Publications by authors named "Shuning Huang"

17 Publications

  • Page 1 of 1

Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice.

Ann Neurol 2021 05 22;89(5):926-941. Epub 2021 Mar 22.

Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.

Objective: Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children and young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% of bAVMs are sporadic without family history, the pathogenesis of sporadic bAVMs is largely unknown, which may account for the lack of therapeutic options. KRAS mutations are frequently observed in cancer, and a recent unprecedented finding of these mutations in human sporadic bAVMs offers a new direction in the bAVM research. Using a novel adeno-associated virus targeting brain endothelium (AAV-BR1), the current study tested if endothelial KRAS mutation induces sporadic bAVMs in mice.

Methods: Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRAS . At 8 weeks after the AAV injection, bAVM formation and characteristics were addressed by histological and molecular analyses. The effect of MEK/ERK inhibition on KRAS -induced bAVMs was determined by treatment of trametinib, a US Food and Drug Administration (FDA)-approved MEK/ERK inhibitor.

Results: The viral-mediated KRAS overexpression induced bAVMs, which were composed of a tangled nidus mirroring the distinctive morphology of human bAVMs. The bAVMs were accompanied by focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, and impaired sensory/cognitive/motor functions. Finally, we confirmed that bAVM growth was inhibited by trametinib treatment.

Interpretation: Our innovative approach using AAV-BR1 confirms that KRAS mutations promote bAVM development via the MEK/ERK pathway, and provides a novel preclinical mouse model of bAVMs which will be useful to develop a therapeutic strategy for patients with bAVM. ANN NEUROL 2021;89:926-941.
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http://dx.doi.org/10.1002/ana.26059DOI Listing
May 2021

Neuropeptides and G-Protein Coupled Receptors (GPCRs) in the Red Palm Weevil Olivier (Coleoptera: Dryophthoridae).

Front Physiol 2020 28;11:159. Epub 2020 Feb 28.

State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops, Fujian Agriculture and Forestry University, Fujian, China.

The red palm weevil is a devastating, invasive pest that causes serious damages to palm trees, and its invasiveness depends on its strong ability of physiological and behavioral adaptability. Neuropeptides and their receptors regulate physiology and behavior of insects, but these protein partners have not been identified from many insects. Here, we systematically identified neuropeptide precursors and the corresponding receptors in the red palm weevil, and analyzed their tissue expression patterns under control conditions and after pathogen infection. A total of 43 putative neuropeptide precursors were identified, including an extra myosuppressin peptide was identified with amino acid substitutions at two conserved sites. Forty-four putative neuropeptide receptors belonging to three classes were also identified, in which neuropeptide F receptors and insulin receptors were expanded compared to those in other insects. Based on qRT-PCR analyses, genes coding for several neuropeptide precursors and receptors were highly expressed in tissues other than the nervous system, suggesting that these neuropeptides and receptors play other roles in addition to neuro-reception. Some of the neuropeptides and receptors, like the tachykinin-related peptide and receptor, were significantly induced by pathogen infection, especially sensitive to and . Systemic identification and initial characterization of neuropeptides and their receptors in the red palm weevil provide a framework for further studies to reveal the functions of these ligand- and receptor-couples in regulating physiology, behavior, and immunity in this important insect pest species.
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http://dx.doi.org/10.3389/fphys.2020.00159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058690PMC
February 2020

Picometer scale vibrometry in the human middle ear using a surgical microscope based optical coherence tomography and vibrometry system.

Biomed Opt Express 2019 Sep 2;10(9):4395-4410. Epub 2019 Aug 2.

Department of Otolaryngology-Head and Neck Surgery, University of Southern California, Los Angeles, CA 90033, USA.

