Tina Bugge Pedersen

Norwegian University of Science and Technology, Trondheim, Sor-Trondelag Fylke, Norway

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Publications (10)31.94 Total impact

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    ABSTRACT: Hypoxia-ischemia (HI) in the neonatal brain results in a prolonged injury process. Longitudinal studies using noninvasive methods can help elucidate the mechanisms behind this process. We have recently demonstrated that manganese-enhanced magnetic resonance imaging (MRI) can depict areas with activated microglia and astrogliosis 7 days after hypoxic-ischemic brain injury. The current study aimed to follow brain injury after HI in rats longitudinally and compare manganese enhancement of brain areas to the development of injury and presence of reactive astrocytes and microglia. The Vannucci model for hypoxic-ischemic injury in the neonatal rat was used. Pups were injected with either MnCl(2) or saline after 6 h and again on day 41 after HI. Longitudinal MRI (T(1) weighted) was performed 1, 3, 7 and 42 days after HI. The brains were prepared for immunohistochemistry after the final MRI. There was severe loss of cerebral tissue from day 7 to day 42 after HI. Most manganese-enhanced areas in the hippocampus, thalamus and basal ganglia at day 7 were liquefied after 42 days. Manganese-enhancement on day 42 corresponded to areas of activated microglia and reactive astrocytes in the remaining cortex, hippocampus and amygdala. However, the main area of enhancement was in the remaining thalamus in a calcified area surrounded by activated microglia and reactive astrocytes. Manganese-enhanced MRI can be a useful tool for in vivo identification of cerebral tissue undergoing delayed cell death and liquefaction after HI. Manganese enhancement at a late stage seems to be related to the accumulation of manganese in calcifications and gliotic tissue.
    Neonatology 07/2011; 100(4):363-72. · 2.57 Impact Factor
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    ABSTRACT: Purpose:To assess optic nerve (ON) regeneration after injury by applying manganese-enhanced MRI (MEMRI) in a study of comparative physiology between nonregenerating rat and mouse species and regenerating frog and fish species.Materials and Methods:The normal visual projections of rats, mice, frogs, and fish was visualized by intravitreal MnCl2 injection followed by MRI. Rats and mice with ON crush (ONC) were divided into nonregenerating (ONC only), and regenerating animals with peripheral nerve graft (ONC+PNG; rats) or lens injury (ONC+LI; mice) and monitored by MEMRI at 1 and 20 days post-lesion (dpl). Frog and fish with ON transection (ONT) were monitored by MEMRI up to 6 months postlesion (mpl).Results:Signal intensity profiles of the Mn2+-enhanced ON were consistent with ON regeneration in the ONC+PNG and ONC+LI rat and mice groups, respectively, compared with the nonregenerating ONC groups. Furthermore, signal intensity profiles of the Mn2+-enhanced ON obtained between 1 mpl and 6 mpl in the fish and frog groups, respectively, were consistent with spontaneous, complete ON regeneration.Conclusion:Taken together, these results demonstrate that MEMRI is a viable method for serial, in vivo monitoring of normal, induced, and spontaneously regenerating optic nerve axons in different species. J. Magn. Reson. Imaging 2011;. © 2011 Wiley-Liss, Inc.
    Journal of Magnetic Resonance Imaging 07/2011; 34(3):670 - 675. · 2.57 Impact Factor
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    ABSTRACT: The purpose of this study was to evaluate the use of dynamic contrast-enhanced (DCE) MRI, in vivo (1)H MRS and ex vivo high resolution magic angle spinning (HR MAS) MRS of tissue samples as methods to detect early treatment effects of docetaxel in a breast cancer xenograft model (MCF-7) in mice. MCF-7 cells were implanted subcutaneously in athymic mice and treated with docetaxel (20, 30, and 40 mg/kg) or saline six weeks later. DCE-MRI and in vivo (1)H MRS were performed on a 7 T MR system three days after treatment. The dynamic images were used as input for a two-compartment model, yielding the vascular parameters K(trans) and v(e). HR MAS MRS, histology, and immunohistochemical staining for proliferation (Ki-67), apoptosis (M30 cytodeath), and vascular/endothelial cells (CD31) were performed on excised tumor tissue. Both in vivo spectra and HR MAS spectra were used as input for multivariate analysis (principal component analysis (PCA) and partial least squares regression analysis (PLS)) to compare controls to treated tumors. Tumor growth was suppressed in docetaxel-treated mice compared to the controls. The anti-tumor effect led to an increase in K(trans) and v(e) values in all the treated groups. Furthermore, in vivo MRS and HR MAS MRS revealed a significant decrease in choline metabolite levels for the treated groups, in accordance with reduced proliferative index as seen on Ki-67 stained sections. In this study DCE-MRI, in vivo MRS and ex vivo HR MAS MRS have been used to demonstrate that docetaxel treatment of a human breast cancer xenograft model results in changes in the vascular dynamics and metabolic profile of the tumors. This indicates that these MR methods could be used to monitor intra-tumoral treatment effects.
