocity recordings in rat brain support close hemodynamic–metabolic coupling by means of CBF and CTTH across a range of physiological conditions. The CTTH reduction improves tissue oxygenation by counteracting inherent reductions in OEFmax as CBF increases, and seemingly secures sufficient oxygenation during episodes of hyperemia resulting from cortical activation or hypoxemia. In hypoperfusion and states of blocked CBF, both lower oxygen tension and CTTH may secure tissue oxygenation. Our model predicts that disturbed capillary flows may cause a condition of malignant CTTH, in which states of higher CBF display lower oxygen availability. We propose that conditions with altered capillary morphology, such as amyloid, diabetic or hypertensive microangiopathy, and ischemia–reperfusion, may disturb CTTH and thereby flow-metabolism coupling and cerebral oxygen metabolism. PMID:22044867

High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio

PubMed Central

Ross, Jaime M.; Öberg, Johanna; Brené, Stefan; Coppotelli, Giuseppe; Terzioglu, Mügen; Pernold, Karin; Goiny, Michel; Sitnikov, Rouslan; Kehr, Jan; Trifunovic, Aleksandra; Larsson, Nils-Göran; Hoffer, Barry J.; Olson, Lars

2010-01-01

At present, there are few means to track symptomatic stages of CNS aging. Thus, although metabolic changes are implicated in mtDNA mutation-driven aging, the manifestations remain unclear. Here, we used normally aging and prematurely aging mtDNA mutator mice to establish a molecular link between mitochondrial dysfunction and abnormal metabolism in the aging process. Using proton magnetic resonance spectroscopy and HPLC, we found that brain lactate levels were increased twofold in both normally and prematurely aging mice during aging. To correlate the striking increase in lactate with tissue pathology, we investigated the respiratory chain enzymes and detected mitochondrial failure in key brain areas from both normally and prematurely aging mice. We used in situ hybridization to show that increased brain lactate levels were caused by a shift in transcriptional activities of the lactate dehydrogenases to promote pyruvate to lactate conversion. Separation of the five tetrameric lactate dehydrogenase (LDH) isoenzymes revealed an increase of those dominated by the Ldh-A product and a decrease of those rich in the Ldh-B product, which, in turn, increases pyruvate to lactate conversion. Spectrophotometric assays measuring LDH activity from the pyruvate and lactate sides of the reaction showed a higher pyruvate → lactate activity in the brain. We argue for the use of lactate proton magnetic resonance spectroscopy as a noninvasive strategy for monitoring this hallmark of the aging process. The mtDNA mutator mouse allows us to conclude that the increased LDH-A/LDH-B ratio causes high brain lactate levels, which, in turn, are predictive of aging phenotypes. PMID:21041631

Cerebral Glucose Metabolism and Sedation in Brain-injured Patients: A Microdialysis Study.

PubMed

Hertle, Daniel N; Santos, Edgar; Hagenston, Anna M; Jungk, Christine; Haux, Daniel; Unterberg, Andreas W; Sakowitz, Oliver W

2015-07-01

Disturbed brain metabolism is a signature of primary damage and/or precipitates secondary injury processes after severe brain injury. Sedatives and analgesics target electrophysiological functioning and are as such well-known modulators of brain energy metabolism. Still unclear, however, is how sedatives impact glucose metabolism and whether they differentially influence brain metabolism in normally active, healthy brain and critically impaired, injured brain. We therefore examined and compared the effects of anesthetic drugs under both critical (<1 mmol/L) and noncritical (>1 mmol/L) extracellular brain glucose levels. We performed an explorative, retrospective analysis of anesthetic drug administration and brain glucose concentrations, obtained by bedside microdialysis, in 19 brain-injured patients. Our investigations revealed an inverse linear correlation between brain glucose and both the concentration of extracellular glutamate (Pearson r=-0.58, P=0.01) and the lactate/glucose ratio (Pearson r=-0.55, P=0.01). For noncritical brain glucose levels, we observed a positive linear correlation between midazolam dose and brain glucose (P<0.05). For critical brain glucose levels, extracellular brain glucose was unaffected by any type of sedative. These findings suggest that the use of anesthetic drugs may be of limited value in attempts to influence brain glucose metabolism in injured brain tissue.

Volumetric spiral chemical shift imaging of hyperpolarized [2-(13) c]pyruvate in a rat c6 glioma model.

PubMed

Park, Jae Mo; Josan, Sonal; Jang, Taichang; Merchant, Milton; Watkins, Ron; Hurd, Ralph E; Recht, Lawrence D; Mayer, Dirk; Spielman, Daniel M

2016-03-01

MRS of hyperpolarized [2-(13)C]pyruvate can be used to assess multiple metabolic pathways within mitochondria as the (13)C label is not lost with the conversion of pyruvate to acetyl-CoA. This study presents the first MR spectroscopic imaging of hyperpolarized [2-(13)C]pyruvate in glioma-bearing brain. Spiral chemical shift imaging with spectrally undersampling scheme (1042 Hz) and a hard-pulse excitation was exploited to simultaneously image [2-(13)C]pyruvate, [2-(13)C]lactate, and [5-(13)C]glutamate, the metabolites known to be produced in brain after an injection of hyperpolarized [2-(13)C]pyruvate, without chemical shift displacement artifacts. A separate undersampling scheme (890 Hz) was also used to image [1-(13)C]acetyl-carnitine. Healthy and C6 glioma-implanted rat brains were imaged at baseline and after dichloroacetate administration, a drug that modulates pyruvate dehydrogenase kinase activity. The baseline metabolite maps showed higher lactate and lower glutamate in tumor as compared to normal-appearing brain. Dichloroacetate led to an increase in glutamate in both tumor and normal-appearing brain. Dichloroacetate-induced %-decrease of lactate/glutamate was comparable to the lactate/bicarbonate decrease from hyperpolarized [1-(13)C]pyruvate studies. Acetyl-carnitine was observed in the muscle/fat tissue surrounding the brain. Robust volumetric imaging with hyperpolarized [2-(13)C]pyruvate and downstream products was performed in glioma-bearing rat brains, demonstrating changes in mitochondrial metabolism with dichloroacetate. © 2015 Wiley Periodicals, Inc.

Irradiation Alters MMP-2/TIMP-2 System and Collagen Type IV Degradation in Brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Won Hee; Warrington, Junie P.; Sonntag, William E.

Purpose: Blood-brain barrier (BBB) disruption is one of the major consequences of radiation-induced normal tissue injury in the central nervous system. We examined the effects of whole-brain irradiation on matrix metalloproteinases (MMPs)/tissue inhibitors of metalloproteinases (TIMPs) and extracellular matrix (ECM) degradation in the brain. Methods and Materials: Animals received either whole-brain irradiation (a single dose of 10 Gy {gamma}-rays or a fractionated dose of 40 Gy {gamma}-rays, total) or sham-irradiation and were maintained for 4, 8, and 24 h following irradiation. mRNA expression levels of MMPs and TIMPs in the brain were analyzed by real-time reverse transcriptase-polymerase chain reaction (PCR).more » The functional activity of MMPs was measured by in situ zymography, and degradation of ECM was visualized by collagen type IV immunofluorescent staining. Results: A significant increase in mRNA expression levels of MMP-2, MMP-9, and TIMP-1 was observed in irradiated brains compared to that in sham-irradiated controls. In situ zymography revealed a strong gelatinolytic activity in the brain 24 h postirradiation, and the enhanced gelatinolytic activity mediated by irradiation was significantly attenuated in the presence of anti-MMP-2 antibody. A significant reduction in collagen type IV immunoreactivity was also detected in the brain at 24 h after irradiation. In contrast, the levels of collagen type IV were not significantly changed at 4 and 8 h after irradiation compared with the sham-irradiated controls. Conclusions: The present study demonstrates for the first time that radiation induces an imbalance between MMP-2 and TIMP-2 levels and suggests that degradation of collagen type IV, a major ECM component of BBB basement membrane, may have a role in the pathogenesis of brain injury.« less

Physiological neuronal decline in healthy aging human brain - An in vivo study with MRI and short echo-time whole-brain (1)H MR spectroscopic imaging.

PubMed

Ding, Xiao-Qi; Maudsley, Andrew A; Sabati, Mohammad; Sheriff, Sulaiman; Schmitz, Birte; Schütze, Martin; Bronzlik, Paul; Kahl, Kai G; Lanfermann, Heinrich

2016-08-15

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70years were studied with MRI and whole-brain (1)H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum. Copyright © 2016 Elsevier Inc. All rights reserved.