We have developed a highly phase stable optical coherence tomography and vibrometry system that attaches directly to the accessory area of a surgical microscope common to both the otology clinic and operating room. Careful attention to minimizing sources of phase noise has enabled a system capable of measuring vibrations of the middle ear with a sensitivity of < 5 pm in an awake human patient. The system is shown to be capable of collecting a wide range of information on the morphology and function of the ear in live subjects, including frequency tuning curves below the hearing threshold, maps of tympanic membrane vibrational modes and thickness, and measures of distortion products due to the nonlinearities in the cochlear amplifier.
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http://dx.doi.org/10.1364/BOE.10.004395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757470PMC
September 2019

Rapid and quantitative chemical exchange saturation transfer (CEST) imaging with magnetic resonance fingerprinting (MRF).

Magn Reson Med 2018 12 13;80(6):2449-2463. Epub 2018 May 13.

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts.

Purpose: To develop a fast magnetic resonance fingerprinting (MRF) method for quantitative chemical exchange saturation transfer (CEST) imaging.

Methods: We implemented a CEST-MRF method to quantify the chemical exchange rate and volume fraction of the N -amine protons of L-arginine (L-Arg) phantoms and the amide and semi-solid exchangeable protons of in vivo rat brain tissue. L-Arg phantoms were made with different concentrations (25-100 mM) and pH (pH 4-6). The MRF acquisition schedule varied the saturation power randomly for 30 iterations (phantom: 0-6 μT; in vivo: 0-4 μT) with a total acquisition time of ≤2 min. The signal trajectories were pattern-matched to a large dictionary of signal trajectories simulated using the Bloch-McConnell equations for different combinations of exchange rate, exchangeable proton volume fraction, and water T and T relaxation times.

Results: The chemical exchange rates of the N -amine protons of L-Arg were significantly (P < 0.0001) correlated with the rates measured with the quantitation of exchange using saturation power method. Similarly, the L-Arg concentrations determined using MRF were significantly (P < 0.0001) correlated with the known concentrations. The pH dependence of the exchange rate was well fit (R  = 0.9186) by a base catalyzed exchange model. The amide proton exchange rate measured in rat brain cortex (34.8 ± 11.7 Hz) was in good agreement with that measured previously with the water exchange spectroscopy method (28.6 ± 7.4 Hz). The semi-solid proton volume fraction was elevated in white (12.2 ± 1.7%) compared to gray (8.1 ± 1.1%) matter brain regions in agreement with previous magnetization transfer studies.

Conclusion: CEST-MRF provides a method for fast, quantitative CEST imaging.
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http://dx.doi.org/10.1002/mrm.27221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234098PMC
December 2018

ATX-MS-1467 Induces Long-Term Tolerance to Myelin Basic Protein in (DR2 × Ob1)F1 Mice by Induction of IL-10-Secreting iTregs.

Neurol Ther 2018 Jun 14;7(1):103-128. Epub 2018 Mar 14.

Neurology eTIP, Translational and Biomarker Research Group, EMD Serono Research and Development Institute, Inc., Billerica, MA, USA.

Introduction: Antigen-specific immunotherapy could provide a targeted approach for the treatment of multiple sclerosis that removes the need for broad-acting immunomodulatory drugs. ATX-MS-1467 is a mixture of four peptides identified as the main immune-dominant disease-associated T-cell epitopes in myelin basic protein (MBP), an autoimmune target for activated autoreactive T cells in multiple sclerosis. Previous animal studies have shown that ATX-MS-1467 treatment prevented the worsening of signs of disease in experimental autoimmune encephalitis (EAE) in the humanized (DR2 × Ob1)F1 mouse in a dose-dependent fashion.

Methods And Results: Our study extends these observations to show that subcutaneous treatment with 100 µg of ATX-MS-1467 after induction of EAE in the same mouse model reversed established clinical disability (p < 0.0001) and histological markers of inflammation and demyelination (p < 0.001) compared with vehicle-treated animals; furthermore, in longitudinal magnetic resonance imaging analyses, disruption of blood-brain barrier integrity was reversed, compared with vehicle-treated animals (p < 0.05). Chronic treatment with ATX-MS-1467 was associated with an enduring shift from a pro-inflammatory to a tolerogenic state in the periphery, as shown by an increase in interleukin 10 secretion, relative to interleukin 2, interleukin 17 and interferon γ, a decrease in splenocyte proliferation and an increase in interleukin 10 Foxp3 T cells in the spleen.