    NMR in Biomedicine 08/2009; 23(1):56-65. · 3.45 Impact Factor
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    ABSTRACT: To evaluate manganese (Mn(2+))-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) as tools for detection of axonal injury and regeneration after intravitreal peripheral nerve graft (PNG) implantation in the rat optic nerve (ON). In adult Fischer rats, retinal ganglion cell (RGC) survival was evaluated in Flurogold (FG) back-filled retinal whole mounts after ON crush (ONC), intravitreal PNG, and intravitreal MnCl(2) injection (150 nmol) at 0 and 20 days post lesion (dpl). MEMRI and echo-planar DTI (DTI-EPI) was obtained of noninjured ON one day after intravitreal MnCl(2) injection, and at 1 and 21 dpl after ONC, intravitreal PNG, and intravitreal MnCl(2) injections given at 0 and 20 dpl. GAP-43 immunohistochemistry was performed after the last MRI. ONC reduced RGC density in retina by 94% at 21 dpl compared to noninjured ON without MnCl(2) injections. Both intravitreal PNG and intravitreal MnCl(2) injections improved RGC survival in retina, which was reduced by 90% (ONC+MnCl(2)), 82% (ONC+PNG), and 74% (ONC+PNG+MnCl(2)) compared to noninjured ON. DTI-derived parameters (fractional anisotropy [FA], mean diffusivity, axial diffusivity lambda( parallel), and radial diffusivity lambda( perpendicular)) were unaffected by the presence of Mn(2+) in the ON. At 1 dpl, CNR(MEMRI) and lambda( parallel) were reduced at the injury site, while at 21 dpl they were increased at the injury site compared to values measured at 1 dpl. GAP-43 immunoreactive axons were present in the ON distal to the ONC injury site. MEMRI and DTI enabled detection of functional and structural degradation after rat ON injury, and there was correlation between the MRI-derived and immunohistochemical measures of axon regeneration.
    Journal of Magnetic Resonance Imaging 01/2009; 29(1):39-51. · 2.57 Impact Factor
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    ABSTRACT: Hypoxic-ischemic injury (HI) to the neonatal brain results in delayed neuronal death with accompanying inflammation for days after the initial insult. The aim of this study was to depict delayed neuronal death after HI using Manganese-enhanced MRI (MEMRI) and to evaluate the specificity of MEMRI in detection of cells related to injury by comparison with histology and immunohistochemistry. 7-day-old Wistar rat pups were subjected to HI (occlusion of right carotid artery and 8% O(2) for 75 min). 16 HI (HI+Mn) and 6 sham operated (Sham+Mn) pups were injected with MnCl(2) (100 mM, 40 mg/kg) and 10 HI-pups (HI+Vehicle) received NaCl i.p. 6 h after HI. 3D T(1)-weighted images (FLASH) and 2D T(2)-maps (MSME) were acquired at 7 T 1, 3 and 7 days after HI. Pups were sacrificed after MR-scanning and brain slices were cut and stained for CD68, GFAP, MAP-2, Caspase-3 and Fluorojade B. No increased manganese-enhancement (ME) was detectable in the injured hemisphere on day 1 or 3 when immunohistochemistry showed massive ongoing neuronal death. 7 days after HI, increased ME was seen on T(1)-w images in parts of the injured cortex, hippocampus and thalamus among HI+Mn pups, but not among HI+Vehicle or Sham+Mn pups. Comparison with immunohistochemistry showed delayed neuronal death and inflammation in these areas with late ME. Areas with increased ME corresponded best with areas with high concentrations of activated microglia. Thus, late manganese-enhancement seems to be related to accumulation of manganese in activated microglia in areas of neuronal death rather than depicting neuronal death per se.
