Gd-DTPA Enhancement Research Articles

Excretable, ultrasmall hexagonal NaGdF4:Yb50% nanoparticles for bimodal imaging and radiosensitization

BackgroundIn this study, we report on the synthesis, imaging, and radiosensitizing properties of ultrasmall β-NaGdF4:Yb50% nanoparticles as a multifunctional theranostic platform. The synthesized nanoparticles act as potent bimodal contrast agents with superior imaging properties compared to existing agents used for magnetic resonance imaging (MRI) and computed tomography (CT). Clonogenic assays demonstrated that these nanoparticles can act as effective radiosensitizers, provided that the nanoparticles are taken up intracellularly.ResultsOur ultrasmall β-NaGdF4:Yb50% nanoparticles demonstrate improvement in T1-weighted contrast over the standard clinical MR imaging agent Gd-DTPA and similar CT signal enhancement capabilities as commercial agent iohexol. A 2 Gy dose of X-ray induced ~ 20% decrease in colony survival when C6 rat glial cells were incubated with non-targeted nanoparticles (NaGdF4:Yb50%), whereas the same X-ray dose resulted in a ~ 60% decrease in colony survival with targeted nanoparticles conjugated to folic acid (NaGdF4:Yb50%-FA). Intravenous administration of nanoparticles resulted in clearance through urine and feces within a short duration, based on the ex vivo analysis of Gd3+ ions via ICP-MS.ConclusionThese biocompatible and in vivo clearable ultrasmall NaGdF4:Yb50% are promising candidates for further evaluation in image-guided radiotherapy applications.

Molecular imaging of myocardial infarction with Gadofluorine P – A combined magnetic resonance and mass spectrometry imaging approach

BackgroundMolecular MRI is becoming increasingly important for preclinical research. Validation of targeted gadolinium probes in tissue however has been cumbersome up to now. Novel methodology to assess gadolinium distribution in tissue after in vivo application is therefore needed. PurposeTo establish combined Magnetic Resonance Imaging (MRI) and Mass Spectrometry Imaging (MSI) for improved detection and quantification of Gadofluorine P deposition in scar formation and myocardial remodeling. Materials and methodsAnimal studies were performed according to institutionally approved protocols. Myocardial infarction was induced by permanent ligation of the left ascending artery (LAD) in C57BL/6J mice. MRI was performed at 7T at 1 week and 6 weeks after myocardial infarction. Gadofluorine P was used for dynamic T1 mapping of extracellular matrix synthesis during myocardial healing and compared to Gd-DTPA. After in vivo imaging contrast agent concentration as well as distribution in tissue were validated and quantified by spatially resolved Matrix-Assisted Laser Desorption Ionization (MALDI) MSI and Laser Ablation – Inductively Coupled Plasma – Mass Spectrometry (LA-ICP-MS) imaging. ResultsBoth Gadofluorine P enhancement as well as local tissue content in the myocardial scar were highest at 15 minutes post injection. R1 values increased from 1 to 6 weeks after MI (1.62 s−1 vs 2.68 s−1, p = 0.059) paralleled by an increase in Gadofluorine P concentration in the infarct from 0.019 mM at 1 week to 0.028 mM at 6 weeks (p = 0.048), whereas Gd-DTPA enhancement showed no differences (3.95 s−1 vs 3.47 s−1, p = 0.701). MALDI-MSI results were corroborated by elemental LA-ICP-MS of Gadolinium in healthy and infarcted myocardium. Histology confirmed increased extracellular matrix synthesis at 6 weeks compared to 1 week. ConclusionAdding quantitative MSI to MR imaging enables a quantitative validation of Gadofluorine P distribution in the heart after MI for molecular imaging.

Gadolinium DTPA Enhancement Characteristics of the Rat Sciatic Nerve after Crush Injury at 4.7T.