Conclusion: Our results suggest that ATX-MS-1467 can induce splenic iTregs and long-term tolerance to MBP with the potential to partially reverse the pathology of multiple sclerosis, particularly during the early stages of the disease.

Funding: EMD Serono, Inc., a business of Merck KGaA.
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http://dx.doi.org/10.1007/s40120-018-0094-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990509PMC
June 2018

Microstructural impact of ischemia and bone marrow-derived cell therapy revealed with diffusion tensor magnetic resonance imaging tractography of the heart in vivo.

Circulation 2014 Apr 11;129(17):1731-41. Epub 2014 Mar 11.

From Martinos Center for Biomedical Imaging, Department of Radiology (D.E.S., C.M., S.H., H.H.C., G.D., R.W., W.J.K., V.J.W.), and Cardiovascular Research Center, Cardiology Division (D.E.S., H.H.C., W.J.K.), Massachusetts General Hospital, Harvard Medical School, Boston, MA; Institute for Biomedical Engineering, University and ETH Zurich, Zurich, Switzerland (C.T.S., S.K.); Cardiac Muscle Research Laboratory, Divisions of Cardiology and Genetics, Brigham and Woman's Hospital, Harvard Medical School, Boston, MA (S.N., J.G., R.L.); and Department of Computer Science, Institute of Mathematics and Statistics, University of São Paulo, São Paulo, Brazil (M.P.J.).

Background: The arrangement of myofibers in the heart is highly complex and must be replicated by injected cells to produce functional myocardium. A novel approach to characterize the microstructural response of the myocardium to ischemia and cell therapy, with the use of serial diffusion tensor magnetic resonance imaging tractography of the heart in vivo, is presented.

Methods And Results: Validation of the approach was performed in normal (n=6) and infarcted mice (n=6) as well as healthy human volunteers. Mice (n=12) were then injected with bone marrow mononuclear cells 3 weeks after coronary ligation. In half of the mice the donor and recipient strains were identical, and in half the strains were different. A positive response to cell injection was defined by a decrease in mean diffusivity, an increase in fractional anisotropy, and the appearance of new myofiber tracts with the correct orientation. A positive response to bone marrow mononuclear cell injection was seen in 1 mouse. The response of the majority of mice to bone marrow mononuclear cell injection was neutral (9/12) or negative (2/12). The in vivo tractography findings were confirmed with histology.

Conclusions: Diffusion tensor magnetic resonance imaging tractography was able to directly resolve the ability of injected cells to generate new myofiber tracts and provided a fundamental readout of their regenerative capacity. A highly novel and translatable approach to assess the efficacy of cell therapy in the heart is thus presented.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.113.005841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034455PMC
April 2014

Classification of coronary atherosclerotic plaques ex vivo with T1, T2, and ultrashort echo time CMR.

JACC Cardiovasc Imaging 2013 Apr 14;6(4):466-74. Epub 2013 Mar 14.

Cardiac MR/PET/CT Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objectives: This study sought to determine whether the classification of human coronary atherosclerotic plaques with T1, T2, and ultrashort echo time (UTE) cardiac magnetic resonance (CMR) would correlate well with atherosclerotic plaque classification by histology.

Background: CMR has been extensively used to classify carotid plaque, but its ability to characterize coronary plaque remains unknown. In addition, the detection of plaque calcification by CMR remains challenging. Here, we used T1, T2, and UTE CMR to evaluate atherosclerotic plaques in fixed post-mortem human coronary arteries. We hypothesized that the combination of T1, T2, and UTE CMR would allow both calcified and lipid-rich coronary plaques to be accurately detected.

