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1.
Sci Rep ; 10(1): 8063, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415137

RESUMO

Saturation transfer MRI can be useful in the characterization of different tumour types. It is sensitive to tumour metabolism, microstructure, and microenvironment. This study aimed to use saturation transfer to differentiate between intratumoural regions, demarcate tumour boundaries, and reduce data acquisition times by identifying the imaging scheme with the most impact on segmentation accuracy. Saturation transfer-weighted images were acquired over a wide range of saturation amplitudes and frequency offsets along with T1 and T2 maps for 34 tumour xenografts in mice. Independent component analysis and Gaussian mixture modelling were used to segment the images and identify intratumoural regions. Comparison between the segmented regions and histopathology indicated five distinct clusters: three corresponding to intratumoural regions (active tumour, necrosis/apoptosis, and blood/edema) and two extratumoural (muscle and a mix of muscle and connective tissue). The fraction of tumour voxels segmented as necrosis/apoptosis quantitatively matched those calculated from TUNEL histopathological assays. An optimal protocol was identified providing reasonable qualitative agreement between MRI and histopathology and consisting of T1 and T2 maps and 22 magnetization transfer (MT)-weighted images. A three-image subset was identified that resulted in a greater than 90% match in positive and negative predictive value of tumour voxels compared to those found using the entire 24-image dataset. The proposed algorithm can potentially be used to develop a robust intratumoural segmentation method.

2.
Magn Reson Med ; 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32301165

RESUMO

PURPOSE: The diagnosis of monoamine-related psychiatric disorders is based on the phenomenological evaluation of symptoms and behavior by trained clinicians. The CEST technique can be sensitive to monoamines such as serotonin. This study quantifies the CEST properties of the compounds in the serotonin biosynthesis pathway with the goal of developing noninvasive techniques aimed at advancing the diagnostic assessment of serotonin dysfunction. METHODS: Saturation transfer-weighted images of L-tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin phantoms were acquired over a range of saturation amplitudes and frequency offsets along with observed T1 , T2 , and B1 efficiency maps at physiological temperature and pH of 5.5, 6.7, and 7.4. The CEST and MT data were fitted to a three-pool Bloch-McConnell model of exchange to estimate the model parameters. RESULTS: At a pH of 5.5, tryptophan, 5-hydroxytryptophan and serotonin exhibited significant CEST contrast at resonance frequency offset, Δω between 2.64 ppm and 2.71 ppm, and magnetization transfer ratio asymmetry amplitudes up to 20% per 30 mM. At a pH of 7.4, all molecules exhibited significant CEST contrast between 5.11 ppm and 5.47 ppm, and magnetization transfer ratio asymmetry amplitudes up to 9.5% per 30 mM. At a pH of 6.7, all studied compounds except melatonin exhibited a CEST peak from each of the preceding two pHs. CONCLUSION: At a pH of 5.5, tryptophan, 5-hydroxytryptophan, and serotonin CEST contrast originates from the NH 3 + side chain, whereas at a pH of 7.4, CEST contrast is due to the chemical exchange between water and the NH proton on the indole ring. The data in this study could be used to inform future investigations aimed at detecting and measuring in vivo serotonin.

3.
PLoS One ; 15(3): e0226584, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32191733

RESUMO

The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates that post-SCI inflammation is severe but the role of reactive astrogliosis not well understood given its implication in ongoing inflammation as damaging or neuroprotective. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-alpha, IL-1beta, IFN-gamma and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.


Assuntos
Aracnoidite/imunologia , Gliose/imunologia , Traumatismos da Medula Espinal/complicações , Medula Espinal/patologia , Animais , Anti-Inflamatórios , Aracnoidite/diagnóstico , Aracnoidite/patologia , Astrócitos/imunologia , Astrócitos/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Gliose/diagnóstico , Gliose/patologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Imagem por Ressonância Magnética , Masculino , Bainha de Mielina/imunologia , Bainha de Mielina/patologia , Ratos , Índice de Gravidade de Doença , Medula Espinal/citologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/imunologia , Traumatismos da Medula Espinal/diagnóstico por imagem , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia , Fatores de Tempo
4.
Neuro Oncol ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31956919