Traumatic peripheral nerve injury is common and results in loss of function and/or neuropathic pain. MR neurography is a well-established technique for evaluating peripheral nerve anatomy and pathology. However, the Gd-DTPA enhancement characteristics of acutely injured peripheral nerves have not been fully examined. This study was performed to determine whether acutely crushed rat sciatic nerves demonstrate Gd-DTPA enhancement and, if so, to evaluate whether enhancement is affected by crush severity. In 26 rats, the sciatic nerve was crushed with either surgical forceps (6- to 20-N compressive force) or a microvascular/microaneurysm clip (0.1-0.6 N). Animals were longitudinally imaged at 4.7T for up to 30 days after injury. T1WI, T2WI, and T1WI with Gd-DTPA were performed. Forceps crush injury caused robust enhancement between days 3 and 21, while clip crush injury resulted in minimal-to-no enhancement. Enhancement after forceps injury peaked at 7 days and was seen a few millimeters proximal to, in the region of, and several centimeters distal to the site of crush injury. Enhancement after forceps injury was statistically significant compared with clip injury between days 3 and 7 (P < .04). Gd-DTPA enhancement of peripheral nerves may only occur above a certain crush-severity threshold. This phenomenon may explain the intermittent observation of Gd-DTPA enhancement of peripheral nerves after traumatic injury. The observation of enhancement may be useful in judging the severity of injury after nerve trauma.

Abstract 3271: Novel orthotopic pediatric high grade glioma xenografts evaluated with magnetic resonance imaging mimic human disease

Abstract Pediatric high grade gliomas (pHGG) may arise supratentorially in the cerebral hemispheres, or in midline structures such as the thalamus or the pons (diffuse intrinsic pontine glioma, DIPG). Tumors have distinct underlying biology compared with adult disease, with genetic subtypes corresponding to anatomical location. Differential mutations in genes encoding histone H3.3/H3.1 variants occur in supratentorial and midline tumors, while mutations in the gene encoding the BMP type I receptor ACVR1 are restricted to the pons and occur in a quarter of DIPGs. Co-option of existing brain vasculature in areas of infiltrative tumor growth leaves the blood brain barrier (BBB) intact. It is imperative to accurately model these tumors in vivo for the evaluation of emerging targeted therapeutics. Assessment of such models in situ is vital and requires sensitive functional imaging. T2-weighted (T2-w) MRI of orthotopically implanted PBT7 cells (supratentorial glioblastoma (GBM), 9yr old, H3F3A wt) showed heterogeneous tumors with relatively well defined borders. Hypointensity on T2-w and fluid-attenuated inversion recovery (FLAIR) images suggests the presence of necrosis and edema. Minimal heterogenous enhancement following Gd-DTPA administration demonstrated some loss of BBB integrity. FLAIR hyperintensity is used clinically to identify infiltrative tumor. Serially xenografted D-212 MG cells (supratentorial giant-cell GBM, 11yr old, H3F3A wt) formed tumors with FLAIR hyperintensity principally at the rim and Gd-DTPA enhancement prevalent at the tumor core. Histopathological assessment of H&amp;E staining confirmed the presence of masses with focal invasion at the periphery. Tumors established following pontine injection of HSJD-DIPG-007 cells (6yr old, H3F3A K27M, ACVR1 R206H) were identifiable by T2-w MRI hyperintensity in the pons and cerebellum. Histology confirmed a highly infiltrative tumor throughout the pons, cerebellum and leptomeninges, including the fissures of the cerebellum, which was validated by human nuclear antigen immunohistochemical staining. No extravasation of Gd-DTPA was observed indicating that the BBB remained intact. SU-DIPG-VI cells (6yr old, H3F3A K27M) grew diffusely in the pons with evidence of edema detected by T2-w MRI hyperintensity and FLAIR hypointensity. Diffusely hyperintense T2-w lesions with indistinct boundaries and limited Gd-DTPA extravasation were observed when imaging the diffusely infiltrative tumors resulting from thalamic implantation of QCTB-R059 primary thalamic GBM cells (10yr old, H3F3A K27M). In vivo propagation of primary and serially xenografted pHGG cells results in tumors that possess features of clinical disease, including infiltrative growth and necrosis. There is substantial potential for the use of these models to evaluate preclinical efficacy of novel therapeutics in a range of anatomical and biological subgroups of GBM and DIPG. Citation Format: Jessica K.R. Boult, Kathryn R. Taylor, Maria Vinci, Sergey Popov, Alexa Jury, Valeria Molinari, Marta M. Alonso, Wendy Ingram, Angel M. Caraboso, Michelle Monje, Suzanne A. Eccles, Chris Jones, Simon P. Robinson. Novel orthotopic pediatric high grade glioma xenografts evaluated with magnetic resonance imaging mimic human disease. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3271. doi:10.1158/1538-7445.AM2015-3271

Surgery for Glioblastoma: Impact of the Combined Use of 5-Aminolevulinic Acid and Intraoperative MRI on Extent of Resection and Survival.