Methods: Twenty-eight plaques from human donor hearts with proven coronary artery disease were imaged at 9.4-T with a T1-weighted 3-dimensional fast low-angle shot (FLASH) sequence (250-μm resolution), a T2-weighted rapid acquisition with refocused echoes (RARE) sequence (in-plane resolution 0.156 mm), and an UTE sequence (300-μm resolution). Plaques showing selective hypointensity on T2-weighted CMR were classified as lipid-rich. Areas of hypointensity on the T1-weighted images, but not the UTE images, were classified as calcified. Hyperintensity on the T1-weighted and UTE images was classified as hemorrhage. Following CMR, histological characterization of the plaques was performed with a pentachrome stain and established American Heart Association criteria.

Results: CMR showed high sensitivity and specificity for the detection of calcification (100% and 90%, respectively) and lipid-rich necrotic cores (90% and 75%, respectively). Only 2 lipid-rich foci were missed by CMR, both of which were extremely small. Overall, CMR-based classification of plaque was in complete agreement with the histological classification in 22 of 28 cases (weighted κ = 0.6945, p < 0.0001).

Conclusions: The utilization of UTE CMR allows plaque calcification in the coronary arteries to be robustly detected. High-resolution CMR with T1, T2, and UTE contrast enables accurate classification of human coronary atherosclerotic plaque.
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http://dx.doi.org/10.1016/j.jcmg.2012.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661771PMC
April 2013

Cerebral blood volume affects blood-brain barrier integrity in an acute transient stroke model.

J Cereb Blood Flow Metab 2013 Jun 6;33(6):898-905. Epub 2013 Mar 6.

Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts, USA.

Insufficient vascular reserve after an ischemic stroke may induce biochemical cascades that subsequently deteriorate the blood-brain barrier (BBB) function. However, the direct relationship between poor cerebral blood volume (CBV) restoration and BBB disruption has not been examined in acute stroke. To quantify BBB integrity at acute stages of transient stroke, in particular for cases in which extravasation of the standard contrast agent (Gd-DTPA) is not observed, we adopted the water exchange index (WEI), a novel magnetic resonance image-derived parameter to estimate the water permeability across the BBB. The apparent diffusion coefficient (ADC) and R2 relaxation rate constant were also measured for outlining the tissue abnormality, while fractional CBV and WEI were quantified for assessing vascular alterations. The significantly decreased ADC and R2 in the ischemic cortices did not correlate with the changes in CBV or WEI. In contrast, a strong negative correlation between the ipsilesional WEI and CBV was found, in which stroke mice were clustered into two groups: (1) high WEI and low CBV and (2) normal WEI and CBV. The low CBV observed for mice with a disrupted BBB, characterized by a high WEI, indicates the importance of CBV restoration for maintaining BBB stability in acute stroke.
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http://dx.doi.org/10.1038/jcbfm.2013.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677109PMC
June 2013

Fiber architecture in remodeled myocardium revealed with a quantitative diffusion CMR tractography framework and histological validation.

J Cardiovasc Magn Reson 2012 Oct 12;14:70. Epub 2012 Oct 12.

Athinoula A, Martinos Center For Biomedical Imaging, Boston, MA, USA.

Background: The study of myofiber reorganization in the remote zone after myocardial infarction has been performed in 2D. Microstructural reorganization in remodeled hearts, however, can only be fully appreciated by considering myofibers as continuous 3D entities. The aim of this study was therefore to develop a technique for quantitative 3D diffusion CMR tractography of the heart, and to apply this method to quantify fiber architecture in the remote zone of remodeled hearts.

Methods: Diffusion Tensor CMR of normal human, sheep, and rat hearts, as well as infarcted sheep hearts was performed ex vivo. Fiber tracts were generated with a fourth-order Runge-Kutta integration technique and classified statistically by the median, mean, maximum, or minimum helix angle (HA) along the tract. An index of tract coherence was derived from the relationship between these HA statistics. Histological validation was performed using phase-contrast microscopy.