Poisoning of wild birds from exposure to anticholinesterase compounds and lead: diagnostic methods and selected cases

USGS Publications Warehouse

Franson, J. Christian; Smith, Milton R.

1999-01-01

Organophosphorus and carbamate compounds have largely replaced chlorinated hydrocarbons for pesticidal use in the United States, and many cases of poisoning resulting from exposure to these anticholinesterase agents have occurred in free-living birds. Although lead shot has been prohibited for waterfowl hunting throughout the United States since 1991, lead poisoning from the ingestion of spent lead shot is still occasionally seen in wild birds, and lead poisoning from the ingestion of fishing sinkers is an emerging issue of concern. A thorough history, a complete necropsy evaluation, and appropriate laboratory analysis of tissues are required to diagnose toxicoses in wild birds, including those caused by anticholinesterase compounds and lead. The interpretation of brain cholinesterase (ChE) activity results depends on the methods of analysis and comparison with expected normal enzyme activities in brain tissue from the same species. Although lead residues in tissues vary among species, many lead poisoned birds have tissue residues that are much higher than the lower threshold commonly accepted for a diagnosis of lead poisoning. We review histories, necropsy findings, and analytical methodologies and results for selected anticholinesterase and lead poisoning cases diagnosed in wild raptors, waterfowl, and loons.

[Tumor-associated prognostic factors of the plasminogen activator family: determination and clinical value of u-PA, t-PA, PAI-1, and PAI-2].

PubMed

Mengele, K; Harbeck, N; Reuning, U; Magdolen, V; Schmitt, M

2005-08-01

Proteolytic factors belonging t the plasminogen activator family (plasmin, u-PA, t-PA, u-PAR, PAI-1, and PAI-2), which usually are involved in blood clotting and degradation of blood clots, are also present in healthy and diseased tissue of the kidney, lung, liver, gastro-intestinal tract, breast, prostate, ovary, and brain. These factors are engaged in brain development, angiogenesis and vascular invasion, wound healing as well as in placenta development and embryogenesis. Plasminogen activators u-PA and t-PA, their inhibitors PAI-1 and PAI-2, and the u-PA-receptor (u-PAR, CD87) are often elevated in solid malignant tumour tissues compared to their normal counterparts. In breast cancer patients, an elevated tumour tissue extract antigen content of u-PA, PAI-1, and u-PAR is associated with increased tumour aggressiveness and poor prognosis; in contrary, an elevated content of t-PA and PAI-2 indicates a favourable prognosis. For clinical relevant determination of these proteolytic factors in tumour tissue extracts, only enzymo-immunometric tests (ELISA) are recommended. Enzymometric and enzymographic tests are actually conducted only in an experimental, preclinical context.

Benefit from NASA

NASA Image and Video Library

1999-01-01

The red light from the Light Emitting Diode (LED) probe shines through the fingers of Dr. Harry Whelan, a pediatric neurologist at the Children's Hospital of Wisconsin in Milwaukee. Dr. Whelan uses the long waves of light from the LED surgical probe to activate special drugs that kill brain tumors. Laser light previously has been used for this type of surgery, but the LED light illuminates through all nearby tissues, reaching parts of tumors that shorter wavelengths of laser light carnot. The new probe is safer because the longer wavelengths of light are cooler than the shorter wavelengths of laser light, making the LED less likely to injure normal brain tissue near the tumor. Also, it can be used for hours at a time while still remaining cool to the touch. The probe was developed for photodynamic cancer therapy under a NASA Small Business Innovative Research Program grant. The program is part of NASA's Technology Transfer Department at the Marshall Space Flight Center.

Outbreak of Minamata Disease (methyl mercury poisoning) in cats on northwestern Ontario Reserves

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takeuchi, T.; D'Itri, F.M.; Fischer, P.V.

1977-04-01

Pathological, histochemical, and analytical studies have confirmed the presence of Minamata Disease in at least one of two cats that lived on or near Indian Reserves in Northwestern Ontario, Canada. These symptoms parallel the Japanese experience in the 1950s and raise ominous health considerations for the Indians who share their diet of fish. After being fed a diet that primarily consisted of fish from the English River, one cat developed such acute neurological symptoms as an ataxic gait, other abnormal movements, uncontrolled howling, and seizures. The total mercury analyses showed high levels in all tissues with 16.4 mg/kg in themore » brain comparable with symptomatic cats in Japan. A second cat that appeared normal had 6.9 mg/kg in its brain tissues, and pathological studies confirmed the presence of latent Minamata Disease.« less

Outbreak of minamata disease (methyl mercury poisoning) in cats on Northwestern Ontario reserves

DOE Office of Scientific and Technical Information (OSTI.GOV)

Takeuchi, T.; D'Itri, F.M.; Fischer, P.V.

1977-04-01

Pathological, histochemical, and analytical studies have confirmed the presence of Minamata Disease in at least one of two cats that lived on or near Indian Reserves in Northwestern Ontario, Canada. These symptoms parallel the Japanese experience in the 1950s and raise ominous health considerations for the Indians who share their diet of fish. After being fed a diet that primarily consisted of fish from the English River, one cat developed such acute neurological symptoms as an ataxic gait, other abnormal movements, uncontrolled howling, and seizures. The total mercury analyses showed high levels in all tissues with 16.4 mg/kg in themore » brain comparable with symptomatic cats in Japan. A second cat that appeared normal had 6.9 mg/kg in its brain tissues, and pathological studies confirmed the presence of latent Minamata Disease.« less

Detection of intracellular lactate with localized diffusion { 1H- 13C}-spectroscopy in rat glioma in vivo

NASA Astrophysics Data System (ADS)

Pfeuffer, Josef; Lin, Joseph C.; DelaBarre, Lance; Ugurbil, Kamil; Garwood, Michael

2005-11-01

The aim of this study was to compare the diffusion characteristic of lactate and alanine in a brain tumor model to that of normal brain metabolites known to be mainly intracellular such as N-acetylaspartate or creatine. The diffusion of 13C-labeled metabolites was measured in vivo with localized NMR spectroscopy at 9.4 T (400 MHz) using a previously described localization and editing pulse sequence known as ACED-STEAM ('adiabatic carbon editing and decoupling'). 13C-labeled glucose was administered and the apparent diffusion coefficients of the glycolytic products, { 1H- 13C}-lactate and { 1H- 13C}-alanine, were determined in rat intracerebral 9L glioma. To obtain insights into { 1H- 13C}-lactate compartmentation (intra- versus extracellular), the pulse sequence used very large diffusion weighting (50 ms/μm 2). Multi-exponential diffusion attenuation of the lactate metabolite signals was observed. The persistence of a lactate signal at very large diffusion weighting provided direct experimental evidence of significant intracellular lactate concentration. To investigate the spatial distribution of lactate and other metabolites, 1H spectroscopic images were also acquired. Lactate and choline-containing compounds were consistently elevated in tumor tissue, but not in necrotic regions and surrounding normal-appearing brain. Overall, these findings suggest that lactate is mainly associated with tumor tissue and that within the time-frame of these experiments at least some of the glycolytic product ([ 13C] lactate) originates from an intracellular compartment.

Reproducibility and Variation of Diffusion Measures in the Squirrel Monkey Brain, In Vivo and Ex Vivo

PubMed Central

Schilling, Kurt; Gao, Yurui; Stepniewska, Iwona; Choe, Ann S; Landman, Bennett A; Anderson, Adam W

2016-01-01

Purpose Animal models are needed to better understand the relationship between diffusion MRI (dMRI) and the underlying tissue microstructure. One promising model for validation studies is the common squirrel monkey, Saimiri sciureus. This study aims to determine (1) the reproducibility of in vivo diffusion measures both within and between subjects; (2) the agreement between in vivo and ex vivo data acquired from the same specimen and (3) normal diffusion values and their variation across brain regions. Methods Data were acquired from three healthy squirrel monkeys, each imaged twice in vivo and once ex vivo. Reproducibility of fractional anisotropy (FA), mean diffusivity (MD), and principal eigenvector (PEV) was assessed, and normal values were determined both in vivo and ex vivo. Results The calculated coefficients of variation (CVs) for both intra-subject and inter-subject MD were below 10% (low variability) while FA had a wider range of CVs, 2–14% intra-subject (moderate variability), and 3–31% inter-subject (high variability). MD in ex vivo tissue was lower than in vivo (30%–50% decrease), while FA values increased in all regions (30–39% increase). The mode of angular differences between in vivo and ex vivo PEVs was 12 degrees. Conclusion This study characterizes the diffusion properties of the squirrel monkey brain and serves as the groundwork for using the squirrel monkey, both in vivo and ex vivo, as a model for diffusion MRI studies. PMID:27587226

The meninges: new therapeutic targets for multiple sclerosis.