RESUMO

BACKGROUND: Local response prediction for brain metastases (BM) after stereotactic radiosurgery (SRS) is challenging, particularly for smaller BM, as existing criteria are based solely on unidimensional measurements. This investigation sought to determine whether radiomic features provide additional value to routinely available clinical and dosimetric variables to predict local recurrence following SRS. METHODS: 408 BM in 87 patients treated with SRS were analyzed. A total of 440 radiomic features were extracted from the tumor core, and the peritumoral regions, using the baseline pre-treatment volumetric post-contrast T1 (T1c) and volumetric T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences. Local tumor progression was determined based on RANO-BM criteria, with a maximum axial diameter growth of >20% on the follow-up T1c indicating local failure. The top radiomic features were determined based on resampled Random Forest (RF) feature importance. An RF classifier was trained using each set of features and evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: The addition of any one of the top ten radiomic features to the set of clinical features resulted in a statistically significant (p<0.001) increase in the AUC. An optimized combination of radiomic and clinical features resulted in a 19% higher resampled AUC (mean = 0.793, 95% C.I. = 0.792-0.795) than clinical features alone (0.669, 0.668-0.671). CONCLUSIONS: The increase in AUC of the RF classifier, after incorporating radiomic features, suggests that quantitative characterization of tumor appearance on pretreatment T1c and FLAIR adds value to known clinical and dosimetric variables for predicting local failure.

5.
Int J Radiat Oncol Biol Phys ; 106(1): 206-215, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31627178

RESUMO

PURPOSE: The current magnetic resonance imaging-computed tomography (MRI-CT) fusion-based workflow for postimplant dosimetry of low-dose-rate (LDR) prostate brachytherapy takes advantage of the superior soft tissue contrast of MRI, but still relies on CT for seed visualization and detection. Recently an MR-only workflow has been proposed that employs standard MR sequences and visualizes conventional implanted seed with positive contrast solely through MR postprocessing. In this work, the novel MR-only based workflow is compared with the clinical CT-MRI fusion approach. METHODS AND MATERIALS: Twenty-four prostate patients with a total of 1775 implanted LDR seeds were scanned using a 3-dimensional multiecho gradient echo sequence on a 3 Tesla MR scanner within 30 days after implantation. Quantitative susceptibility mapping was used for seed visualization. Seeds were automatically segmented and localized on the quantitative susceptibility mapping using convolutional neural network and k-means clustering, respectively. To assess the MR-only seed localization error, CT and MR-derived seed positions were coregistered, and ultimately, the resulting dose-volume histograms were compared. RESULTS: The MR-based seed visualization, segmentation, and localization generated comparable results to the CT-MR registration approach. The accuracy of the MRI-only based seed identification was 99.1%. After a rigid registration between the MR and CT-derived seed centroids, the average localization error was 0.8 ± 0.8 mm. The average prostate D90, V100, V150, and V200 for MRI-only and CT-MR fusion based dosimetry were 114.3 ± 12.5% versus 113.9 ± 11.9%, 95.1 ± 3.7% versus 95.3 ± 3.8%, 54.5 ± 14.5% versus 55.0 ± 13.2% and 22.9 ± 6.8% versus 23.2 ± 6.7%, respectively. No significant differences were observed in 3-dimensional seed positions and dosimetric parameters between MR-only and CT-MR fusion-based workflows (P > 0.2). CONCLUSIONS: The MRI-only LDR postimplant dosimetry is feasible and has very good potential to eliminate the need for CT-based seed identification.


Assuntos
Braquiterapia/métodos , Imagem por Ressonância Magnética , Imagem Multimodal/métodos , Neoplasias da Próstata/diagnóstico por imagem , Neoplasias da Próstata/radioterapia , Tomografia Computadorizada por Raios X , Fluxo de Trabalho , Algoritmos , Braquiterapia/instrumentação , Estudos de Viabilidade , Gases , Humanos , Radioisótopos do Iodo/administração & dosagem , Masculino , Neoplasias da Próstata/patologia , Radiometria/métodos , Reto/diagnóstico por imagem , Fatores de Tempo
6.
Sci Rep ; 9(1): 19830, 2019 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882597