BackgroundThere is rising evidence that in glioblastoma(GBM) surgery an increase of extent of resection(EoR) leads to an increase of patient’s survival. Based on histopathological assessments tumor depiction of Gd-DTPA enhancement and 5-aminolevulinic-acid-fluorescence(5-ALA) might be synergistic for intraoperative resection control.ObjectiveTo assess impact of additional use of 5-ALA in intraoperative MRI(iMRI) assisted surgery of GBMs on extent of resection(EoR), progression free survival(PFS) and overall survival(OS).MethodsWe prospectively enrolled 33 patients with GBMs eligible for gross-total-resection(GTR) and performed a combined approach using 5-ALA and iMRI. As a control group, we performed a retrospective matched pair assessment, based on 144 patients with iMRI-assisted surgery. Matching criteria were, MGMT promotor methylation, recurrent surgery, eloquent location, tumor size and age. Only patients with an intended GTR and primary GBMs were included. We calculated Kaplan Mayer estimates to compare OS and PFS using the Log-Rank-Test. We used the T-test to compare volumetric results of EoR and the Chi-Square-Test to compare new permanent neurological deficits(nPND) and general complications between the two groups.ResultsMedian follow up was 31 months. No significant differences between both groups were found concerning the matching criteria. GTR was achieved significantly more often (p <0.010) using 5-ALA&iMRI (100%) compared to iMRI alone(82%). Mean EoR was significantly(p<0.004) higher in 5-ALA&iMRI-group(99.7%) than in iMRI-alone-group(97.4%) Rate of complications did not differ significantly between groups(21% iMRI-group,27%5-ALA&iMRI-group,p<0.518). nPND were found in 6% in both groups. Median PFS (6mo resp.;p<0.309) and median OS(iMRI:17mo;5-ALA&iMRI-group:18mo;p<0.708)) were not significantly different between both groups.ConclusionWe found a significant increase of EoR when combining 5-ALA&iMRI compared to use of iMRI alone. Maximizing EoR did not lead to an increase of complications or neurological deficits if used with neurophysiological monitoring in eloquent lesions. No final conclusion can be drawn whether a further increase of EoR benefits patient’s progression free survival and overall survival.

Comparison of USPIO-enhanced MRI and Gd-DTPA enhancement during the subacute stage of focal cerebral ischemia in rats

Being one class of magnetic resonance imaging (MRI) contrast agents, ultrasmall superparamagnetic particles of iron oxides (USPIO) bear the potential to study neuroinflammation following stroke, but there is still debate over whether the iron oxides particles may enter the brain tissue passively over a damaged blood-brain barrier (BBB). To compare the enhancement patterns of USPIO and gadopentate dimeglumine (Gd-DTPA) during the subacute stage of focal cerebral ischemia, to examine the relationship between USPIO enhancement and BBB disturbance, as well as with neuroinflammatory cell response. Multiple MR sequences were obtained on days 3 and 6 after transient middle cerebral artery occlusion induced in rats with and without the application of USPIO and Gd-DTPA. The enhancement patterns of the two contrast agents were compared and correlated to histology, including IgG for BBB permeability, Prussian Blue staining for iron particle detection, and CD68 immunohistochemistry staining to identify macrophage/microglia. Gd-DTPA enhancement depicted BBB breakdown being in line with IgG leakage. The USPIO enhanced images demonstrated both diffuse and focal signal alteration in ischemic lesions. The diffuse enhanced pattern had a similar spatial and temporal profile as with Gd-DTPA enhancement. In addition, focal enhanced signal loss was visible on T1-, T2-, and T2*-weighted images, with a peak tendency of MR signal loss, macrophage/microglia concentration and iron particle accumulation at a later phase of the study. After focal cerebral ischemia, Gd-DTPA-enhanced MRI showed a higher sensitivity in detecting BBB alterations than did USPIO enhancement. USPIO provided complementary information regarding inflammatory cell activity in neuroinflammatory to cerebral ischemia that had not been visualized using conventional Gd-DTPA. The assessment using multiple MR parameters may identify intracellular and extracellular USPIO in vivo.