PubMed

Russi, Abigail E; Brown, Melissa A

2015-02-01

The central nervous system (CNS) largely comprises nonregenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell-mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an "immune-specialized" status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data have established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood-brain barrier (BBB) integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the BBB. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of vitro preservation on mechanical properties of brain tissue

NASA Astrophysics Data System (ADS)

Zhang, Wei; Liu, Yi-fan; Liu, Li-fu; Niu, Ying; Ma, Jian-li; Wu, Cheng-wei

2017-05-01

To develop the protective devices for preventing traumatic brain injuries, it requires the accurate characterization of the mechanical properties of brain tissue. For this, it necessary to elucidate the effect of vitro preservation on the mechanical performance of brain tissue as usually the measurements are carried out in vitro. In this paper, the thermal behavior of brain tissue preserved for various period of time was first investigated and the mechanical properties were also measured. Both reveals the deterioration with prolonged preservation duration. The observations of brain tissue slices indicates the brain tissue experiences karyorrhexis and karyorrhexis in sequence, which accounts for the deterioration phenomena.

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

PubMed

Hainsworth, Atticus H; Minett, Thais; Andoh, Joycelyn; Forster, Gillian; Bhide, Ishaan; Barrick, Thomas R; Elderfield, Kay; Jeevahan, Jamuna; Markus, Hugh S; Bridges, Leslie R

2017-10-01

We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study). Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T 2 magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1). Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P =0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P =0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P =0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P =0.007). Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers. © 2017 American Heart Association, Inc.

Diagnosis of meningioma by time-resolved fluorescence spectroscopy.

PubMed

Butte, Pramod V; Pikul, Brian K; Hever, Aviv; Yong, William H; Black, Keith L; Marcu, Laura

2005-01-01

We investigate the use of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as an adjunctive tool for the intraoperative rapid evaluation of tumor specimens and delineation of tumor from surrounding normal tissue. Tissue autofluorescence is induced with a pulsed nitrogen laser (337 nm, 1.2 ns) and the intensity decay profiles are recorded in the 370 to 500 nm spectral range with a fast digitizer (0.2 ns resolution). Experiments are conducted on excised specimens (meningioma, dura mater, cerebral cortex) from 26 patients (97 sites). Spectral intensities and time-dependent parameters derived from the time-resolved spectra of each site are used for tissue characterization. A linear discriminant analysis algorithm is used for tissue classification. Our results reveal that meningioma is characterized by unique fluorescence characteristics that enable discrimination of tumor from normal tissue with high sensitivity (>89%) and specificity (100%). The accuracy of classification is found to increase (92.8% cases in the training set and 91.8% in the cross-validated set correctly classified) when parameters from both the spectral and the time domain are used for discrimination. Our findings establish the feasibility of using TR-LIFS as a tool for the identification of meningiomas and enables further development of real-time diagnostic tools for analyzing surgical tissue specimens of meningioma or other brain tumors.

Diagnosis of meningioma by time-resolved fluorescence spectroscopy

PubMed Central

Butte, Pramod V.; Pikul, Brian K.; Hever, Aviv; Yong, William H.; Black, Keith L.; Marcu, Laura

2010-01-01

We investigate the use of time-resolved laser-induced fluorescence spectroscopy (TR-LIFS) as an adjunctive tool for the intraoperative rapid evaluation of tumor specimens and delineation of tumor from surrounding normal tissue. Tissue autofluorescence is induced with a pulsed nitrogen laser (337 nm, 1.2 ns) and the intensity decay profiles are recorded in the 370 to 500 nm spectral range with a fast digitizer (0.2 ns resolution). Experiments are conducted on excised specimens (meningioma, dura mater, cerebral cortex) from 26 patients (97 sites). Spectral intensities and time-dependent parameters derived from the time-resolved spectra of each site are used for tissue characterization. A linear discriminant analysis algorithm is used for tissue classification. Our results reveal that meningioma is characterized by unique fluorescence characteristics that enable discrimination of tumor from normal tissue with high sensitivity (>89%) and specificity (100%). The accuracy of classification is found to increase (92.8% cases in the training set and 91.8% in the cross-validated set correctly classified) when parameters from both the spectral and the time domain are used for discrimination. Our findings establish the feasibility of using TR-LIFS as a tool for the identification of meningiomas and enables further development of real-time diagnostic tools for analyzing surgical tissue specimens of meningioma or other brain tumors. PMID:16409091

Brain tissue volumes in relation to cognitive function and risk of dementia.

PubMed

Ikram, M Arfan; Vrooman, Henri A; Vernooij, Meike W; den Heijer, Tom; Hofman, Albert; Niessen, Wiro J; van der Lugt, Aad; Koudstaal, Peter J; Breteler, Monique M B

2010-03-01

We investigated in a population-based cohort study the association of global and lobar brain tissue volumes with specific cognitive domains and risk of dementia. Participants (n=490; 60-90 years) were non-demented at baseline (1995-1996). From baseline brain MRI-scans we obtained global and lobar volumes of CSF, GM, normal WM, white matter lesions and hippocampus. We performed neuropsychological testing at baseline to assess information processing speed, executive function, memory function and global cognitive function. Participants were followed for incident dementia until January 1, 2005. Larger volumes of CSF and WML were associated with worse performance on all neuropsychological tests, and an increased risk of dementia. Smaller WM volume was related to poorer information processing speed and executive function. In contrast, smaller GM volume was associated with worse memory function and increased risk of dementia. When investigating lobar GM volumes, we found that hippocampal volume and temporal GM volume were most strongly associated with risk of dementia, even in persons without objective and subjective cognitive deficits at baseline, followed by frontal and parietal GM volumes. Copyright 2008 Elsevier Inc. All rights reserved.

Detection of Normal Aging Effects on Human Brain Metabolite Concentrations and Microstructure with Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging.

PubMed

Eylers, V V; Maudsley, A A; Bronzlik, P; Dellani, P R; Lanfermann, H; Ding, X-Q

2016-03-01

Knowledge of age-related physiological changes in the human brain is a prerequisite to identify neurodegenerative diseases. Therefore, in this study whole-brain (1)H-MRS was used in combination with quantitative MR imaging to study the effects of normal aging on healthy human brain metabolites and microstructure. Sixty healthy volunteers, 21-70 years of age, were studied. Brain maps of the metabolites NAA, creatine and phosphocreatine, and Cho and the tissue irreversible and reversible transverse relaxation times T2 and T2' were derived from the datasets. The relative metabolite concentrations and the values of relaxation times were measured with ROIs placed within the frontal and parietal WM, centrum semiovale, splenium of the corpus callosum, hand motor area, occipital GM, putamen, thalamus, pons ventral/dorsal, and cerebellar white matter and posterior lobe. Linear regression analysis and Pearson correlation tests were used to analyze the data. Aging resulted in decreased NAA concentrations in the occipital GM, putamen, splenium of the corpus callosum, and pons ventral and decreased creatine and phosphocreatine concentrations in the pons dorsal and putamen. Cho concentrations did not change significantly in selected brain regions. T2 increased in the cerebellar white matter and decreased in the splenium of the corpus callosum with aging, while the T2' decreased in the occipital GM, hand motor area, and putamen, and increased in the splenium of the corpus callosum. Correlations were found between NAA concentrations and T2' in the occipital GM and putamen and between creatine and phosphocreatine concentrations and T2' in the putamen. The effects of normal aging on brain metabolites and microstructure are region-dependent. Correlations between both processes are evident in the gray matter. The obtained data could be used as references for future studies on patients. © 2016 by American Journal of Neuroradiology.

Regional brain glucose metabolism in patients with brain tumors before and after radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, G.J.; Volkow, N.D.; Lau, Y.H.