RESUMO

About 20-40% of cancer patients develop brain metastases, causing significant morbidity and mortality. Stereotactic radiation treatment is an established option that delivers high dose radiation to the target while sparing the surrounding normal tissue. However, up to 20% of metastatic brain tumours progress despite stereotactic treatment, and it can take months before it is evident on follow-up imaging. An early predictor of radiation therapy outcome in terms of tumour local failure (LF) is crucial, and can facilitate treatment adjustments or allow for early salvage treatment. In this study, an MR-based radiomics framework was proposed to derive and investigate quantitative MRI (qMRI) biomarkers for the outcome of LF in brain metastasis patients treated with hypo-fractionated stereotactic radiation therapy (SRT). The qMRI biomarkers were constructed through a multi-step feature extraction/reduction/selection framework using the conventional MR imaging data acquired from 100 patients (133 lesions), and were applied in conjunction with machine learning techniques for outcome prediction and risk assessment. The results indicated that the majority of the features in the optimal qMRI biomarkers characterize the heterogeneity in the surrounding regions of tumour including edema and tumour/lesion margins. The optimal qMRI biomarker consisted of five features that predict the outcome of LF with an area under the curve (AUC) of 0.79, and a cross-validated sensitivity and specificity of 81% and 79%, respectively. The Kaplan-Meier analyses showed a statistically significant difference in local control (p-value < 0.0001) and overall survival (p = 0.01). Findings from this study are a step towards using qMRI for early prediction of local failure in brain metastasis patients treated with SRT. This may facilitate early adjustments in treatment, such as surgical resection or salvage radiation, that can potentially improve treatment outcomes. Investigations on larger cohorts of patients are, however, required for further validation of the technique.

7.
Brachytherapy ; 18(6): 863-874, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337542

RESUMO

PURPOSE: The lack of positive contrast from brachytherapy seeds in conventional MR images remains a major challenge toward an MRI-only workflow for postimplant dosimetry of low-dose-rate brachytherapy. In this work, the feasibility of our recently proposed MRI-only workflow in clinically relevant scenarios is investigated and the necessary modifications in image acquisition and processing pipeline are proposed for transition to the clinic. METHODS AND MATERIALS: Four prostate phantoms with a total of 321 I-125 implanted dummy seeds and three patients with a total of 168 implanted seeds were scanned using a gradient echo sequence on 1.5 T and 3T MR scanners. Quantitative susceptibility mapping (QSM) was performed for seed visualization. Before QSM, the seed-induced distortion correction was performed followed by edge enhancement. Seed localization was performed using spatial clustering algorithms and was compared with CT. In addition, feasibility of the proposed method on detection of prostatic calcifications was studied. RESULTS: The proposed susceptibility-based algorithm generated consistent positive contrast for the seeds in phantoms and patients. All the 321 seeds in the four phantoms were correctly identified; the MR-derived seeds centroids agreed well with CT-derived positions (average error = 0.5 ± 0.3 mm). The proposed algorithm for seed visualization was found to be orientation invariant. In patient cases, all seeds were visualized and correctly localized (average error = 1.2 ± 0.9 mm); no significant differences between dose volume histogram parameters were found. Prostatic calcifications were depicted with negative contrast on QSM and spatially agreed with CT. CONCLUSIONS: The proposed MRI-based approach has great potential to replace the current CT-based practices. Additional patient studies are necessary to further optimize and validate the workflow.

8.
Phys Med Biol ; 64(14): 145013, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31151120

RESUMO

Magnetic resonance-guided radiation therapy (MR-GRT) offers great potential to improve radiation treatment outcomes by providing more accurate and patient-tailored therapy. Despite superior soft tissue contrast in MRI, one of the challenges towards MRI-only workflows is that the process often requires some sort of 'MR-invisible' metal-based devices. In this study, the feasibility of quantitative susceptibility mapping (QSM) for visualization of some MR-invisible radiation therapy devices was studied. Our recently proposed QSM-based algorithm for brachytherapy seed visualization was modified and the feasibility of the optimized algorithm for visualization of different devices including: brachytherapy seeds, plastic interstitial needles, CT-markers and obturators, and different types of fiducial markers in agar, prostate and meat phantoms were studied. All phantoms were scanned using 3T MR scanner with a 3D multi-echo gradient recalled echo (ME-GRE) pulse sequence. The QSM results in all phantoms were compared to CT images for spatial accuracy of the QSM. The applied post-processing algorithm was found to be insensitive to the seeds' type; also, presence of nearby calcifications had no effect on seed visualization. QSM successfully generated positive contrast for both types of investigated fiducial markers with high spatial accuracy compared to CT. Interstitial needles containing both aluminum-based CT-maker and titanium-based obturators were accurately depicted on the QSM. The proposed QSM-based technique relies on the standard MR pulse sequences and visualize the conventional MR-invisible metallic devices with CT-like positive contrast solely through post-processing. Upon in vivo validation of the technique, QSM may have the potential to replace CT for an MR-only guided radiation therapy.