Diagnostic value of combined versus individual MRI parameters in distinguishing adenomatous from non-adenomatous adrenal lesions in cancer patients

PurposeOur aim was to evaluate the diagnostic value of MRI using different parameters in differentiation of adenomas versus non-adenomas adrenal lesions. Materials and methodsForty-five patients with 48 adrenal masses (28 lipid rich adenomas, 3 lipid poor adenomas, 15 metastases and 2 lymphoma) were retrospectively evaluated with MRI. The mean diameter of adrenal mass, T2WI signal, signal drop on chemical shift imaging (CSI) and enhancement pattern were assessed separately and in various combinations. Accuracies, sensitivities, specificities, PPV, NPV and P values by Chi-square test were calculated for individual and combined parameters. ResultsSignal drop on CSI and enhancement pattern were the most statistically significant diagnostic discriminators of adenomatous and non-adenomatous lesions with accuracies, specificities and sensitivities of 93.8%, 90.3%, 100% and 91.7%, 93.5%, 88.2%, respectively (P-value <0.0001). The best performance of a combination of parameters was obtained after exclusion of the size, with an accuracy of 89.6% (P-value <0.0001). ConclusionThe most specific predictors for adrenal mass characterization were CSI signal drop and Gd-DTPA enhancement characteristics. Combining the MR parameters did not prove superior to those two individual parameters, however it yielded a valuable diagnostic protocol for distinguishing the adrenal masses, considering that size criterion should not be used as an individual discriminator.

Sunitinib–CLIO Conjugate: A VEGFR/PDGFR-Targeting Active MR Probe

This study was conducted to evaluate feasibility of sunitinib-CLIO conjugate as a vascular endothelial growth factor receptor/platelet-derived growth factor receptor (VEGFR/PDGFR)-specific magnetic resonance (MR) probe. VEGFR/PDGFR-targeting MR probe was synthesized by conjugating cross-linked iron-oxide (CLIO) with tyrosine-kinase inhibitor (sunitinib). In VEGFR/PDGFR-positive (U118MG) and VEGFR/PDGFR-negative (HT29) cells and tumor models, conjugate-driven ΔR 2 was estimated, while CLIO was used as control. Prussian-blue staining was performed for quantifying the amount of tumor-binding conjugates. ΔR 2 between sunitinib-CLIO-treated and non-treated cells was greater in U118MG (mean, 2.1/s) than in HT29 cells (1.0/s). In in vivo study, conjugate induced a greater ΔR 2 in U118MG (11.2/s) than HT29 tumors (5.9/s). Conjugate-induced R 2 changes were not correlated with degree of Gd-DTPA enhancement, demonstrating that tumor binding of sunitinib-CLIO was independent of enhanced permeability and retention effect. % area of Prussian-blue staining was greater in U118MG (8.5 %) than in HT29 (1.4 %). Sunitinib-CLIO conjugate can be used as an active MR probe for quantifying VEGFR/PDGFR.

Abstract 18847: Visualization of Inflammation and Characterization of Lesions in Viral Myocarditis Mouse Model by Combined 19F-MR Cell Tracking and 1H Cardiac MRI