Results: In normal hearts, the subendocardial and subepicardial myofibers had a positive and negative HA, respectively, forming a symmetric distribution around the midmyocardium. However, in the remote zone of the infarcted hearts, a significant positive shift in HA was observed. The ratio between negative and positive HA variance was reduced from 0.96 ± 0.16 in normal hearts to 0.22 ± 0.08 in the remote zone of the remodeled hearts (p < 0.05). This was confirmed histologically by the reduction of HA in the subepicardium from -52.03° ± 2.94° in normal hearts to -37.48° ± 4.05° in the remote zone of the remodeled hearts (p < 0.05).

Conclusions: A significant reorganization of the 3D fiber continuum is observed in the remote zone of remodeled hearts. The positive (rightward) shift in HA in the remote zone is greatest in the subepicardium, but involves all layers of the myocardium. Tractography-based quantification, performed here for the first time in remodeled hearts, may provide a framework for assessing regional changes in the left ventricle following infarction.
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http://dx.doi.org/10.1186/1532-429X-14-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506570PMC
October 2012

Dynamic monitoring of blood-brain barrier integrity using water exchange index (WEI) during mannitol and CO2 challenges in mouse brain.

NMR Biomed 2013 Apr 11;26(4):376-85. Epub 2012 Oct 11.

Health Science and Technology (HST), Massachusetts Institute of Technology, Cambridge, MA, USA; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA.

The integrity of the blood-brain barrier (BBB) is critical to normal brain function. Traditional techniques for the assessment of BBB disruption rely heavily on the spatiotemporal analysis of extravasating contrast agents. However, such methods based on the leakage of relatively large molecules are not suitable for the detection of subtle BBB impairment or for the performance of repeated measurements in a short time frame. Quantification of the water exchange rate constant (WER) across the BBB using strictly intravascular contrast agents could provide a much more sensitive method for the quantification of the BBB integrity. To estimate WER, we have recently devised a powerful new method using a water exchange index (WEI) biomarker and demonstrated BBB disruption in an acute stroke model. Here, we confirm that WEI is sensitive to even very subtle changes in the integrity of the BBB caused by: (i) systemic hypercapnia and (ii) low doses of a hyperosmolar solution. In addition, we have examined the sensitivity and accuracy of WEI as a biomarker of WER using computer simulation. In particular, the dependence of the WEI-WER relation on changes in vascular blood volume, T1 relaxation of cellular magnetization and transcytolemmal water exchange was explored. Simulated WEI was found to vary linearly with WER for typically encountered exchange rate constants (1-4 Hz), regardless of the blood volume. However, for very high WER (>5 Hz), WEI became progressively more insensitive to increasing WER. The incorporation of transcytolemmal water exchange, using a three-compartment tissue model, helped to extend the linear WEI regime to slightly higher WER, but had no significant effect for most physiologically important WERs (WER < 4 Hz). Variation in cellular T1 had no effect on WEI. Using both theoretical and experimental approaches, our study validates the utility of the WEI biomarker for the monitoring of BBB integrity.
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http://dx.doi.org/10.1002/nbm.2871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029920PMC
April 2013

Molecular MRI of acute necrosis with a novel DNA-binding gadolinium chelate: kinetics of cell death and clearance in infarcted myocardium.

Circ Cardiovasc Imaging 2011 Nov 11;4(6):729-37. Epub 2011 Aug 11.

Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

Background: Current techniques to image cell death in the myocardium are largely nonspecific. We report the use of a novel DNA-binding gadolinium chelate (Gd-TO) to specifically detect the exposed DNA in acutely necrotic (ruptured) cells in vivo.