    NeuroImage 01/2009; 45(3):880-90. · 6.25 Impact Factor
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    ABSTRACT: To provide dose-response data for the safe and effective use of MnCl(2) for manganese (Mn(2+)) -enhanced MRI (MEMRI) of the visual pathway. Retinal ganglion cell (RGC) toxicity, CNR in MEMRI, axon density resolution for MEMRI, mode of axonal transport and clearance of Mn(2+) from the vitreous after ivit were investigated. After 0, 30, 150, 300, 1500, and 3000 nmol ivit MnCl(2), neural toxicity was measured by counting surviving RGC back-filled with FluroGold (FG), CNR of the vitreous body and visual pathway by three-dimensional (3D) MEMRI, resolution of ON axon density by correlating CNR with axon density, and axonal transport of Mn(2+) by studying CNR in 3D MEMRI of the ON after ion of 200 nmol MnCl(2). There were no changes in RGC density after ivit MnCl(2) <or= 150 nmol, and reductions of 12%, 57%, and 94% occurred after 300, 1500, and 3000 nmol MnCl(2). CNR increased in the visual pathway with MnCl(2) <or= 300 nmol, and decreased when the dose was raised further. Minimum detectable ON axon densities were 125,000/mm(2). After 200 nmol ion MnCl(2), CNR>0 were recorded distally from the ion site, but there was no signal in the retina. At ivit doses >1500 nmol, clearance from the vitreous body was impaired. The optimal dose for MEMRI of the rat visual pathway was found to be 150-300 nmol ivit MnCl(2). Higher doses are toxic, causing RGC death, impair active clearance from the vitreous, and loss of Mn(2+) enhancement throughout the visual pathway. Mn(2+) traffic within RGC axons is mediated mainly by anterograde transport.
    Journal of Magnetic Resonance Imaging 11/2008; 28(4):855-65. · 2.57 Impact Factor
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    ABSTRACT: Tumour angiogenesis is a tightly regulated process involving cross-talk between tumour cells and the host tissue. The underlying mechanisms that regulate such interactions remain largely unknown. NG2 is a transmembrane proteoglycan whose presence on transformed cells has been demonstrated to increase proliferation in vitro and angiogenesis in vivo. To study the effects of NG2 during tumour growth and progression, we engineered an NG2 positive human glioma cell line (U251-NG2) from parental NG2 negative cells (U251-WT) and implanted both cell types stereotactically into immunodeficient nude rat brains. The tumours were longitudinally monitored in vivo using multispectral MRI employing two differently sized contrast agents (Gd-DTPA-BMA and Gadomer) to assess vascular leakiness, vasogenic oedema, tumour volumes and necrosis. Comparisons of Gd-DTPA-BMA and Gadomer revealed differences in their spatial distribution in the U251-NG2 and U251-WT tumours. The U251-NG2 tumours exhibited a higher leakiness of the larger molecular weight Gadomer and displayed a stronger vasogenic oedema (69.9 +/- 15.2, P = 0.018, compared to the controls (10.7 +/- 7.7). Moreover, immunohistochemistry and electron microscopy revealed that the U251-NG2 tumours had a higher microvascular density (11.81 +/- 0.54; P = 0.0010) compared to controls (5.76 +/- 0.87), with vessels that displayed larger gaps between the endothelial cells. Thus, tumour cells can regulate both the function and structure of the host-derived tumour vasculature through NG2 expression, suggesting a role for NG2 in the cross-talk between tumour-host compartments.
    NeuroImage 03/2006; 29(3):965-76. · 6.25 Impact Factor
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    ABSTRACT: Conflicting results have been reported concerning the antitumor efficacy of the angiogenesis inhibitor endostatin. This may be due to differences in the biological distribution of endostatin between studies or to the varying biological efficacies of the different protein forms that were examined. To address this issue, the authors used a local delivery approach in which each tumor cell secreted endostatin, providing uniform endostatin levels throughout the tumors. This allowed a direct assessment of the biological efficacy of soluble endostatin in vivo. The authors genetically engineered BT4C gliosarcoma cells so that they would stably express and secrete either the human or murine form of endostatin. Endostatin-producing cells or mock-infected cells were implanted intracerebrally in syngeneic BD-IX rats. The antitumor efficacy of endostatin was evaluated on the basis of survival data and tumor volume comparisons. In addition, microvascular parameters were assessed. The authors confirmed the continuous release of endostatin by the BT4C cells. A magnetic resonance imaging-assisted comparison of tumor volumes revealed that local production of murine endostatin significantly inhibited tumor growth. Notably, 40% of the animals in this treatment group experienced long-term survival without histologically verifiable tumors 7 months after cell implantation. After local treatment with murine endostatin, tumor blood plasma volumes were reduced by 71%, microvessel density counts by 84%, and vascular area fractions by 75%. In contrast, human endostatin did not inhibit tumor growth significantly in this model. Centrally located regions of necrosis were present in tumors secreting both the human and the murine species-specific form of endostatin. The results suggest that endostatin inhibits tumor angiogenesis in vivo in a species-specific manner.
