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Contains fulltext : 57305.pdf (Publisher’s version ) (Closed access) Localized in vivo 1H magnetic resonance spectroscopy (MRS) was used to investigate metabolite levels in the brain of adult Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes mellitus. This study focussed on the hippocampus, assumed to be one of the main brain areas affected by this disease. Together with an almost 5-fold increase in blood glucose concentration measured by glucose oxidation, significant increases were found in the hippocampal concentrations of glucose (4.93 vs 1.66 mM p < 0.001), myo-inositol (6.52 vs 4.30 mM; p < 0.05), and total creatine (12.71 vs 10.50 mM; p < 0.05) in ZDF rats (n = 5) compared with littermates (n = 5). Although no obvious alterations were detected in the hippocampal levels of other metabolites, including NAA + NAAG and choline-containing compounds in the ZDF rats, the increase in Glc and Ins levels is in line with elevated brain tissue contents of these metabolites in patients with diabetes mellitus.

We have previously shown that the dense vascular network in mouse brain allows for growth of human melanoma xenografts (Mel57) by co-option of preexisting vessels. Overexpression of recombinant vascular endothelial growth factor-A (VEGF-A) by such xenografts induced functional and morphologic alterations of preexisting vessels. We now describe the effects of VEGF-A expression on visualization of these brain tumors in mice by magnetic resonance imaging (MRI), using gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA) and ultra small paramagnetic iron oxide particles (USPIO) as contrast agents. Brain lesions derived from (mock-transfected) Mel57 cells were undetectable in MRI after Gd-DTPA injection. However, the majority of such lesions became visible after injection of USPIO, due to the lower vascular density in the lesions as compared to the surrounding parenchyma. In contrast, VEGF-A-expressing lesions were visualized using Gd-DTPA-enhanced MRI by a rapid circumferential enhancement, due to leaky peritumoral vasculature. USPIO-enhanced MRI of these tumors corroborated the immunohistochemic finding that peritumorally located, highly irregular and dilated vessels were present, while intratumoral vessel density was low. Our study shows that VEGF-A is a key factor in imaging of brain neoplasms. Our data also demonstrate that, at least in brain, blood-pool agent-enhanced MRI may be a valuable diagnostic tool to detect malignancies that are not visible on Gd-DTPA-enhanced MRI. Furthermore, the involvement of VEGF-A in MRI visibility suggests that care must be taken with MRI-based evaluation of antiangiogenic therapy, as anti-VEGF treatment might revert a tumor to a co-opting phenotype, resulting in loss of contrast enhancement in MRI.

Molecular imaging is likely to have a significant impact onhealthcare through the early detection of disease on a cellularand molecular level. Among the clinical imaging modalities,magnetic resonance imaging (MRI) offers a unique combi-nation of advantages including the recording of anatomicaland contrast-enhanced images with a high spatial resolution,while avoiding the use of ionizing radiation. The use of MRIfor imaging sparse molecular epitopes present on diseasedcells is hampered by its low sensitivity, which can potentiallybe overcome with new contrast-amplifying nanocarriers.

Fluorine MRI ((19) F MRI) is receiving an increasing attention as a viable alternative to proton-based MRI ((1) H MRI) for dedicated application in molecular imaging. The (19) F nucleus has a high gyromagnetic ratio, a 100% natural abundance and is furthermore hardly present in human tissues allowing for hot spot MR imaging. The applicability of (19) F MRI as a molecular and cellular imaging technique has been exploited, ranging from cell tracking to detection and imaging of tumors in preclinical studies. In addition to applications, developing new contrast materials with improved relaxation properties has also been a core research topic in the field, since the inherently low longitudinal relaxation rates of perfluorocarbon compounds result in relatively low imaging efficiency. Borrowed from (1) H MRI, the incorporation of lanthanides, specifically Gd(III) complexes, as signal modulating ingredients in the nanoparticle formulation has emerged as a promising approach to improvement of the fluorine signal. Three different perfluorocarbon emulsions were investigated at five different magnetic field strengths. Perfluoro-15-crown-5-ether was used as the core material and Gd(III)DOTA-DSPE, Gd(III)DOTA-C6-DSPE and Gd(III)DTPA-BSA as the relaxation altering components. While Gd(III)DOTA-DSPE and Gd(III)DOTA-C6-DSPE were favorable constructs for (1) H NMR, Gd(III)DTPA-BSA showed the strongest increase in (19F) R(1). These results show the potential of the use of paramagnetic lipids to increase (19F) R(1) at clinical field strengths (1.5-3 T). At higher field strengths (6.3-14 T), gadolinium does not lead to an increase in (19F) R(1) compared with emulsions without gadolinium, but leads to an significant increase in (19F) R(2). Our data therefore suggest that the most favorable situation for fluorine measurements is at high magnetic fields without the inclusion of gadolinium constructs.