Introduction Myocarditis is a challenging disease for diagnosis and treatment. Recently, we have established a non-invasive cellular 19F-MR method to visualize inflammation of myocarditis in mice [1]. In this study, we correlated detection of inflammation by 19F-MR and tissue characterization by 1H-MR in viral myocarditis mouse model. Methods Viral myocarditis was induced by infecting ABY mice (n=5 infected+3 control) with CVB3. 19F-perfluorocarbon emulsion (PFC) (150μl) was injected i.v. 13 days post-infection to label monocytes and macrophages in blood. The labeling efficiency was examined by FACS in blood samples. 19F/1H-images were acquired at a 7T MR. 19F-MRI was superimposed on 1H-Cine to localize inflammation in myocardium. Lesions were characterized by T2WI, T2*WI and Gd-DTPA enhancement. MR findings were examined by Histology and immunohistochemistry (IHC). Results Blood FACS and confocal microscopy on IHC revealed that the 19F-MR signal in myocardium was due to internalized PFC in macrophages. 19F-MR detected macrophage infiltrating myocarditis lesions. Edema and Gd enhancement could be found in some lesions. Interestingly, most patchy 19F signal co-localized with T2* hypo-intense signal in lesions, which has been reported in various mouse strains post CVB3 infection [2]. Necrosis, T cells, fibrosis, and mineral deposition were found in lesions by histology and IHC. Conclusion 19F-MRI unambiguously detected active recruitment of macrophages to myocarditis lesions. On T2*WI signal voids in lesions were closely related to 19F signal in location and volume, which indicates its association to inflammation. Caution should be taken to apply iron oxide particles to visualizing inflammation in viral myocarditis, while the significance and mechanism of this contrast, especially its existence in human, need further investigation. 1. Ye et al ISMRM proceeding 2012. 2. Helluy et al. ISMRM proceeding 2011. This work was supported partly by BMBF 01EZ0816.

In Vivo Characterization of Changing Blood-Tumor Barrier Permeability in a Mouse Model of Breast Cancer Metastasis

The current lack of efficacy for any chemo- or molecular therapeutic in the treatment of brain metastases is thought to be due, in part, to the heterogeneous permeability of the blood-brain-barrier (BBB). Little is known about how heterogeneous permeability develops, or how it varies among individual metastases. Understanding the BBB's role in metastasis will be crucial to the development of new, more effective therapies. In this article, we developed the first magnetic resonance imaging-based strategy to detect and measure the volumes of BBB permeable and nonpermeable metastases and studied the development of altered BBB permeability in metastases in vivo, over time in a mouse model of breast cancer metastasis to the brain. Animals bearing human experimental brain metastases of breast cancer (231-BR cells) were imaged, using 3-dimensional balanced steady-state free precession to visualize total metastases, and contrast-enhanced T1-weighted spin echo with gadopentetic acid (Gd-DTPA) to visualize which of these displayed contrast enhancement, as Gd-DTPA leakage is indicative of altered BBB permeability. Metastases detected 20 days after injection showed no Gd-DTPA enhancement. At day 25, 6.1% ± 6.3% (mean ± standard deviation) of metastases enhanced, and by day 30, 28.1% ± 14.2% enhanced (P < 0.05). Enhancing metastases (mid: 0.14 ± 0.18 mm, late: 0.24 ± 0.32 mm) had larger volumes than nonenhancing (mid: 0.04 ± 0.04 mm, late: 0.09 ± 0.09 mm, P < 0.05); however, there was no significant difference between the growth rates of the 2. A significant number of brain metastases were uniformly nonpermeable, which highlights the need for developing treatment strategies that can overcome the permeability of the BBB. The model developed herein can provide the basis for in vivo evaluation of both BBB permeable and nonpermeable metastases response to therapy.

Assessment of Gadolinium Leakage Into Traumatic Spinal Cord Lesion Using Magnet Resonance Imaging

Exploratory study in patients with acute spinal cord trauma using magnetic resonance imaging (MRI). The aim of this study was to assess the leakage of Gd-DTPA into traumatic lesions of the human spinal cord using MRI. While MRI of acute spinal cord trauma is a routine type of clinical investigation, the time course of Gd-DTPA enhancement in traumatic spinal cord injury is not known. In early stage after spinal cord injury (<24 hours) and at follow-up on day 4, 7, 14, 21, 28, and 84, the accumulation of Gd-DTPA within 30 minutes after bolus injection was investigated in sagittal and axial T2-weighted images and T1-weighted images. In 4 men aged between 23 and 55 years with severe paraparesis, the traumatic spinal cord lesion had a maximum of spatial extent after 7 days. Gd-enhancement was first detected on day 4 in T1-weighted images, was most pronounced between day 7 and 28 but absent on day 84. The Gd-enhancement progressively increased in intensity after intravenous injection between 5 and 10 minutes when a maximum was reached, which remained stable for up to 30 minutes. We used MRI to study the dynamics of post-traumatic Gd-DTPA leakage into the injured spinal cord. This appears as a promising approach for monitoring the local secondary lesion changes.