9.
Front Oncol ; 9: 440, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214496

RESUMO

Brain metastases are the most common intracranial tumors and occur in 20-40% of all cancer patients. Lung cancer, breast cancer, and melanoma are the most frequent primary cancers to develop brain metastases. Treatment options include surgical resection, whole brain radiotherapy, stereotactic radiosurgery, and systemic treatment such as targeted or immune therapy. Anatomical magnetic resonance imaging (MRI) of the tumor (in particular post-Gadolinium T1-weighted and T2-weighted FLAIR) provide information about lesion morphology and structure, and are routinely used in clinical practice for both detection and treatment response evaluation for brain metastases. Advanced MRI biomarkers that characterize the cellular, biophysical, micro-structural and metabolic features of tumors have the potential to improve the management of brain metastases from early detection and diagnosis, to evaluating treatment response. Magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), quantitative magnetization transfer (qMT), diffusion-based tissue microstructure imaging, trans-membrane water exchange mapping, and magnetic susceptibility weighted imaging (SWI) are advanced MRI techniques that will be reviewed in this article as they pertain to brain metastases.

10.
Magn Reson Med ; 82(5): 1684-1699, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31228291

RESUMO

PURPOSE: To compare magnetization transfer (MT) and CEST effects between 1.5T and 3T in phantom and in vivo experiments. METHODS: A pulsed saturation scheme using block-shaped pulses separated by gaps was used to overcome the single RF amplifier duty cycle limitations of a clinical 1.5T scanner. Modeling was performed by incorporating the extended phase graph formalism into a Bloch-McConnell simulation. Two saturation pulse types (with long and short pulses) were used. Estimated parameters for MT (the semi-solid pool fraction, M0 B ; the semi-solid transverse relaxation time, T2 B ) and CEST (asymmetry; areas) were compared between 1.5T and 3T in phantoms and in the healthy brain. RESULTS: Improved fits were shown after inclusion of extended phase graphs. Semi-solid pool fractions in phantom (for agar with ammonium chloride) were higher for short compared to long pulses at 3T (by 19% over all concentrations) and higher at 1.5T compared to 3T (by 5%) using short pulses. In the in vivo experiments, differentiation of white and gray matter was seen in the brain at both field strengths with improved white-gray matter contrast at 3T. In white matter, the mean semi-solid fractions were 18 ± 2% at 3T and 15 ± 2% at 1.5T. The CEST asymmetry in white matter was negative (-4.9 ± 0.4%) at 3T and zero (0.0 ± 0.3%) at 1.5T. CONCLUSIONS: The pulsed saturation method with short pulses, using the extended phase graph formalism in the Bloch McConnell simulations, led to improved model fits to the data, when compared to those without extended phase graphs.

11.
Behav Neurol ; 2019: 9518309, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31001362

RESUMO

The goal of this study was to identify neurostructural frontal lobe correlates of cognitive and speaking rate changes in amyotrophic lateral sclerosis (ALS). 17 patients diagnosed with ALS and 12 matched controls underwent clinical, bulbar, and neuropsychological assessment and structural neuroimaging. Neuropsychological testing was performed via a novel computerized frontal battery (ALS-CFB), based on a validated theoretical model of frontal lobe functions, and focused on testing energization, executive function, emotion processing, theory of mind, and behavioral inhibition via antisaccades. The measure of speaking rate represented bulbar motor changes. Neuroanatomical assessment was performed using volumetric analyses focused on frontal lobe regions, postcentral gyrus, and occipital lobes as controls. Partial least square regressions (PLS) were used to predict behavioral (cognitive and speech rate) outcomes using volumetric measures. The data supported the overall hypothesis that distinct behavioral changes in cognition and speaking rate in ALS were related to specific regional neurostructural brain changes. These changes did not support a notion of a general dysexecutive syndrome in ALS. The observed specificity of behavior-brain changes can begin to provide a framework for subtyping of ALS. The data also support a more integrative framework for clinical assessment of frontal lobe functioning in ALS, which requires both behavioral testing and neuroimaging.