Objectives: To validate near-infrared (NIR)-based optical spectroscopy measurements of hepatic fat content using a minimally invasive needle-like probe with integrated optical fibers, enabling real-time feedback during percutaneous interventions. The results were compared with magnetic resonance spectroscopy (MRS) as validation and with histopathology, being the clinical gold standard. Additionally, ex vivo magic angle spinning nuclear magnetic resonance spectroscopy and high-performance thin-layer chromatography were performed for comparison. Materials and Methods: Ten mice were used for the study, of which half received a regular chow diet and the other half received a high-fat diet to induce obesity and hepatosteatosis. The mice were imaged with a clinical 3-Tesla MR to select a region of interest within the right and left lobes of the liver, where MRS measurements were acquired in vivo. Subsequently, optical spectra were measured ex vivo at the surface of the liver at 6 different positions immediately after resection. Additionally, hepatic fat was determined by magic angle spinning nuclear magnetic resonance spectroscopy and high-performance thin-layer chromatography. Histopathologic analyses were performed and used as the reference standard. Pearson correlation and linear regression analyses were performed to assess the correlation of the various techniques with NIR. A 1-way analysis of variance including post hoc Tukey multiple comparison tests was used to study the difference in fat estimation between the various techniques. Results: For both the mice groups, the estimated fat fractions by the various techniques were significantly similar (P = 0.072 and 0.627 for chow diet and high-fat diet group, respectively). The Pearson correlation value between NIR and the other techniques for fat determination showed the same strong linear correlation (P above 0.990; P < 0.001), whereas for histopathologic analyses, which is a rather qualitative measure, the Pearson correlation value was slightly lower (P = 0.925, P < 0.001) . Linear regression coefficient computed to compare NIR with the other techniques resulted in values close to unity with MRS having the narrowest confidence interval (r = 0.935, 95% confidence interval: 0.860-1.009), demonstrating highly correlating results between NIR and MRS. Conclusions: NIR spectroscopy measurements from a needle-like probe with integrated optical fibers for sensing at the tip of the needle can quickly and accurately determine hepatic fat content during an interventional procedure and might therefore be a promising novel diagnosing tool in the clinic. © 2012 by Lippincott Williams & Wilkins.