Clinical significance of intramedullary Gd-DTPA enhancement in cervical myelopathy

Prospective multicenter study. To clarify the significance of intramedullary Gd-DTPA enhancement in cervical myelopathy, the prevalence, morphologic features, clinical relevance and postoperative change were investigated. Four hospitals in Japan. A total of 683 patients with cervical myelopathy who underwent decompressive surgery were consecutively examined. T1, 2 and Gd-DTPA-enhanced MRI were taken before surgery. Fifty consecutive cases without intramedullary enhancement were allocated in the non-enhancement group. The following variables were investigated: prevalence of the enhancement, the morphologic feature, the relationship between the enhancement and T2 high-intensity areas, the change of the Japanese Orthopedic Association (JOA) score for cervical myelopathy and the change of the enhancement after surgery. Intramedullary enhancement was observed in 50 cases (7.3%). The enhancements were observed between the most severely compressed disc and the cranial half of the lower vertebral body. On axial images, they were observed at the posterior or posterolateral periphery of the spinal cord. Enhancement areas were observed within T2 high-intensity areas and smaller than them. The preoperative JOA score was 9.8+/-2.8 points in the enhancement group and 9.8+/-3.3 points in the non-enhancement group (NS). The postoperative JOA score was 12.7+/-2.9 points in the enhancement group and 14.2+/-2.4 in the non-enhancement group (P=0.006). Intramedullary enhancement disappeared in 60% of the patients 1 year after surgery. Intramedullary enhancement indicated not the severity of preoperative symptoms, but a sign of a worse prognosis.

The establishment of a multiple sclerosis model for clinical MRI study

Objective To establish a rat model of multiple sclerosis (MS) for clinical MRI study. Methods The Lewis (LEW) rats were immunized by myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) emulsified with complete Freunds adjuvant/incomplete Freunds adjuvant. Twenty LEW rats were selected. Group A rats were 5, group B rats were 10 and control group rats were 5. MRI and histopathology analysis were observed on group A and control group, and clinical course were observed on group B. The clinical course was observed and the brain and spinal cord of EAE rats were scanned on 3. 0 T MR system with quadrature wrist joint coil on the third day of the acute stage of disease. The T2/T1 weighted images and Gadolinium enhanced T1 weighted images in 3D volume were obtained respectively. The magnetization transfer ratio (MTR) images were calculated with special software in workstation. Rats were sacrificed within 24 h after MRI, and the histopathological changes of central nervous system were observed. Results Twice immunization of MOG35-55 was used and a rat model of MS was successfully induced with all the rats. The model had varied clinical symptoms. The lesions of central nervous system at acute stage on group A (5 rats) were depicted on MRI. The lesions located in the brain and the spinal cord with main manifestation of hyperintensity on T2 weighed images and hypointensity on T1 weighted images. Some lesions had Gd-DTPA enhancement, and the value of MTR decreased. The infiltration of mononuclear cells around blood vessels and the extensive distribution of lesions of demyelination in brain and spinal cord were verified by histological examination. Conclusions Twice immunization of MOG35-55 could produce a rat model which mimics MS.The model is stable with higher incidence, and the antigen is cheap and obtained easily. The intravital monitoring of brain and spinal cord lesions in MOG35-55 induced rat model is possible on 3.0 T clinical whole-body MR scanner with a quadrature wrist joint coil. MOG35-55 induced rat model is an ideal MS model for clinical MRI study. Key words: Multiple sclerosis; Models; animal; Rats; Magnetic resonance imaging

Near-infrared fluorescence imaging with fluorescently labeled albumin: A novel method for non-invasive optical imaging of blood–brain barrier impairment after focal cerebral ischemia in mice