Methods And Results: In vivo MRI was performed in 20 mice with myocardial infarction (MI). The mice were injected with Gd-TO or Gd-DTPA at varying time points after MI. MRI was performed 2 hours after probe injection, to avoid nonspecific signal from the late gadolinium enhancement effect. Cell rupture (Gd-TO uptake) was present within 2 hours of infarction but peaked 9 to 18 hours after the onset of injury. A significant increase in the longitudinal relaxation rate (R(1)) in the infarct was seen in mice injected with Gd-TO within 48 hours of MI, but not in those injected more than 72 hours after MI (R(1)=1.24±0.08 and 0.92±0.03 s(-1), respectively, P<0.001). Gd-DTPA, unlike Gd-TO, washed completely out of acute infarcts within 2 hours of injection (P<0.001). The binding of Gd-TO to exposed DNA in acute infarcts was confirmed with fluorescence microscopy.

Conclusions: Gd-TO specifically binds to acutely necrotic cells and can be used to image the mechanism and chronicity of cell death in injured myocardium. Cell rupture in acute MI begins early but peaks many hours after the onset of injury. The ruptured cells are efficiently cleared by the immune system and are no longer present in the myocardium 72 hours after injury.
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http://dx.doi.org/10.1161/CIRCIMAGING.111.966374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3370828PMC
November 2011

Molecular and Microstructural Imaging of the Myocardium.

Curr Cardiovasc Imaging Rep 2010 Feb;3(1):26-33

CNY, Massachusetts General Hospital, 5416, 149 13th Street, Charlestown, MA 02129, USA.

The past year has witnessed ongoing progress in the field of molecular MRI of the myocardium. In addition, several novel fluorescent agents have been introduced and used to image remodeling in the injured myocardium. New techniques to image myocardial microstructure, such as diffusion spectrum MRI, have also been introduced and have tremendous potential for integration and synergy with molecular MRI. In the current review we focus on these and other advances in the field that have occurred over the past year.
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http://dx.doi.org/10.1007/s12410-010-9007-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2916196PMC
February 2010

Manipulation of tissue contrast using contrast agents for enhanced MR microscopy in ex vivo mouse brain.

Neuroimage 2009 Jul 2;46(3):589-99. Epub 2009 Mar 2.

Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Detailed 3D mouse brain images may promote better understanding of phenotypical differences between normal and transgenic/mutant mouse models. Previously, a number of magnetic resonance microscopy (MRM) studies have successfully established brain atlases, revealing genotypic traits of several commonly used mouse strains. In such studies, MR contrast agents, mainly gadolinium (Gd) based, were often used to reduce acquisition time and improve signal-to-noise ratio (SNR). In this paper, we intended to extend the utility of contrast agents for MRM applications. Using Gd-DTPA and MnCl(2), we exploited the potential use of MR contrast agents to manipulate image contrast by drawing upon the multiple relaxation mechanisms and tissue-dependent staining properties characteristic of each contrast agent. We quantified r(1) and r(2) of Gd-DTPA and MnCl(2) in both aqueous solution and brain tissue and demonstrated the presence of divergent relaxation mechanisms between solution and tissue for each contrast agent. Further analyses using nuclear magnetic resonance dispersion (NMRD) of Mn(2+) in ex vivo tissue strongly suggested macromolecule binding of Mn(2+), leading to increased T(1) relaxation. Moreover, inductively coupled plasma (ICP) mass spectroscopy revealed that MnCl(2) had higher tissue affinity than Gd-DTPA. As a result, multiple regions of the brain stained by the two agents exhibited different image contrasts. Our results show that differential MRM staining can be achieved using multiple MR contrast agents, revealing detailed cytoarchitecture, and may ultimately offer a window for investigating new techniques by which to understand biophysical MR relaxation mechanisms and perhaps to visualize tissue anomalies even at the molecular level.
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http://dx.doi.org/10.1016/j.neuroimage.2009.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441733PMC
July 2009

Characterization of cerebrovascular responses to hyperoxia and hypercapnia using MRI in rat.