Assuntos
Esclerose Amiotrófica Lateral/fisiopatologia , Lobo Frontal/fisiopatologia , Idoso , Encéfalo/fisiopatologia , Cognição/fisiologia , Transtornos Cognitivos/psicologia , Progressão da Doença , Função Executiva/fisiologia , Feminino , Lobo Frontal/anatomia & histologia , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fala
12.
Conf Proc IEEE Eng Med Biol Soc ; 2019: 463-466, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31945938

RESUMO

Brain metastasis is the most common intracranial malignancy with a poor overall survival (OS) after treatment. The standard stereotactic radiation therapy (SRT) planning procedure for brain metastasis requires delineating the tumour volume on magnetic resonance (MR) images. MR images are also acquired at multiple follow-up scans after SRT to monitor the treatment outcome through measuring changes in the physical dimensions of the tumour. Such measurements require manual segmentation of the tumour volume on multiple slices of several follow-up images which is tedious and impedes the SRT evaluation work flow considerably. In this study, an automatic framework was proposed to segment the tumour volume on longitudinal MR images acquired at standard follow-up scans after SRT. The multi-step segmentation framework was based on region growing and morphological snakes models that applied the standard SRT planning tumour contour as a basis to approximate the tumour shape and location at each follow-up scan for an accurate automatic segmentation of tumour volume. The framework was evaluated using the MR imaging data acquired from five patients prior to and at three follow-up scans after SRT. The preliminary results indicated that the Dice similarity coefficient between the ground truth tumour masks and their automatically segmented counterparts ranged between 0.84 and 0.90, while the average Dice coefficient for all the follow-up scans was 0.88. The results obtained implied a good potential of the proposed framework for being incorporated into the SRT treatment planning and evaluation systems as well as outcome prediction models.


Assuntos
Neoplasias Encefálicas , Radiocirurgia , Algoritmos , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Cintilografia
13.
Conf Proc IEEE Eng Med Biol Soc ; 2019: 1022-1025, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31946067

RESUMO

Despite recent advances in cancer treatment, patients with brain metastasis still suffer from poor overall survival (OS) after standard treatment. Predicting the treatment outcome before or early after the treatment can potentially assist the physicians in improving the therapy outcome by adjusting a standard treatment on an individual patient basis. In this study, a data-driven computational framework was proposed and investigated to predict the local control/failure (LC/LF) outcome in patients with brain metastasis treated with hypo-fractionated stereotactic radiation therapy (SRT). The framework extracted several geometrical and textural features from the magnetic resonance (MR) images of the tumour and edema regions acquired for 38 patients. Subsequent to a multi-step feature reduction/selection, a quantitative MR biomarker consisting of two features was constructed. A support vector machine classifier was used for outcome prediction using the constructed MR biomarker. The bootstrap .632+ and leave-one-patient-out cross-validation methods were used to assess the model's performance. The results indicated that the outcome of LF after SRT could be predicted with an area under the curve of 0.80 and a cross-validated accuracy of 82%. The results obtained implied a good potential of the proposed framework for local outcome prediction in patients with brain metastasis treated with SRT and encourage further investigations on a larger cohort of patients.