1994-05-01

This study was performed to measure regional glucose metabolism in nonaffected brain regions of patients with primary or metastatic brain tumors. Seven female and four male patients (mean age 51.5{plus_minus}14.0 years old) were compared with eleven age and sex matched normal subjects. None of the patients had hydrocephalus and/or increased intracranial pressure. Brain glucose metabolism was measured using FDG-PET scan. Five of the patients were reevaluated one week after receiving radiation treatment (RT) to the brain. Patients were on Decadron and/or Dilantin at the time of both scan. PET images were analyzed with a template of 115 nonoverlapping regions ofmore » interest and then grouped into eight gray matter regions on each hemisphere. Brain regions with tumors and edema shown in MR imaging were excluded. Z scores were used to compare individual patients` regional values with those of normal subjects. The number of regional values with Z scores of less than - 3.0 were considered abnormal and were quantified. The mean global glucose metabolic rate (mean of all regions) in nonaffected brain regions of patients was significantly lower than that of normal controls (32.1{plus_minus}9.0 versus 44.8{plus_minus}6.3 {mu}mol/100g/min, p<0.001). Analyses of individual subjects revealed that none of the controls and 8 of the 11 patients had at least one abnormal region. In these 8 patients the regions which were abnormal were most frequently localized in right (n=5) and left occipital (n=6) and right orbital frontal cortex (n=7) whereas the basal ganglia was not affected. Five of the patients who had repeated scans following RT showed decrements in tumor metabolism (41{plus_minus}20.5%) and a significant increase in whole brain metabolism (8.6{plus_minus}5.3%, p<0.001). The improvement in whole brain metabolism after RT suggests that the brain metabolic decrements in the patients were related to the presence of tumoral tissue and not just a medication effect.« less

SU-E-T-230: Creating a Large Number of Focused Beams with Variable Patient Head Tilt to Improve Dose Fall-Off for Brain Radiosurgery

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chiu, J; Ma, L

2015-06-15

Purpose: To develop a treatment delivery and planning strategy by increasing the number of beams to minimize dose to brain tissue surrounding a target, while maximizing dose coverage to the target. Methods: We analyzed 14 different treatment plans via Leksell PFX and 4C. For standardization, single tumor cases were chosen. Original treatment plans were compared with two optimized plans. The number of beams was increased in treatment plans by varying tilt angles of the patient head, while maintaining original isocenter and the beam positions in the x-, y- and z-axes, collimator size, and beam blocking. PFX optimized plans increased beammore » numbers with three pre-set tilt angles, 70, 90, 110, and 4C optimized plans increased beam numbers with tilt angles increasing arbitrarily from range of 30 to 150 degrees. Optimized treatment plans were compared dosimetrically with original treatment plans. Results: Comparing total normal tissue isodose volumes between original and optimized plans, the low-level percentage isodose volumes decreased in all plans. Despite the addition of multiple beams up to a factor of 25, beam-on times for 1 tilt angle versus 3 or more tilt angles were comparable (<1 min.). In 64% (9/14) of the studied cases, the volume percentage decrease by >5%, with the highest value reaching 19%. The addition of more tilt angles correlates to a greater decrease in normal brain irradiated volume. Selectivity and coverage for original and optimized plans remained comparable. Conclusion: Adding large number of additional focused beams with variable patient head tilt shows improvement for dose fall-off for brain radiosurgery. The study demonstrates technical feasibility of adding beams to decrease target volume.« less

Global and regional brain mean diffusivity changes in patients with heart failure.

PubMed

Woo, Mary A; Palomares, Jose A; Macey, Paul M; Fonarow, Gregg C; Harper, Ronald M; Kumar, Rajesh

2015-04-01

Heart failure (HF) patients show gray and white matter changes in multiple brain sites, including autonomic and motor coordination areas. It is unclear whether the changes represent acute or chronic tissue pathology, a distinction necessary for understanding pathological processes that can be resolved with diffusion tensor imaging (DTI)-based mean diffusivity (MD) procedures. We collected four DTI series from 16 HF (age 55.1 ± 7.8 years, 12 male) and 26 control (49.7 ± 10.8 years, 17 male) subjects with a 3.0-Tesla magnetic resonance imaging scanner. MD maps were realigned, averaged, normalized, and smoothed. Global and regional MD values from autonomic and motor coordination sites were calculated by using normalized MD maps and brain masks; group MD values and whole-brain smoothed MD maps were compared by analysis of covariance (covariates; age and gender). Global brain MD (HF vs. controls, units × 10(-6) mm(2) /sec, 1103.8 ± 76.6 vs. 1035.9 ± 69.4, P = 0.038) and regional autonomic and motor control site values (left insula, 1,085.4 ± 95.7 vs. 975.7 ± 65.4, P = 0.001; right insula, 1,050.2 ± 100.6 vs. 965.7 ± 58.4, P = 0.004; left hypothalamus, 1,419.6 ± 165.2 vs. 1,234.9 ± 136.3, P = 0.002; right hypothalamus, 1,446.5 ± 178.8 vs. 1,273.3 ± 136.9, P = 0.004; left cerebellar cortex, 889.1 ± 81.9 vs. 796.6 ± 46.8, P < 0.001; right cerebellar cortex, 797.8 ± 50.8 vs. 750.3 ± 27.5, P = 0.001; cerebellar deep nuclei, 1,236.1 ± 193.8 vs. 1,071.7 ± 107.1, P = 0.002) were significantly higher in HF vs. control subjects, indicating chronic tissue changes. Whole-brain comparisons showed increased MD values in HF subjects, including limbic, basal-ganglia, thalamic, solitary tract nucleus, frontal, and cerebellar regions. Brain injury occurs in autonomic and motor control areas, which may contribute to deficient function in HF patients. The chronic tissue changes likely result from processes that develop over a prolonged period. © 2014 Wiley Periodicals, Inc.

Segmentation of magnetic resonance images using fuzzy algorithms for learning vector quantization.

PubMed

Karayiannis, N B; Pai, P I

1999-02-01

This paper evaluates a segmentation technique for magnetic resonance (MR) images of the brain based on fuzzy algorithms for learning vector quantization (FALVQ). These algorithms perform vector quantization by updating all prototypes of a competitive network through an unsupervised learning process. Segmentation of MR images is formulated as an unsupervised vector quantization process, where the local values of different relaxation parameters form the feature vectors which are represented by a relatively small set of prototypes. The experiments evaluate a variety of FALVQ algorithms in terms of their ability to identify different tissues and discriminate between normal tissues and abnormalities.

O2 -sensitive MRI distinguishes brain tumor versus radiation necrosis in murine models.

PubMed

Beeman, Scott C; Shui, Ying-Bo; Perez-Torres, Carlos J; Engelbach, John A; Ackerman, Joseph J H; Garbow, Joel R

2016-06-01

The goal of this study was to quantify the relationship between the (1) H longitudinal relaxation rate constant, R1 , and oxygen (O2 ) concentration (relaxivity, r1 ) in tissue and to quantify O2 -driven changes in R1 (ΔR1 ) during a breathing gas challenge in normal brain, radiation-induced lesions, and tumor lesions. R1 data were collected in control-state mice (n = 4) during three different breathing gas (and thus tissue O2 ) conditions. In parallel experiments, pO2 was measured in the thalamus of control-state mice (n = 4) under the same breathing gas conditions using an O2 -sensitive microprobe. The relaxivity of tissue O2 was calculated using the R1 and pO2 data. R1 data were collected in control-state (n = 4) mice, a glioma model (n = 7), and a radiation necrosis model (n = 6) during two breathing gas (thus tissue O2 ) conditions. R1 and ΔR1 were calculated for each cohort. O2 r1 in the brain was 9 × 10(-4)  ± 3 × 10(-4) mm Hg(-1) · s(-1) at 4.7T. R1 and ΔR1 measurements distinguished radiation necrosis from tumor (P< 0.03 and P< 0.01, respectively). The relaxivity of O2 in the brain is determined. R1 and ΔR1 measurements differentiate tumor lesions from radiation necrosis lesions in the mouse models. These pathologies are difficult to distinguish by traditional imaging techniques; O2 -driven changes in R1 holds promise in this regard. Magn Reson Med 75:2442-2447, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

Automated identification of brain tumors from single MR images based on segmentation with refined patient-specific priors

PubMed Central

Sanjuán, Ana; Price, Cathy J.; Mancini, Laura; Josse, Goulven; Grogan, Alice; Yamamoto, Adam K.; Geva, Sharon; Leff, Alex P.; Yousry, Tarek A.; Seghier, Mohamed L.