The solid state and solution structure of a series of lanthanide complexes of the decadentate ligand triethylenetetramine-N,N,N',N'',N''',N'''-hexaacetamide, (ttham), its two decadentate derivatives di-tert-butyl N,N,N''',N'''-tetra(carbamoylmethyl)-triethylenetetramine-N',N''-diacetate (Bu(2)ttha-tm) and N,N,N''',N'''-tetra(carbamoylmethyl)-triethylenetetramine-N',N''-diacetic acid (H(2)ttha-tm), and its two nonadentate derivatives N-benzyl-triethylenetetramine-N,N',N'',N''',N'''-pentaacetamide (1bttpam) and N'-benzyl-triethylenetetramine-N,N,N'',N''',N'''-pentaacetamide (4bttpam) have been investigated by infrared and Raman spectroscopy, X-ray crystallography, cyclovoltammetry, and NMR spectroscopy. In these mononuclear lanthanide complexes, the first coordination sphere is generally saturated by four amine nitrogens of the triethylenetetramine ligand backbone and five or six carbonyl oxygen atoms of the pendent amide or acetate donor groups. In the [Ln(ttham)](3+) complex series, a switch from a decadentate to a nonadentate coordination occurs between [Er(ttham)](3+) and [Tm(ttham)](3+). This switch in coordination mode, which is caused by decreasing metal ion radii going from lanthanum to lutetium (lanthanide contraction), has no significant effect on the T(1)-relaxivity of these complexes. It is shown that the T(1)-relaxivity is dominated by second coordination sphere interactions, with an ascendant contribution of the classical dipolar relaxation mechanism for the earlier (Ce-Sm) and very late (Tm, Yb) lanthanides, and a prevailing Curie relaxation mechanism for most of the remaining paramagnetic lanthanide ions. In chemical exchange-dependent saturation transfer (CEST) (1)H NMR experiments, most of the above complexes exhibit multiple strong CEST peaks of the paramagnetically shifted amide protons spread over a100 ppm chemical shift range. The effective CEST effect of the studied thulium complexes strongly depends on temperature and pH. The pH at which the CEST effect maximizes (generally between pH 7 and 8) is determined by the overall charge of the complex. Depending on the used saturation frequency offset, the temperature-dependence varies between the extremes of strongly linearly dependent and fully independent in the case of [Tm(ttham)](3+). In combination with the strong pH-dependence of the CEST effect at the latter frequency offset, this complex is highly suitable for simultaneous temperature and pH mapping using magnetic resonance imaging.

The ligand triethylenetetramine-N,N,N',N'',N''',N'''-hexaacetamide (ttham) was synthesized with the aim of forming lanthanide complexes suitable as contrast agents for magnetic resonance imaging applications utilizing the chemical exchange-dependent saturation transfer (CEST) effect. It was designed to exclude water molecules from the first coordination sphere and provide a high number of CEST active amide protons per lanthanide ion. The ligand was characterized by its protonation behavior and its complexation properties with ytterbium ions in aqueous solution. The basicity of the ttham backbone amine protons decreases in the order N(central(1))N(terminal(1))N(terminal(2))N(central(2)), as deduced from NMR titration experiments and from a comparison of its protonation constants with those of two ttham derivatives, in which either a terminal (N-benzyl-triethylenetetramine-N,N',N'',N''',N'''-pentaacetamide, 1bttpam) or a central acetamide group (N'-benzyl-triethylenetetramine-N,N,N'',N''',N'''-pentaacetamide, 4bttpam) is substituted with a benzyl group. This protonation sequence results from the combined influence of inductive effects, the intramolecular hydrogen bonding network, and the Coulomb repulsion between protonated ammonium groups. The ytterbium complex of ttham, [Yb(ttham)]Cl(3), is coordinatively frustrated. Due to steric constraints, in addition to the four backbone nitrogen atoms, only three of the four symmetry-equivalent terminal acetamide donors can coordinate simultaneously to the ytterbium ion, and the dangling fourth one exchanges quickly with the other three. The ytterbium complexes of a total of five ligands (ttham, 1bttpam, 4bttpam, 2,2',2''-triaminotriethylaminehexaacetamide (ttaham), and diethylenetriamine-N,N,N',N'',N''-pentaacetamide (dtpam)) were studied with respect to their CEST properties. In solution, all of these complexes have a low symmetry. The presence of multiple magnetically different amide groups in each complex prevents the realization of very high CEST effects. These results nevertheless form an excellent basis for a further optimization of this class of ligands.

MRI contrast agents based on chemical exchange-dependent saturation transfer (CEST), such as Yb(III)DOTAM complexes, are highly suitable for pH mapping. In this paper, the synthesis of Yb(III)DOTAM-functionalized poly(propylene imine) dendrimers is described. The applicability of these dendritic PARACEST MRI agents for pH mapping has been evaluated on a 7 T NMR spectrometer and on a 3 T clinical MRI scanner. As expected, based on the different numbers of exchangeable amide protons, the lowest detectable concentration of the first and third generation dendritic PARACEST agents is by a respective factor of about 4 and 16 lower than that of a mononuclear reference complex. The pH dependence of the CEST effect observed for these compounds depends on the generation of the poly(propylene imine) dendrimer. Upon going to higher generations of the Yb(III)DOTAM-terminated dendrimer, a shift of the maximum CEST effect towards lower pH values was observed. This allows for a fine-tuning of the responsive pH region by varying the dendritic framework.