Neuroimage 2009 May 14;45(4):1126-34. Epub 2008 Dec 14.

Laboratory of Neuroprotection, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.

Understanding cerebrovascular responses to hyperoxia and hypercapnia is important for investigating exogenous regulation of cerebral hemodynamics. We characterized gas-induced vascular changes in the brains of anesthetized healthy rats using magnetic resonance imaging (MRI) while the rats inhaled 100% O(2) (hyperoxia) and 5% CO(2) (hypercapnia). We used echo planar imaging (EPI), arterial spin labeling (ASL), and intravascular superparamagnetic iron oxide nanoparticles (SPION) to quantify vascular responses as measured by blood oxygenation level dependence (BOLD), cerebral blood flow (CBF), cerebral blood volume (CBV), microvascular volume (MVV), and vessel size index (VSI) in multiple brain regions. Hyperoxia resulted in a statistically significant increase in BOLD-weighted MRI signal and significant decrease in CBF and CBV (P<0.05). During hypercapnia, we observed significant increases in BOLD signal, CBF, MVV, and CBV (P<0.05). Despite the regional variability, general trends of vasoconstriction and vasodilation were reflected in VSI changes during O(2) and CO(2) challenges. Interestingly, there was an evident spatial disparity between the O(2) and CO(2) stimuli-induced functional activation maps; that is, cortical and subcortical regions of the brain exhibited notable differences in response to the two gases. Hemodynamic parameters measured in the cortical regions showed greater reactivity to CO(2), whereas these same parameters measured in subcortical regions showed greater responsivity to O(2). Our results demonstrate significant changes of hemodynamic MRI parameters during systemic hypercapnia and hyperoxia in normal cerebral tissue. These gas-dependent changes are spatiotemporally distinctive, suggesting important feasibility for exogenously controlling local cerebral perfusion.
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http://dx.doi.org/10.1016/j.neuroimage.2008.11.037DOI Listing
May 2009

Using magnetic resonance microscopy to study the growth dynamics of a glioma spheroid in collagen I: A case study.

BMC Med Imaging 2008 Jan 29;8. Epub 2008 Jan 29.

Harvard-MIT (HST) Athinoula A, Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA.

Background: Highly malignant gliomas are characterized by rapid growth, extensive local tissue infiltration and the resulting overall dismal clinical outcome. Gaining any additional insights into the complex interaction between this aggressive brain tumor and its microenvironment is therefore critical. Currently, the standard imaging modalities to investigate the crucial interface between tumor growth and invasion in vitro are light and confocal laser scanning microscopy. While immensely useful in cell culture, integrating these modalities with this cancer's clinical imaging method of choice, i.e. MRI, is a non-trivial endeavour. However, this integration is necessary, should advanced computational modeling be able to utilize these in vitro data to eventually predict growth behaviour in vivo. We therefore argue that employing the same imaging modality for both the experimental setting and the clinical situation it represents should have significant value from a data integration perspective. In this case study, we have investigated the feasibility of using a specific form of MRI, i.e. magnetic resonance microscopy or MRM, to study the expansion dynamics of a multicellular tumor spheroid in a collagen type I gel.

Methods: An U87mEGFR human giloblastoma multicellular spheroid (MTS) containing approximately 4.103 cells was generated and pipetted into a collagen I gel. The sample was then imaged using a T2-weighted 3D spoiled gradient echo pulse sequence on a 14T MRI scanner over a period of 12 hours with a temporal resolution of 3 hours at room temperature. Standard histopathology was performed on the MRM sample, as well as on control samples.

Results: We were able to acquire three-dimensional MR images with a spatial resolution of 24 x 24 x 24 microm3. Our MRM data successfully documented the volumetric growth dynamics of an MTS in a collagen I gel over the 12-hour period. The histopathology results confirmed cell viability in the MRM sample, yet displayed distinct patterns of cell proliferation and invasion as compared to control.