2013-01-01

Brain tumors can have different shapes or locations, making their identification very challenging. In functional MRI, it is not unusual that patients have only one anatomical image due to time and financial constraints. Here, we provide a modified automatic lesion identification (ALI) procedure which enables brain tumor identification from single MR images. Our method rests on (A) a modified segmentation-normalization procedure with an explicit “extra prior” for the tumor and (B) an outlier detection procedure for abnormal voxel (i.e., tumor) classification. To minimize tissue misclassification, the segmentation-normalization procedure requires prior information of the tumor location and extent. We therefore propose that ALI is run iteratively so that the output of Step B is used as a patient-specific prior in Step A. We test this procedure on real T1-weighted images from 18 patients, and the results were validated in comparison to two independent observers' manual tracings. The automated procedure identified the tumors successfully with an excellent agreement with the manual segmentation (area under the ROC curve = 0.97 ± 0.03). The proposed procedure increases the flexibility and robustness of the ALI tool and will be particularly useful for lesion-behavior mapping studies, or when lesion identification and/or spatial normalization are problematic. PMID:24381535

Long live the axon. Parallels between ageing and pathology from a presynaptic point of view.

PubMed

Grillo, Federico W

2016-10-01

All animals have to find the right balance between investing resources into their reproductive cycle and protecting their tissues from age-related damage. In higher order organisms the brain is particularly vulnerable to ageing, as the great majority of post-mitotic neurons are there to stay for an entire life. While ageing is unavoidable, it may progress at different rates in different individuals of the same species depending on a variety of genetic and environmental factors. Inevitably though, ageing results in a cognitive and sensory-motor decline caused by changes in neuronal structure and function. Besides normal ageing, age-related pathological conditions can develop in a sizeable proportion of the population. While this wide array of diseases are considerably different compared to physiological ageing, the two processes share many similarities and are likely to interact. At the subcellular level, two key structures are involved in brain ageing: axons and their synapses. Here I highlight how the ageing process affects these structures in normal and neurodegenerative states in different brain areas. Copyright © 2016 Elsevier B.V. All rights reserved.

Studies of the endothelial origin of cells in systemic angioendotheliomatosis and other vascular lesions of the brain and meninges using ulex europaeus lectin stains.

PubMed

Schelper, R L; Olson, S P; Carroll, T J; Hart, M N; Witters, E

1986-01-01

Ulex europaeus agglutinin I (UEA-I) is a plant lectin which binds specifically to alpha-L-fucose moieties on the surface glycoproteins of human endothelial cells. The binding is completely inhibited by preincubation of the lectin with fucose. UEA-I can be conjugated directly to fluorescein or peroxidase and can be used to stain endothelium of paraffin embedded tissues. UEA-I staining was evaluated on normal and infarcted brain, systemic angioendotheliomatosis, metastatic epidural angiosarcoma, hemangioendothelioma, hemangioblastoma, angioblastic meningioma of both the hemangioblastic and hemangiopericytic types, and vascular meningioma. The endothelium, but not neuropil of normal and infarcted brain was positive for UEA-I. The tumor cells of hemangioendothelioma and angiosarcoma also stained. However, no staining was seen in malignant intravascular cells of angioendotheliomatosis, the stromal cells of hemangioblastoma, or pericytes of angioblastic meningioma. It is concluded that the malignant cells in angioendotheliomatosis, the stromal cells of hemangioblastoma and the pericytes of angioblastic meningioma do not produce surface glycoproteins characteristic of endothelial cells.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Langen, K.J.; Roosen, N.; Coenen, H.H.

SPECT studies with L-3-(123I)iodo-alpha-methyl tyrosine (IMT) were carried out in 10 patients with different types of brain tumors--first under fasting conditions (basal) and a week later during intravenous infusion of a mixture of naturally-occurring L-amino acids (AA load). An uptake index (UI) was calculated by dividing tissue count rates by the integral of plasma count rates. The UI decreased by 45.6% {plus minus} 15.4% (n = 10, p less than 0.001) for normal brain and by 53.2% {plus minus} 14.1% for gliomas (n = 5, p less than 0.01) during AA load compared to basal conditions, while two meningiomas andmore » a metastasis showed only a minor decrease (23.9 {plus minus} 5.7%, n.s.). Two pituitary adenomas could not be delineated on the SPECT scans. These data indicate that IMT competes with naturally-occurring L-amino acids for transport into normal brain and gliomas. Transport characteristics of IMT into tumors of nonglial origin appear to be different from those of gliomas. For both types of tumors, it is advisable to perform IMT-SPECT under fasting conditions.« less

Effects of irregular cerebrospinal fluid production rate in human brain ventricular system

NASA Astrophysics Data System (ADS)

Hadzri, Edi Azali; Shamsudin, Amir Hamzah; Osman, Kahar; Abdul Kadir, Mohammed Rafiq; Aziz, Azian Abd

2012-06-01

Hydrocephalus is an abnormal accumulation of fluid in the ventricles and cavities in the brain. It occurs when the cerebrospinal fluid (CSF) flow or absorption is blocked or when excessive CSF is secreted. The excessive accumulation of CSF results in an abnormal widening of the ventricles. This widening creates potentially harmful pressure on the tissues of the brain. In this study, flow analysis of CSF was conducted on a three-dimensional model of the third ventricle and aqueduct of Sylvius, derived from MRI scans. CSF was modeled as Newtonian Fluid and its flow through the region of interest (ROI) was done using EFD. Lab software. Different steady flow rates through the Foramen of Monro, classified by normal and hydrocephalus cases, were modeled to investigate its effects. The results show that, for normal and hydrocephalus cases, the pressure drop of CSF flow across the third ventricle was observed to be linearly proportionally to the production rate increment. In conclusion, flow rates that cause pressure drop of 5 Pa was found to be the threshold for the initial sign of hydrocephalus.

Widespread and highly persistent gene transfer to the CNS by retrovirus vector in utero: implication for gene therapy to Krabbe disease.

PubMed

Shen, Jin-Song; Meng, Xing-Li; Yokoo, Takashi; Sakurai, Ken; Watabe, Kazuhiko; Ohashi, Toya; Eto, Yoshikatsu

2005-05-01

Brain-directed prenatal gene therapy may benefit some lysosomal storage diseases that affect the central nervous system (CNS) before birth. Our previous study showed that intrauterine introduction of recombinant adenoviruses into cerebral ventricles results in efficient gene transfer to the CNS in the mouse. However, transgene expression decreased with time due to the non-integrative property of adenoviral vectors. In this study, in order to obtain permanent gene transduction, we investigated the feasibility of retrovirus-mediated in utero gene transduction. Concentrated retrovirus encoding the LacZ gene was injected into the cerebral ventricles of the embryos of normal and twitcher mice (a murine model of Krabbe disease) at embryonic day 12. The distribution and maintenance of the transgene expression in the recipient brain were analyzed histochemically, biochemically and by the quantitative polymerase chain reaction method pre- and postnatally. Efficient and highly persistent gene transduction to the brain was achieved both in normal and the twitcher mouse. Transduced neurons, astrocytes and oligodendrocytes were distributed throughout the brain. The transduced LacZ gene, its transcript and protein expression in the brain were maintained for 14 months without decrement. In addition, gene transduction to multiple tissues other than the brain was also detected at low levels. This study suggests that brain-directed in utero gene transfer using retrovirus vector may be beneficial to the treatment of lysosomal storage diseases with severe brain damage early in life, such as Krabbe disease. Copyright (c) 2005 John Wiley & Sons, Ltd.

Sensitization of cerebral tissue in nude mice with photodynamic therapy induces ADAM17/TACE and promotes glioma cell invasion

PubMed Central

Zheng, Xuguang; Jiang, Feng; Katakowski, Mark; Zhang, Xuepeng; Jiang, Hao; Zhang, Zheng Gang; Chopp, Michael

2008-01-01

In the present study, we tested the hypothesis that a mild cerebral tissue injury promotes subsequent glioma invasion via activation of the ADAM17-EGFR-PI3K-Akt pathway. Mild injury was induced by Photodynamic therapy (PDT), which employs tissue-penetrating laser light exposure following systemic administration of a tumor-localizing photosensitizer. Athymic nude mice were treated with sublethal PDT (80J/cm2 with 2mg/kg Photofrin). Hypoxic stress and ADAM17-EGFR-PI3K-Akt were measured using Western blot and immunostaining. Additional groups with/without pro-sublethal PDT were subsequently implanted with U87 glioma tumor cell. Tumor invasion and ADAM17-EGFR-PI3K-Akt pathway in tumor area were measured. After a sublethal dose of PDT, HIF-1α expression was increased by a factor of three in PDT-treated normal brain tissue compared to contralateral control brain tissue. PDT-treated brain tissue exhibited a significant increase in ADAM17, p-EGFR, p-Akt expression compared to non-treated tissue. ADAM17 positive area significantly increased from 1.78% to 10.89%. The percentage of p-EGFR and p-Akt positive cells significantly increased from 9.50% and 14.50% to 21.31% and 32.29%,respectively, PDT treatment significantly increased subsequent implanted U87 glioma cell invasion by 3.68-fold and increased ADAM17, EGFR, p-EGFR, Akt, p-Akt expression by 178%, 43.9%,152.7%, 89.6%,and 164.2%, respectively, compared to control group. Our data showed that a sublethal sensitization of cerebral tissue with PDT significantly increased U87 cell invasion in nude mice, and that glioma cell invasion is highly correlated with activation of the ADAM17-EGFR-PI3K-Akt pathway (r=0.928, 0.775, 0.870, 0.872, and 0.883, respectively), most likely via HIF-1α. PMID:18358600

[Expression of aquaporin-4 during brain edema in rats with thioacetamide-induced acute encephalopathy].