Assuntos
Neoplasias Encefálicas , Radiocirurgia , Neoplasias Encefálicas/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Estudos Retrospectivos , Máquina de Vetores de Suporte , Resultado do Tratamento
14.
Stroke ; 49(9): 2173-2181, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354983

RESUMO

Background and Purpose- Recent evidence suggests great potential of metabolically targeted interventions for treating neurological disorders. We investigated the use of the endogenous ketone body ß-hydroxybutyrate (BHB) as an alternate metabolic substrate for the brain in the acute phase of ischemia because postischemic hyperglycemia and brain glucose metabolism elevation compromise functional recovery. Methods- We delivered BHB (or vehicle) 1 hour after ischemic insult induced by cortical microinjection of endothelin-1 in sensorimotor cortex of rats. Two days after ischemic insult, the rats underwent multimodal characterization of the BHB effects. We examined glucose uptake on 2-Deoxy-d-glucose chemical exchange saturation transfer magnetic resonance imaging, cerebral hemodynamics on continuous arterial spin labeling magnetic resonance imaging, resting-state field potentials by intracerebral multielectrode arrays, Neurological Deficit Score, reactive oxygen species production, and astrogliosis and neuronal death. Results- When compared with vehicle-administered animals, BHB-treated cohort showed decreased peri-infarct neuronal glucose uptake which was associated with reduced oxidative stress, diminished astrogliosis and neuronal death. Functional examination revealed ameliorated neuronal functioning, normalized perilesional resting perfusion, and ameliorated cerebrovascular reactivity to hypercapnia, suggesting improved functioning. Cellular and functional recovery of the neurogliovascular unit in the BHB-treated animals was associated with improved performance on the withdrawal test. Conclusions- We characterize the effects of the ketone body BHB administration at cellular and system levels after focal cortical stroke. The results demonstrate that BHB curbs the peri-infarct glucose-metabolism driven production of reactive oxygen species and astrogliosis, culminating in improved neurogliovascular and functional recovery.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Astrócitos/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Encéfalo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Ácido 3-Hidroxibutírico/metabolismo , Acetoacetatos/metabolismo , Animais , Astrócitos/patologia , Glicemia/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/patologia , Morte Celular/efeitos dos fármacos , Circulação Cerebrovascular , Modelos Animais de Doenças , Fenômenos Eletrofisiológicos , Endotelina-1 , Hemodinâmica , Imagem por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Microinjeções , Neurônios/patologia , Ratos , Espécies Reativas de Oxigênio/metabolismo , Córtex Sensório-Motor
15.
J Biomech Eng ; 140(11)2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30267049

RESUMO

Accurate characterization of the craniomaxillofacial (CMF) skeleton using finite element (FE) modeling requires representation of complex geometries, heterogeneous material distributions, and physiological loading. Musculature in CMF FE models are often modeled with simple link elements that do not account for fiber bundles (FBs) and their differential activation. Magnetic resonance (MR) diffusion-tensor imaging (DTI) enables reconstruction of the three-dimensional (3D) FB arrangement within a muscle. However, 3D quantitative validation of DTI-generated FBs is limited. This study compares 3D FB arrangement in terms of pennation angle (PA) and fiber bundle length (FBL) generated through DTI in a human masseter to manual digitization. CT, MR-proton density, and MR-DTI images were acquired from a single cadaveric specimen. Bone and masseter surfaces were reconstructed from CT and MR-proton density images, respectively. PA and FBL were estimated from FBs reconstructed from MR-DTI images using a streamline tracking (STT) algorithm (n = 193) and FBs identified through manual digitization (n = 181) and compared using the Mann-Whitney test. DTI-derived PAs did not differ from the digitized data (p = 0.411), suggesting that MR-DTI can be used to simulate FB orientation and the directionality of transmitted forces. Conversely, a significant difference was observed in FBL (p < 0.01) which may have resulted due to the tractography stopping criterion leading to early tract termination and greater length variability. Overall, this study demonstrated that DTI can yield muscle FB orientation data suitable to representative directionality of physiologic muscle loading in patient-specific CMF FE modeling.


Assuntos
Imagem de Tensor de Difusão , Processamento de Imagem Assistida por Computador/métodos , Músculo Masseter/diagnóstico por imagem , Feminino , Humanos , Lactente , Tomografia Computadorizada por Raios X
16.
Oncotarget ; 9(59): 31490-31501, 2018 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-30140385