Conclusion: In this study, we demonstrate that a specific form of MRI, i.e. magnetic resonance microscopy or MRM, can be used to study the dynamic growth of a multicellular tumor spheroid (MTS) with a single cell scale spatial resolution that approaches the level of light microscopy. We argue that MRM can be employed as a complementary non-invasive tool to characterize microscopic MTS expansion, and thus, together with integrative computational modeling, may allow bridging of the experimental and clinical scales more readily.
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http://dx.doi.org/10.1186/1471-2342-8-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270258PMC
January 2008

Forebrain ischemia-reperfusion simulating cardiac arrest in mice induces edema and DNA fragmentation in the brain.

Mol Imaging 2007 May-Jun;6(3):156-70

A.A. Martinos Center for Biomedical Imaging Charlestown, MA, USA.

Brain injury affects one-third of persons who survive after heart attack, even with restoration of spontaneous circulation by cardiopulmonary resuscitation. We studied brain injury resulting from transient bilateral carotid artery occlusion (BCAO) and reperfusion by simulating heart attack and restoration of circulation, respectively, in live C57Black6 mice. This model is known to induce neuronal death in the hippocampus, striatum, and cortex. We report the appearance of edema after transient BCAO of 60 minutes and 1 day of reperfusion. Hyperintensity in diffusion-weighted magnetic resonance imaging (MRI) was detectable in the striatum, thalamus, and cortex but not in the hippocampus. To determine whether damage to the hippocampus can be detected in live animals, we infused a T(2) susceptibility magnetic resonance contrast agent (superparamagnetic iron oxide nanoparticles [SPIONs]) that was linked to single-stranded deoxyribonucleic acid (DNA) complementary in sequence to c-fos messenger ribonucleic acid (SPION-cfos); we acquired in vivo T(2)*-weighted MRI 3 days later. SPION retention was measured as T(2)* (milliseconds) signal reduction or R(2)* value (s(-1)) elevation. We found that animals treated with 60-minute BCAO and 7-day reperfusion exhibited significantly less SPION retention in the hippocampus and cortex than sham-operated animals. These findings suggest that brain injury induced by cardiac arrest can be detected in live animals.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2644455PMC
December 2007

MR contrast probes that trace gene transcripts for cerebral ischemia in live animals.

FASEB J 2007 Sep 3;21(11):3004-15. Epub 2007 May 3.

AA Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, USA.

The aim of this research was to validate transcription magnetic resonance (MR) imaging (MRI) for gene transcript targeting in acute neurological disorders in live subjects. We delivered three MR probe variants with superparamagnetic iron oxide nanoparticles (SPION, a T2 susceptibility agent) linked to a phosphorothioate-modified oligodeoxynucleotide (sODN) complementary to c-fos mRNA (SPION-cfos) or beta-actin mRNA (SPION-beta-actin) and to sODN with random sequence (SPION-Ran). Each probe (1 microg Fe in 2 microl) was delivered via intracerebroventricular infusion to the left cerebral ventricle of male C57Black6 mice. We demonstrated SPION retention, measured as decreased T2* signal or increased R2* value (R2* = 1/T2*). Animals that received the SPION-beta-actin probe exhibited the highest R2* values, followed (in descending order) by SPION-cfos and SPION-Ran. SPION-cfos retention was localized in brain regions where SPION-cfos was present and where hybrids of SPION-cfos and its target c-fos mRNA were detected by in situ reverse transcription PCR. In animals that experienced cerebral ischemia, SPION-cfos retention was significantly increased in locations where c-fos mRNA increased in response to the ischemic insult; these elevations were not observed for SPION-beta-actin and SPION-Ran. This study should enable MR detection of mRNA alteration in disease models of the central nervous system.
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http://dx.doi.org/10.1096/fj.07-8203comDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657320PMC
September 2007