PubMed

Wang, Li-Qing; Zhu, Sheng-Mei; Zhou, Heng-Jun; Pan, Cai-Fei

2011-09-27

To investigate the expression of aquaporin-4 (AQP4) during brain edema in rats with thioacetamide-induced acute liver failure and encephalopathy. The rat model of acute hepatic failure and encephalopathy was induced by intraperitoneal injection of thioacetamide (TAA) at a 24-hour interval for 2 consecutive days. Thirty-two SD rats were randomly divided into the model group (n = 24) and the control group (normal saline, n = 8). And then the model group was further divided into 3 subgroups by the timepoint of decapitation: 24 h (n = 8), 48 h (n = 8) and 60 h (n = 8). Then we observed their clinical symptoms and stages of HE, indices of liver function and ammonia, liver histology and brain water content. The expression of AQP4 protein in brain tissues was measured with Western blot and the expression of AQP4mRNA with RT-PCR (reverse transcription-polymerase chain reaction). Typical clinical manifestations of hepatic encephalopathy occurred in all TAA-administrated rats. The model rats showed the higher indices of ALT (alanine aminotransferase), AST (aspartate aminotransferase), TBIL (total bilirubin) and ammonia than the control rats (P < 0.05). The brain water content was significantly elevated in TAA-administrated rats compared with the control (P < 0.05). The expressions of AQP4 protein and mRNA in brain tissues significantly increased in TAA-administrated rats (P < 0.05). In addition, the expressions of AQP4 protein and mRNA were positively correlated with brain water content (r = 0.536, P < 0.01; r = 0.566, P = 0.01). The high expression of AQP4 in rats with TAA-induced acute liver failure and encephalopathy plays a significant role during brain edema. AQP4 is one of the molecular mechanisms for the occurrence of brain edema in hepatic encephalopathy.

Probing focal cortical dysplasia in formalin fixed samples using tissue optical spectroscopy

NASA Astrophysics Data System (ADS)

Anand, Suresh; Cicchi, Riccardo; Giordano, Flavio; Buccoliero, Anna Maria; Conti, Valerio; Guerrini, Renzo; Pavone, Francesco Saverio

2016-03-01

Focal cortical dysplasia (FCD) is one of most common causes of intractable epilepsy in pediatric population and these are often insensitive to anti-epileptic drugs. FCD is characterized by a disarray in localized regions of the cerebral cortex and abnormal neurons which results them to misfire with incorrect signals. Resective neurosurgery to remove or disconnect the affected parts from the rest of the brain seems to be a viable option to treat FCD. Before neurosurgery the subject could undergo imaging studies including magnetic resonance imaging (MRI) or computed tomography (CT) scans. On the downside FCD could be elusive in MRI images and may be practically invisible in CT scans. Furthermore, unnecessary removal of normal tissues is to be taken into consideration as this could lead to neurological defects. In this context, optical spectroscopy have been widely investigated as an alternative technique for the detection of abnormal tissues in different organ sites. Disease progression is accompanied by a number of architectural, biochemical and morphological changes. These variations are reflected in the spectral intensity and line shape. Here, in this proof of concept study we propose to investigate the application of tissue optical spectroscopy based on fluorescence excitation at two wavelength 378 and 445 nm coupled along with Raman spectroscopy for the detection of FCD on formalin fixed tissue specimens from pediatric subjects. For fluorescence at both the excitation wavelengths FCD showed a decreased intensity at longer wavelength when compared to normal tissues. Also, differences exist in the Raman spectral profiles of normal and FCD.

Canine treatment with SnET2 for photodynamic therapy

NASA Astrophysics Data System (ADS)

Frazier, Donita L.; Milligan, Andrew J.; Vo-Dinh, Tuan; Morgan, Alan R.; Overholt, Bergein F.

1990-07-01

Photodynamic therapy is a treatment technique that utilizes the photoactived species of a drug to destroy tumor tissue. To be successful, the drug must localize in tumor tissue preferentially over normal tissue and must be activated by light of a specific wavelength. Currently the only drug to be approved for clinical use is Heinatoporphyrin Derivative (HpD) although a series of new drugs are being developed for use in the near future. One of the drugs belongs to a class called purpurins which display absorp-' tions between 630-711 nm. Along with several other investigators, we are currently exploring the characteristics of a specific purpurin (SnET2) in normal and tumorous canine tissue. The use of this compound has demonstrated increased tumor control rates in spontaneous dog tumors. Preliminary pharmacokinetic studies have been performed on 6 normal beagle dogs. SnET2 (2 mg/kg) was injected intravenously over 10 minutes and blood was collected at 5, 15, 30, 45 minutes and at 1, 2, 4, 8, 12 and 24 hours following administration for determination of drug concentration and calculation of pharinacokinetic parameters. Skin biopsies were collected at 1, 4, 8, 12 and 24 hours. Dogs were euthanized at 24 hours and tissues (liver, kidney muscle, esophagus, stomach, duodenum, jejunum, ileura, colon, adrenal gland, thyroid, heart, lung, urinary bladder, prostate, pancreas, eye, brain) were collected for drug raeasurement. Drug was shown to persist in liver and kidney for a prolonged period of time coiapared to other tissues. Knowledge of the pharmacokinetic properties of the drug will greatly add to the ability to treat patients with effective protocols.

Neurosteroid hydroxylase CYP7B: vivid reporter activity in dentate gyrus of gene-targeted mice and abolition of a widespread pathway of steroid and oxysterol hydroxylation.

PubMed

Rose, K; Allan, A; Gauldie, S; Stapleton, G; Dobbie, L; Dott, K; Martin, C; Wang, L; Hedlund, E; Seckl, J R; Gustafsson, J A; Lathe, R

2001-06-29

The major adrenal steroid dehydroepiandrosterone (DHEA) enhances memory and immune function but has no known dedicated receptor; local metabolism may govern its activity. We described a cytochrome P450 expressed in brain and other tissues, CYP7B, that catalyzes the 7alpha-hydroxylation of oxysterols and 3beta-hydroxysteroids including DHEA. We report here that CYP7B mRNA and 7alpha-hydroxylation activity are widespread in rat tissues. However, steroids related to DHEA are reported to be modified at positions other than 7alpha, exemplified by prominent 6alpha-hydroxylation of 5alpha-androstane-3beta,17beta-diol (A/anediol) in some rodent tissues including brain. To determine whether CYP7B is responsible for these and other activities we disrupted the mouse Cyp7b gene by targeted insertion of an IRES-lacZ reporter cassette, placing reporter enzyme activity (beta-galactosidase) under Cyp7b promoter control. In heterozygous mouse brain, chromogenic detection of reporter activity was strikingly restricted to the dentate gyrus. Staining did not exactly reproduce the in situ hybridization expression pattern; post-transcriptional control is inferred. Lower level staining was detected in cerebellum, liver, and kidney, and which largely paralleled mRNA distribution. Liver and kidney expression was sexually dimorphic. Mice homozygous for the insertion are viable and superficially normal, but ex vivo metabolism of DHEA to 7alpha-hydroxy-DHEA was abolished in brain, spleen, thymus, heart, lung, prostate, uterus, and mammary gland; lower abundance metabolites were also eliminated. 7alpha-Hydroxylation of 25-hydroxycholesterol and related substrates was also abolished, as was presumed 6alpha-hydroxylation of A/anediol. These different enzyme activities therefore derive from the Cyp7b gene. CYP7B is thus a major extrahepatic steroid and oxysterol hydroxylase and provides the predominant route for local metabolism of DHEA and related molecules in brain and other tissues.