    Journal of Neurosurgery 02/2006; 104(1):118-28. · 3.15 Impact Factor
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    ABSTRACT: To evaluate manganese (Mn2+)-enhanced MRI in a longitudinal study of normal and injured rat visual projections. MRI was performed 24 hours after unilateral intravitreal injection of MnCl2 (150 nmol) into adult Fischer rats that were divided into four groups: 1) controls (N = 5), 2) dose-response (N = 10, 0.2-200 nmol), 3) time-response with repeated MRI during 24-168 hours post injection (N = 4), and 4) optic nerve crush (ONC) immediately preceding the MnCl2 injection (N = 7). Control and ONC animals were reinjected with MnCl2 20 days after the first injection, and MRI was performed 24 hours later. In the control group, the optic projection was visualized from the retina to the superior colliculus, with indications of transsynaptic transport to the cortex. There was a semilogarithmic relationship between the Mn2+ dose and Mn2+ enhancement from 4 to 200 nmol, and the enhancement decayed gradually to 0 by 168 hours. No Mn2+-enhanced signal was detected distal to the ON crush site. In the control group, similar enhancement was obtained after the first and second MnCl2 injections, while in the ONC group the enhancement proximal to the crush site was reduced 20 days post lesion (20 dpl). Mn2+-enhanced MRI is a viable method for temporospatial visualization of normal and injured ON in the adult rat. The observed reduction in the Mn2+ signal proximal to the ONC is probably a result of retrograde damage to the retinal ganglion cells, and not of Mn2+ toxicity.
    Journal of Magnetic Resonance Imaging 11/2005; 22(4):492-500. · 2.57 Impact Factor
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    ABSTRACT: INTRODUCTION Brain stem encephalitis may arise during infection with the bacterium Listeria monocytogenes (LM) (1, 2). Early diagnosis is of vital importance in this life threatening condition. The aim of this study was to test the ability of sequential cerebral MRI (7T) to visualize early brain stem encephalitis in mice. METHODS Experimental brain stem encephalitis may be induced in mice after inoculation of LM into cranial nerves. 32 Female Hsd/ICR mice weighing 20-30g (Harlan, UK) underwent inoculation into the cut left facial nerve before cerebral MRI and parallel histological examination from day 4 of inoculation and onwards. The mice were monitored daily for neurological deficits and killed either at the occurrence of sub-clinical MRI lesions (see below) or brain stem deficits. Surgical anesthesia was applied during the inoculation procedure, MR imaging and sacrifice. National authorities approved the experiments. MRI was performed at 7T on a Bruker Biospec 70/20 AS with BGA-12 400mT/m gradients. A 72mm volume resonator was used for RF transmit and a dedicated mouse brain surface coil was used for receive only with active decoupling. The MRI protocol consisted of tri-axial and sagittal scout scans, axial T2-w, and axial or 3D T1-w started ~10 min after i.p. injection of Gadodiamide (0.2ml diluted 1:5 ≈ 0.7mmol/kg). Key parameters for MRI: 2D RARE (T2): TE-eff.=45ms, TR=6000ms, FOV=25x25mm, Matrix=256x256, Slice thickness=0.5mm (8 slices, interslice=0), NEX=8, Acq.time=26min. 3D FLASH (T1): TR/TE=15/2.9ms, Flip angle=20º, FOV=20x40x20, Matrix=128x256x128, NEX=4, Acq.time 33min. 2D MDEFT (T1): TR/TE/TI=15/5/1000ms, FOV=25x25mm, Matrix=256x256, Slice thickness=0.5mm (8 slices, interslice=0), NEX=8, Acq.time=33min. The MR images were visually inspected on the MRI console (PV3.0.2). The brain stems from all 32 mice were fixated after sacrifice and H/E stained serial histological sections prepared as previously described (3). 24 of the 32 mice underwent cerebral MR examination from day 4 after inoculation, while 8 did not; these 8 remained clinically healthy until the end of study. 4 scans were partial since the animals developed respiratory failure at anesthesia during MRI. RESULTS AND DISCUSSION 7-T MRI can visualize brain stem listeriosis, also at a sub-clinical stage: 10 of the 24 scanned mice exhibited definite radiological brain stem pathology and were killed for parallel histological examination. 5 of these 10 had developed clinical brain stem deficits while 5 were clinically healthy. In animals with brain stem deficits radiological pathology was massive (Fig 1), while it was less extensive in symptom-free mice (sub-clinical brain stem encephalitis) (Figure 2). MRI pathology was absent in the remaining 14 scanned mice. T2-weighted imaging (data not shown) was less sensitive in detecting the pathology compared with T1-weighted post contrast imaging (Figure 1). Radiological pathology in mice with brain stem deficits: In the clinical stage, MRI revealed edema and contrast enhancement mainly on the side of inoculation in the pons. The contralateral side was also, but less affected (Figure 1A). Histological examination revealed sub-acute inflammation in the corresponding area and necrotizing inflammation in the nucleus of the inoculated facial nerve (Figure 1B). Radiological pathology in mice without brain stem deficits: Radiologically visible pathology, contrast enhancement on MRI (Figure 2A-D) and acute inflammation at neuropathological examination (not shown) were present as early as on day 4 after inoculation (in some mice as early as three days before onset of clinical brain stem deficits). Early lesions were selectively located along the intracerebral pathway of the facial nerve (Figures 2A-D).