RESUMO

Purpose: Detecting cell death and predicting tumor response early in a course of chemotherapy could help optimize treatment regimens and improve clinical outcomes. Chemical exchange saturation transfer (CEST) MRI was investigated in vivo to study properties that may be able to detect cancer death. Results: Using a magnetization transfer ratio (MTR) cutoff of 0.12 at 1.8 ppm was able to differentiate between viable tumor and cell death regions. Comparison of MTR values at this frequency showed significant differences (p < 0.0001) between viable tumor and cell death regions, matching patterns seen on histology. Using this cutoff, the mean increase in cell death index (± standard error of the mean) after chemotherapy was 4 ± 4%, 10% ± 7%, 10 ± 8%, and 4 ± 9% at 4, 8, 12, and 24 h, respectively. Conclusions: CEST MRI can detect cell death in MDA-231 xenografts but further work is needed to characterize the clinical applications of this finding. Maximum response to chemotherapy occurred at 8-12 h after chemotherapy injection in this in vivo tumor model. Materials and Methods: Breast cancer xenografts (MDA-MB-231) were scanned using 7 T MRI before and after chemotherapy. As a measure of CEST effect at 0.5 µT saturation amplitude, MTR values at frequency offsets of 1.8 and -3.3 ppm were evaluated. CEST signals after chemotherapy treatment were compared to cell-death histopathology of tumors.

17.
Sci Rep ; 8(1): 10447, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29992999

RESUMO

The ability of MRI to differentiate between normal and radioresistant cancer was investigated in prostate tumour xenografts in mice. Specifically, the process of magnetization exchange between water and other molecules was studied. It was found that magnetization transfer from semisolid macromolecules (MT) and chemical exchange saturation transfer (CEST) combined were significantly different between groups (p < 0.01). Further, the T2 relaxation of the semisolid macromolecular pool (T2,B), a parameter specific to MT, was found to be significantly different (p < 0.01). Also significantly different were the rNOE contributions associated with methine groups at -0.9 ppm with a saturation B1 of 0.5 µT (p < 0.01) and with other aliphatic groups at -3.3 ppm with 0.5 and 2 µT (both p < 0.05). Independently, using a live-cell metabolic assay, normal cells were found to have a greater metabolic rate than radioresistant ones. Thus, MRI provides a novel, in vivo method to quantify the metabolic rate of tumours and predict their radiosensitivity.


Assuntos
Imagem por Ressonância Magnética/métodos , Neoplasias da Próstata/diagnóstico , Tolerância a Radiação , Animais , Metabolismo Basal , Linhagem Celular , Diagnóstico Diferencial , Xenoenxertos , Humanos , Magnetismo , Masculino , Camundongos , Consumo de Oxigênio , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/fisiopatologia
18.
Int J Radiat Oncol Biol Phys ; 101(3): 713-723, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29893279

RESUMO

PURPOSE: To monitor cellular and metabolic characteristics of glioblastoma (GBM) over the course of standard 6-week chemoradiation treatment with chemical exchange saturation transfer (CEST)-MRI; and to identify the earliest time point CEST could determine subsequent therapeutic response. METHODS AND MATERIALS: Nineteen patients with newly diagnosed GBM were recruited, and CEST-MRI was acquired immediately before (Day0), 2 weeks (Day14) and 4 weeks (Day28) into treatment, and 1 month after the end of treatment (Day70). Several CEST metrics, including magnetization transfer ratio and area under the curve of CEST peaks corresponding to nuclear Overhauser effect (NOE) and amide protons (MTRNOE, MTRAmide, CESTNOE, and CESTAmide respectively), magnetization transfer (MT), and direct water effect were investigated. Lack of early progression was determined as no increase in tumor size or worsening of clinical symptoms according to routine post-chemoradiation serial structural MRI. RESULTS: Changes in MTRNOE (nonprogressors = 1.35 ± 0.18, progressors = 0.97 ± 0.22, P = .006) and MTRAmide (nonprogressors = 1.25 ± 0.17, progressors = 0.99 ± 0.10, P = .017) between baseline (Day0) and Day14 resulted in the best separation of nonprogressors from progressors. Moreover, the baseline (Day0) MTRNOE (nonprogressors = 6.5% ± 1.6%, progressors = 9.1% ± 2.1%, P = .015), MTRAmide (nonprogressors = 6.7% ± 1.7%, progressors = 8.9% ± 1.9%, P = .028), MT (nonprogressors = 3.8% ± 0.9%, progressors = 5.4% ± 1.4%, P = .019), and CESTNOE (nonprogressors = 4.1%cHz ± 1.7%cHz, progressors = 6.1%cHz ± 1.9%cHz, P = .044) were able to identify progressors even before the start of the treatment. CONCLUSIONS: Chemical exchange saturation transfer (CEST) provides imaging-based biomarkers of GBM response as early as 2 weeks into the treatment. Certain CEST metrics can characterize tumor aggressiveness and identify early progressors even before beginning the treatment. Such an early biomarker of response may allow for adjusting the GBM treatment plan for adaptive radiation therapy in early progressors and more confidently continuing standard adjuvant treatment for nonprogressors.