A New Antigen Retrieval Technique for Human Brain Tissue

PubMed Central

Byne, William; Haroutunian, Vahram; García-Villanueva, Mercedes; Rábano, Alberto; García-Amado, María; Prensa, Lucía; Giménez-Amaya, José Manuel

2008-01-01

Immunohistochemical staining of tissues is a powerful tool used to delineate the presence or absence of an antigen. During the last 30 years, antigen visualization in human brain tissue has been significantly limited by the masking effect of fixatives. In the present study, we have used a new method for antigen retrieval in formalin-fixed human brain tissue and examined the effectiveness of this protocol to reveal masked antigens in tissues with both short and long formalin fixation times. This new method, which is based on the use of citraconic acid, has not been previously utilized in brain tissue although it has been employed in various other tissues such as tonsil, ovary, skin, lymph node, stomach, breast, colon, lung and thymus. Thus, we reported here a novel method to carry out immunohistochemical studies in free-floating human brain sections. Since fixation of brain tissue specimens in formaldehyde is a commonly method used in brain banks, this new antigen retrieval method could facilitate immunohistochemical studies of brains with prolonged formalin fixation times. PMID:18852880

The role of "mixed" orexigenic and anorexigenic signals and autoantibodies reacting with appetite-regulating neuropeptides and peptides of the adipose tissue-gut-brain axis: relevance to food intake and nutritional status in patients with anorexia nervosa and bulimia nervosa.

PubMed

Smitka, Kvido; Papezova, Hana; Vondra, Karel; Hill, Martin; Hainer, Vojtech; Nedvidkova, Jara

2013-01-01

Eating disorders such as anorexia (AN) and bulimia nervosa (BN) are characterized by abnormal eating behavior. The essential aspect of AN is that the individual refuses to maintain a minimal normal body weight. The main features of BN are binge eating and inappropriate compensatory methods to prevent weight gain. The gut-brain-adipose tissue (AT) peptides and neutralizing autoantibodies play an important role in the regulation of eating behavior and growth hormone release. The mechanisms for controlling food intake involve an interplay between gut, brain, and AT. Parasympathetic, sympathetic, and serotoninergic systems are required for communication between brain satiety centre, gut, and AT. These neuronal circuits include neuropeptides ghrelin, neuropeptide Y (NPY), peptide YY (PYY), cholecystokinin (CCK), leptin, putative anorexigen obestatin, monoamines dopamine, norepinephrine (NE), serotonin, and neutralizing autoantibodies. This extensive and detailed report reviews data that demonstrate that hunger-satiety signals play an important role in the pathogenesis of eating disorders. Neuroendocrine dysregulations of the AT-gut-brain axis peptides and neutralizing autoantibodies may result in AN and BN. The circulating autoantibodies can be purified and used as pharmacological tools in AN and BN. Further research is required to investigate the orexigenic/anorexigenic synthetic analogs and monoclonal antibodies for potential treatment of eating disorders in clinical practice.

Effects of tissue susceptibility on brain temperature mapping.

PubMed

Maudsley, Andrew A; Goryawala, Mohammed Z; Sheriff, Sulaiman

2017-02-01

A method for mapping of temperature over a large volume of the brain using volumetric proton MR spectroscopic imaging has been implemented and applied to 150 normal subjects. Magnetic susceptibility-induced frequency shifts in gray- and white-matter regions were measured and included as a correction in the temperature mapping calculation. Additional sources of magnetic susceptibility variations of the individual metabolite resonance frequencies were also observed that reflect the cellular-level organization of the brain metabolites, with the most notable differences being attributed to changes of the N-Acetylaspartate resonance frequency that reflect the intra-axonal distribution and orientation of the white-matter tracts with respect to the applied magnetic field. These metabolite-specific susceptibility effects are also shown to change with age. Results indicate no change of apparent brain temperature with age from 18 to 84 years old, with a trend for increased brain temperature throughout the cerebrum in females relative for males on the order of 0.1°C; slightly increased temperatures in the left hemisphere relative to the right; and a lower temperature of 0.3°C in the cerebellum relative to that of cerebral white-matter. This study presents a novel acquisition method for noninvasive measurement of brain temperature that is of potential value for diagnostic purposes and treatment monitoring, while also demonstrating limitations of the measurement due to the confounding effects of tissue susceptibility variations. Copyright © 2016 Elsevier Inc. All rights reserved.

Quantification of heat shock protein mRNA expression in warm and cold anoxic turtles (Trachemys scripta) using an external RNA control for normalization.

PubMed

Stecyk, Jonathan A W; Couturier, Christine S; Fagernes, Cathrine E; Ellefsen, Stian; Nilsson, Göran E

2012-03-01

The mRNA expression of heat-shock protein 90 (HSP90) and heat-shock cognate 70 (HSC70) was examined in cardiac chambers and telencephalon of warm- (21°C) and cold-acclimated (5°C) turtles (Trachemys scripta) exposed to normoxia, prolonged anoxia or anoxia followed by reoxygenation. Additionally, the suitability of total RNA as well as mRNA from β-actin, glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and cyclophilin A (PPIA) for normalizing gene expression data was assessed, as compared to the use of an external RNA control. Measurements of HSP90 and HSC70 mRNA expression revealed that anoxia and reoxygenation have tissue- and gene-specific effects. By and large, the alterations support previous investigations on HSP protein abundance in the anoxic turtle heart and brain, as well as the hypothesized roles of HSP90 and HSC70 during stress and non-stress conditions. However, more prominent was a substantially increased HSP90 and HSC70 mRNA expression in the cardiac chambers with cold acclimation. The finding provides support for the notion that cold temperature induces a number of adaptations in tissues of anoxia-tolerant vertebrates that precondition them for winter anoxia. β-actin, GAPDH and PPIA mRNA expression and total RNA also varied with oxygenation state and acclimation temperature in a tissue- and gene-specific manner, as well as among tissue types, thus disqualifying them as suitable for real-time RT-PCR normalization. Thus, the present data highlights the advantages of normalizing real-time RT-PCR data to an external RNA control, an approach that also allows inter-tissue and potentially inter-species comparisons of target gene expression. Copyright © 2011 Elsevier Inc. All rights reserved.

JV Task 96 - Phase 2 - Investigating the Importance of the Mercury-Selenium Interaction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nicholas Ralston; Laura Raymond

2008-03-01

In order to improve the understanding of the mercury issue, it is vital to study mercury's effects on selenium physiology. While mercury present in the environment or food sources may pose health risks, the protective effects of selenium have not been adequately considered in establishing regulatory policy. Numerous studies report that vulnerability to mercury toxicity is inversely proportional to selenium status or level. However, selenium status has not been considered in the development of the reference dosage levels for mercury exposure. Experimental animals fed low-selenium diets are far more vulnerable to mercury toxicity than animals fed normal selenium, and animalsmore » fed selenium-rich diets are even more resistant. Selenium-dependent enzymes in brain and endocrine tissues can be impaired by excessive mercury exposure, apparently because mercury has an extremely high binding affinity for selenium. When selenium becomes bound to mercury, it is unable to participate in the metabolic cycling of selenoprotein synthesis. Because of mercury-dependent impairments of selenoprotein synthesis, various antioxidant and regulatory functions in brain biochemistry are compromised. This report details a 2-year multiclient-funded research program designed to examine the interactions between mercury and selenium in animal models. The studies explored the effects of dietary intakes of toxic amounts of methylmercury and the protective effects of the normal dietary range of selenium in counteracting mercury toxicity. This study finds that the amounts of selenium present in ocean fish are sufficient to protect against far larger quantities of methylmercury than those present in typical seafoods. Toxic effects of methylmercury exposure were not directly proportional to mercury concentrations in blood, brain, or any other tissues. Instead, mercury toxicity was proportional to molar ratios of mercury relative to selenium. In order to accurately assess risk associated with methylmercury or mercury exposures, mercury-selenium ratios appear to be far more accurate and effective in identifying risk and protecting human and environmental health. This study also finds that methylmercury toxicity can be effectively treated by dietary selenium, preventing the death and progressive disabilities that otherwise occur in methylmercury-treated subjects. Remarkably, the positive response to selenium therapy was essentially equivalent regardless of whether or not toxic amounts of methylmercury were still administered. The findings of the Physiologically Oriented Integration of Nutrients and Toxins (POINT) models of the effects of mercury and selenium developed in this project are consistent with the hypothesis that mercury toxicity arises because of mercury-dependent inhibition of selenium availability in brain and endocrine tissues. This appears to occur through synergistic effects of mercury-dependent inhibition of selenium transport to these tissues and selective sequestration of the selenium present in the tissues. Compromised transport of selenium to the brain and endocrine tissues would be particularly hazardous to the developing fetus because the rapidly growing tissues of the child have no selenium reserves. Therefore, maternal consumption of foods with high mercury-selenium ratios is hazardous. In summation, methylmercury exposure is unlikely to cause harm in populations that eat selenium-rich diets but may cause harm among populations that consume certain foods that have methylmercury present in excess of selenium.« less

Morphofunctional study of the therapeutic efficacy of human mesenchymal and neural stem cells in rats with diffuse brain injury.