Impairment of the blood–brain barrier (BBB) after cerebral ischemia leads to extravasation of plasma constituents into the brain parenchyma. We describe a novel method using non-invasive near-infrared fluorescence (NIRF) imaging and bovine serum albumin labeled with a NIRF dye (NIRF–BSA) to detect BBB impairment after middle cerebral artery occlusion (MCAO) in mice. We first explored the time course of BBB impairment after transient MCAO using Evans blue (EB), which binds to plasma albumin in vivo. An initial BBB impairment was observed at 4–8 h and a second impairment at 12–16 h after reperfusion. No EB extravasation was detected at 8–12 h. Non-invasive NIRF imaging with NIRF–BSA confirmed biphasic BBB impairment. Upon co-injection of NIRF–BSA with EB we found a strong correlation between the detected NIRF signal and the amount of extravasated EB ( r = 0.857, P = 0.00178). When MCAO mice received NIRF–BSA together with gadolinium–diethylene triamine penta-acetic acid (Gd–DTPA), T1-weighted images showed Gd–DTPA enhancement at all times while NIRF imaging showed biphasic BBB impairment. In conclusion, NIRF–BSA is a suitable marker of plasma albumin extravasation in the mouse brain. Non-invasive NIRF imaging with NIRF–BSA is a useful tool to study BBB integrity in preclinical models of central nervous system pathology.

Gd-DTPA enhancement of cranial nerves on MR imaging. Neoplastic lesions.

This study describes a radiological finding - enhancement of cranial nerves and correlates patients' clinical findings and outcome. Seven patients with enhancement of cranial nerves on postcontrast MR were retrospectively reviewed. Cranial nerves having contrast enhancement were optic, oculomotor, trigeminal, facial, acoustic, glossopharyngeal, vagus and accessory nerves. The patients' underlying diseases were malignant lymphoma (3), leukemia (1 patient) and metastatic tumor (2 lung, 1 rectum cancer). Most of the cases (4 out of 7) developed parenchymatous lesion later. Seven patients had CSF cytology study, positive in 3 cases, negative in 4 cases at first spinal tap. In 1 case (case 5) of negative cytology, elevated CEA (carcinogen antibody) was noted. In 2 cases, initial symptoms were sudden hearing loss. Autopsy was done for 1 case of metastatic tumor involving cranial nerves. Contrast MR is a useful examination for depicting cranial nerve involvement with neoplastic change.

91. Clinical Significance of Intramedullary Gd-DTPA Enhancement in Cervical Myelopathy

91. Clinical Significance of Intramedullary Gd-DTPA Enhancement in Cervical Myelopathy

Pulse Repetition Time and Contrast Enhancement

To investigate theoretically enhancement and optimal pulse repetition times for Gd-BOPTA and Gd-DTPA enhanced brain imaging at 0.23, 1.5, and 3.0 T. The theoretical relaxation times of unenhanced, conventional contrast agent (Gd-DTPA) and new generation contrast agent (Gd-BOPTA) enhanced glioma were calculated. Then, simulation of the signals and contrasts as a function of concentration and pulse repetition time (TR) in spin echo sequence was done at 0.23, 1.5, and 3.0 T. The effect of echo time (TE) on tumor-white matter contrast was also clarified. Three patient cases were imaged at 0.23 T as a test of principle. Gd-BOPTA may give substantially better glioma-to-white matter contrast than Gd-DTPA but is more sensitive to the length of TR. These characteristics are accentuated at 0.23 T. Optimal TR lengths are shorter for Gd-BOPTA than for Gd-DTPA enhanced imaging at all field strengths. TR optimized for Gd-DTPA may thus give suboptimal contrast in Gd-BOPTA enhanced imaging. Higher enhancement with Gd-BOPTA is further accentuated by short TE. Appropriate TRs at 0.23 T appear to be approximately 300 to 400 milliseconds and 250 to 300 milliseconds, at 1.5 T 500 to 600 milliseconds and 400 to 450 milliseconds and at 3.0 T 550 to 650 milliseconds and 475 to 525 milliseconds using Gd-DTPA and Gd-BOPTA, respectively. For Gd-BOPTA enhanced imaging, it seems justified to optimize TR according to contrast and seek options like parallel excitation (Hadamard encoding) for increasing the number of slices and SNR.