Assuntos
Quimiorradioterapia , Glioblastoma/diagnóstico por imagem , Glioblastoma/terapia , Imagem por Ressonância Magnética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do Tratamento
19.
Chemistry ; 24(36): 9148-9156, 2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29645309

RESUMO

The rapid formation of hydrazones under physiological conditions was exploited for the detection of aldehydes through chemical exchange saturation transfer magnetic resonance imaging (CEST-MRI). A metal-free, diamagnetic contrast agent derived from N-amino anthranilic acid was introduced, which selectively "turned-on" upon hydrazone formation through an effect termed Hydrazo-CEST. While the hydrazine form of the probe produced no CEST-MRI signal enhancement, the formation of the aryl hydrazone resulted in >20 % intensity decrease in the bulk water signal through the CEST effect, as measured by 300 MHz 1 H NMR, 3 T and 7 T MRI. Both the electronic contributions of the N-amino anthranilate and the aldehyde binding partner were shown to directly impact the exchange rate of the proton on the ring-proximal nitrogen, and thus the imaging signal. Additionally, the presence of the carboxylic acid moiety ortho to the hydrazine was necessary not only for contrast production, but also for rapid hydrazone formation and prolonged hydrazone product stability under physiological conditions. This work provided the first example of an MRI-based contrast agent capable of a "turn on" response upon reaction with bioactive aldehydes, and outlined both the structural and electronic requirements to expand on Hydrazo-CEST, a novel, hydrazone-dependent subtype of diamagnetic CEST-MRI.

20.
J Neurooncol ; 139(1): 97-106, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29594656

RESUMO

PURPOSE: The objective was to investigate (with quantitative MRI) whether the normal appearing white matter (NAWM) of glioblastoma (GBM) patients on the contralateral side (cNAWM) was different from NAWM of healthy controls. METHODS: Thirteen patients with newly diagnosed GBM and nine healthy age-matched controls were MRI-scanned with quantitative magnetization transfer (qMT), chemical exchange saturation transfer (CEST), and transverse relaxation time (T2)-mapping. MRI scans were performed after surgery and before chemo-radiation treatment. Comprehensive qMT, CEST, T2 data were acquired. A two-pool MT model was fit to qMT data in transient state, to calculate MT model parameters [Formula: see text]. CEST signal was isolated by removing the contributions from the MT and direct water saturation, and CEST signal was calculated for Amide (CESTAmide), Amine (CESTAmine) and nuclear overhauser effect, NOE (CESTNOE). RESULTS: There was no difference between GBM patients and normal controls in the qMT properties of the macromolecular pool [Formula: see text]. However, their free water pool spectrum was different (1/RaT2a,patient = 28.1 ± 3.9, 1/RaT2a,control = 25.0 ± 1.1, p = 0.03). This difference could be attributed to the difference in their T2 time ([Formula: see text] = 83 ± 4, [Formula: see text] = 88 ± 1, p = 0.004). CEST signals were statistically significantly different with the CESTAmide having the largest difference between the two cohorts (CESTAmide,patient = 2.8 ± 0.4, CESTAmide,control = 3.4 ± 0.5, p = 0.009). CONCLUSIONS: CEST in cNAWM of GBM patients was lower than healthy controls which could be caused by modified brain metabolism due to tumor cell infiltration. There was no difference in MT properties of the patients and controls, however, the differences in free water pool properties were mainly due to reduced T2 in cNAWM of the patients (resulting from structural changes and increased cellularity).


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Imagem por Ressonância Magnética , Substância Branca/diagnóstico por imagem , Neoplasias Encefálicas/terapia , Feminino , Lateralidade Funcional , Glioblastoma/terapia , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade
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