PubMed

Tsyb, A F; Yuzhakov, V V; Roshal', L M; Sukhikh, G T; Konoplyannikov, A G; Sushkevich, G N; Yakovleva, N D; Ingel', I E; Bandurko, L N; Sevan'kaeva, L E; Mikhina, L N; Fomina, N K; Marei, M V; Semenova, Zh B; Konoplyannikova, O A; Kal'sina, S Sh; Lepekhina, L A; Semenkova, I V; Agaeva, E V; Shevchuk, A S; Pavlova, L N; Tokarev, O Yu; Karaseva, O V; Chernyshova, T A

2009-01-01

We studied the effect of transplantation of human stem cells from various tissues on reparative processes in the brain of rats with closed craniocerebral injury. Combined treatment with standard drugs and systemic administration of xenogeneic stem cells had a neuroprotective effect. The morphology of neurons rapidly returned to normal after administration of fetal neural stem cells. Fetal mesenchymal stem cells produced a prolonged effect on proliferative activity of progenitor cells in the subventricular zone of neurogenesis. Adult mesenchymal stem cells had a strong effect on recovery of the vascular bed in ischemic regions.

Age-specific MRI templates for pediatric neuroimaging

PubMed Central

Sanchez, Carmen E.; Richards, John E.; Almli, C. Robert

2012-01-01

This study created a database of pediatric age-specific MRI brain templates for normalization and segmentation. Participants included children from 4.5 through 19.5 years, totaling 823 scans from 494 subjects. Open-source processing programs (FSL, SPM, ANTS) constructed head, brain and segmentation templates in 6 month intervals. The tissue classification (WM, GM, CSF) showed changes over age similar to previous reports. A volumetric analysis of age-related changes in WM and GM based on these templates showed expected increase/decrease pattern in GM and an increase in WM over the sampled ages. This database is available for use for neuroimaging studies (blindedforreview). PMID:22799759

Therapeutic efficacy of aldoxorubicin in an intracranial xenograft mouse model of human glioblastoma.

PubMed

Marrero, Luis; Wyczechowska, Dorota; Musto, Alberto E; Wilk, Anna; Vashistha, Himanshu; Zapata, Adriana; Walker, Chelsey; Velasco-Gonzalez, Cruz; Parsons, Christopher; Wieland, Scott; Levitt, Daniel; Reiss, Krzysztof; Prakash, Om

2014-10-01

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a median survival of 12 to 15 months after diagnosis. Acquired chemoresistance, high systemic toxicity, and low penetration of the blood brain barrier by many anticancer drugs contribute to the failure of anti-GBM therapies. To circumvent some of these obstacles, we tested a novel prodrug approach to evaluate anti-GBM efficacy by utilizing serum albumin-binding doxorubicin (Doxo), aldoxorubicin (Aldoxo), which is less toxic, is released from albumin in an acidic environment and accumulates in tumor tissues. A human GBM cell line that expresses a luciferase reporter (U87-luc) was stereotactically injected into the left striatum of the brain of immunodeficient mice. Following initial tumor growth for 12 days, mice were injected once a week in the tail-vein with Aldoxo [24 mg/kg or 18 mg/kg of doxorubicin equivalents-3/4 maximum tolerated dose (MTD)], Doxo [6 mg/kg (3/4 MTD)], or vehicle. Aldoxo-treated mice demonstrated significantly slower growth of the tumor when compared to vehicle-treated or Doxo-treated mice. Five out of eight Aldoxo-treated mice remained alive more than 60 days with a median survival of 62 days, while the median survival of vehicle- and Doxo-treated mice was only 26 days. Importantly, Aldoxo-treated mice exhibited high levels of Doxo within the tumor tissue, accompanied by low tumor cell proliferation (Ki67) and abundant intratumoral programmed cell death (cleaved caspase-3). Effective accumulation of Aldoxo in brain tumor tissues but not normal brain, its anti-tumor efficacy, and low toxicity, provide a strong rationale for evaluating this novel drug conjugate as a treatment for patients afflicted with GBM.

Resonant Raman spectra of grades of human brain glioma tumors reveal the content of tryptophan by the 1588 cm-1 mode

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Zhou, Lixin; Zhu, Ke; Liu, Yulong; Zhang, Lin; Boydston-White, Susie; Cheng, Gangge; Pu, Yang; Bidyut, Das; Alfano, Robert R.

2015-03-01

RR spectra of brain normal tissue, gliomas in low grade I and II, and malignant glioma tumors in grade III and IV were measured using a confocal micro Raman spectrometer. This report focus on the relative contents of tryptophan (W) in various grades of brain glioma tumors by the intrinsic molecular resonance Raman (RR) spectroscopy method using the 1588cm-1 of tryptophan mode by 532 nm excitation. The RR spectra of key fingerprints of tryptophan, with a main vibrational mode at 1588cm-1 (W8b), were observed. It was found that tryptophan contribution was accumulated in grade I to IV gliomas and the mode of 1588cm-1 in grade III and IV malignant gliomas were enhanced by resonance.

A comparison of neural network and fuzzy clustering techniques in segmenting magnetic resonance images of the brain

NASA Technical Reports Server (NTRS)

Hall, Lawrence O.; Bensaid, Amine M.; Clarke, Laurence P.; Velthuizen, Robert P.; Silbiger, Martin S.; Bezdek, James C.

1992-01-01

Magnetic resonance (MR) brain section images are segmented and then synthetically colored to give visual representations of the original data with three approaches: the literal and approximate fuzzy c-means unsupervised clustering algorithms and a supervised computational neural network, a dynamic multilayered perception trained with the cascade correlation learning algorithm. Initial clinical results are presented on both normal volunteers and selected patients with brain tumors surrounded by edema. Supervised and unsupervised segmentation techniques provide broadly similar results. Unsupervised fuzzy algorithms were visually observed to show better segmentation when compared with raw image data for volunteer studies. However, for a more complex segmentation problem with tumor/edema or cerebrospinal fluid boundary, where the tissues have similar MR relaxation behavior, inconsistency in rating among experts was observed.

Human Mesenchymal Stem Cell Treatment Normalizes Cortical Gene Expression after Traumatic Brain Injury.

PubMed

Darkazalli, Ali; Vied, Cynthia; Badger, Crystal-Dawn; Levenson, Cathy W

2017-01-01

Traumatic brain injury (TBI) results in a progressive disease state with many adverse and long-term neurological consequences. Mesenchymal stem cells (MSCs) have emerged as a promising cytotherapy and have been previously shown to reduce secondary apoptosis and cognitive deficits associated with TBI. Consistent with the established literature, we observed that systemically administered human MSCs (hMSCs) accumulate with high specificity at the TBI lesion boundary zone known as the penumbra. Substantial work has been done to illuminate the mechanisms by which MSCs, and the bioactive molecules they secrete, exert their therapeutic effect. However, no such work has been published to examine the effect of MSC treatment on gene expression in the brain post-TBI. In the present study, we use high-throughput RNA sequencing (RNAseq) of cortical tissue from the TBI penumbra to assess the molecular effects of both TBI and subsequent treatment with intravenously delivered hMSCs. RNAseq revealed that expression of almost 7000 cortical genes in the penumbra were differentially regulated by TBI. Pathway analysis using the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database revealed that TBI regulated a large number of genes belonging to pathways involved in metabolism, receptor-mediated cell signaling, neuronal plasticity, immune cell recruitment and infiltration, and neurodegenerative disease. Remarkably, hMSC treatment was found to normalize 49% of all genes disrupted by TBI, with notably robust normalization of specific pathways within the categories mentioned above, including neuroactive receptor-ligand interactions (57%), glycolysis and gluconeogenesis (81%), and Parkinson's disease (100%). These data provide evidence in support of the multi-mechanistic nature of stem cell therapy and suggest that hMSC treatment is capable of simultaneously normalizing a wide variety of important molecular pathways that are disrupted by brain injury.