Early MRI changes in a mouse model of multiple sclerosis are predictive of severe inflammatory tissue damage

MRI is routinely used for in vivo detection of multiple sclerosis (MS) lesions. Histopathological correlates of MRI signal alterations are still poorly defined. In the present study, we describe a mouse model of MS presenting with inflammatory brain lesions. During the acute disease phase, two independent lesion patterns were identified by T1- and T2-weighted high-resolution 3D MRI: lesions with reduced signal intensity on both T1- and T2-weighted images (type A) and lesions with slightly reduced signal intensity on T1-weighted images and increased signal intensity on T2-weighted images (type B). Type A lesions were characterized by significantly denser inflammatory cell infiltrates and more myelin loss than type B lesions. Lesion cellularity, myelin loss and immunoglobulin deposition correlated with MRI signal intensities in both lesion types. Gd-DTPA enhancement correlated with Ig deposition and spacially matched to areas with abundant activated microglia cells at the lesion border. Using serial MRI, type A lesions revealed a persistent hypointense pattern reflecting axon and myelin loss. Signal intensity increases on T2-weighted images of type B lesions decreased during lesion evolution, and no significant T1 signal alterations developed. Taken together, MRI of mouse EAE models with brain lesions provide new insights into lesion pathology and evolution and may prove useful for the in vivo assessment of new therapeutic strategies in MS.

Detection of toxoplasmic lesions in mouse brain by USPIO-enhanced magnetic resonance imaging

The objective of this study was to examine the feasibility of detecting toxoplasmic brain lesions in a mouse model of cerebral toxoplasmosis by ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI). Toxoplasmosis encephalitis was induced in Kunming mice by intracerebral injection of Toxoplasma gondii tachyzoites. T2- and T2*--weighted MRI was performed 1, 3, 4, 5 and 6 days after infection before USPIO injection; immediately after USPIO injection; and 24 h later. A comparison of USPIO enhancement and Gd-DTPA enhancement was made in three toxoplasmic mice 4 days after infection. Hematoxylin and eosin staining and Prussian blue staining were performed to detect inflammatory reactions and presence of iron in and around the toxoplasmic brain lesions. Nonenhanced T2-/T2*-weighted imaging detected few abnormalities in the brain up to 5 days. Most mice developed prominent hydrocephalus at 6 days. Gd-DTPA-enhanced imaging showed prominent enhancement of the cerebral ventricles but revealed only few space-occupying lesions in the parenchyma. USPIO-enhanced T2*-weighted imaging showed improved detection of toxoplasmic brain lesions that were invisible to nonenhanced T2-/T2*-weighted imaging and gadolinium-enhanced imaging. Most of the enhancing lesions showed nodular enhancement immediately after USPIO injection, some of which changed appearance 24 h later, having a ring enhancement at the outer rim. It can be concluded that USPIO enhancement of the toxoplasmic lesions may reflect blood-brain barrier impairment and/or inflammatory reactions associated with these lesions. USPIO-enhanced imaging may be used in combination with gadolinium-enhanced imaging to provide better characterization of toxoplasmic brain lesions and, potentially, improve the differential diagnosis of toxoplasmosis encephalitis.

Intramedullary spinal cord germinoma—2 case reports

Background Primary intramedullary spinal cord germinoma is very rare. We encountered 2 patients with primary intramedullary spinal cord germinoma. We describe herein our comprehensive management system for CNS germinoma, including intramedullary spinal cord germinoma, along with a review of the literature. This is the first report to describe successful application of ICE chemotherapy for intramedullary germinoma. Case Descriptions A 16-year-old adolescent girl (case 1) experienced lumbago and subsequently noticed gait disturbance that aggravated gradually. On admission, paraparesis and urinary retention were noted. Magnetic resonance imaging demonstrated marked cord swelling between T9 and T12, with slight enhancement in the spinal cord. Astrocytic tumor was initially suspected, and partial removal was performed. However, pathologic examination identified germinoma. Successful treatment with ICE chemotherapy and radiotherapy was implemented, with no evidence of recurrence apparent at 48 months postoperatively. A 34-year-old woman (case 2) presented with paraparesis and sensory disturbance. Magnetic resonance imaging demonstrated cord swelling between T8 and T10, with slight Gd-DTPA enhancement. Because the lesion did not respond to steroid pulse therapy, spinal cord tumor was suspected and biopsy was performed. Pathologic examination verified primary germinoma of the spine. Successful treatment with ICE chemotherapy and radiotherapy was implemented with no exacerbation of neurologic deficits. No evidence of recurrence was apparent at 36 months postoperatively. Conclusion Correct diagnosis of very rare primary intramedullary spinal cord germinoma is important, because these patients can be treated successfully using chemo- and radiotherapy without neurologic deterioration.