Contains fulltext : 57929.pdf (Publisher’s version ) (Open Access) The aim of this study was to further explore the use of magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and dual-energy X-ray absorptiometry (DEXA) to assess bone formation and blood circulation in a pedicled bone graft substitute. In 14 Wistar rats, initially 10 weeks old, heterogeneous demineralized femur bone matrix implants were wrapped in pedicled adductor thigh muscle flaps. One rat died after surgery. Subsequently, bone formation and maintenance of blood vessel functionality were evaluated in six rats 6 weeks postimplantation by means of in vivo MRI/MRA and postmortem histomorphometry. The other seven rats were left for 12 weeks, whereafter bone formation was evaluated by in vivo DEXA and postmortem histomorphometry. The results demonstrated that after 6 weeks bone formation was present in four of six animals, quantified as 42 (+/-35)% and 25 (+/-19)% by means of MRI and histomorphometry, respectively. MRA was able to show patency of the pedicles of these four rats only, which suggests that the lack of blood supply in the other two rats is the cause of the failure to form bone. In the 12-week group, histology showed increased bone formation without signs of osteolysis, which was quantified histomorphometrically to be as high as 48 (+/-15)%. DEXA failed to show bone formation. It is concluded that in vivo MRI proved to be a reliable method for monitoring ectopic bone formation in a rat model, whereas in vivo DEXA was unable to detect the implants. Furthermore, in vivo MRA proved to be a useful technique for studying the circulation of muscle flaps in this animal model.

Item does not contain fulltext In animal studies of tissue engineering of bone, histology remains the standard for assessing bone formation. As longitudinal studies with this method are feasible only at the cost of large numbers of animals, we looked for an alternative. Therefore, demineralized bone matrix (DBM) and inactivated demineralized bone matrix (iDBM) implants were subcutaneously implanted in a rat. At 1, 3, 5, and 7 weeks postimplantation soft X-ray and magnetic resonance imaging (MRI) were done to monitor bone formation in the implants. At 7 weeks, the animal was killed and the implants were retrieved for histology. Our results showed that in vivo MRI is well suited to assess bone formation larger than 0.5 mm in diameter and to monitor the complete three-dimensional shape of the newly formed bone noninvasively and longitudinally. The MRI results matched well with the histology results obtained at 7 weeks. In contrast, X-ray imaging appeared inappropriate to monitor the bone formation process in DBM.

A novel temperature-sensitive liposomal MRI contrast agent has been developed, which allows drug carrier localization using (1)H CEST with simultaneous quantification of the drug release using (19)F MR imaging in response to a local temperature increase.

Background Proton resonance frequency shift (PRFS) magnetic resonance (MR) thermometry exploits the local magnetic field changes induced by the temperature dependence of the electron screening constant of water protons. Any other local magnetic field changes will therefore translate into incorrect temperature readings and need to be considered accordingly. Here, we investigated the susceptibility changes induced by the inflow and presence of a paramagnetic MR contrast agent and their implications on PRFS thermometry. Methods Phantom measurements were performed to demonstrate the effect of sudden gadopentetate dimeglumine (Gd-DTPA) inflow on the phase shift measured using a PRFS thermometry sequence on a clinical 3 T magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) system. By proton nuclear magnetic resonance spectroscopy, the temperature dependence of the Gd-DTPA susceptibility was measured, as well as the effect of liposomal encapsulation and release on the bulk magnetic susceptibility of Gd-DTPA. In vivo studies were carried out to measure the temperature error induced in a rat hind leg muscle upon intravenous Gd-DTPA injection. Results The phantom study showed a significant phase shift inside the phantom of 0.6 ± 0.2 radians (mean ± standard deviation) upon Gd-DTPA injection (1.0 mM, clinically relevant amount). A Gd-DTPA-induced magnetic susceptibility shift of ΔχGd-DTPA = 0.109 ppm/mM was measured in a cylinder parallel to the main magnetic field at 37°C. The temperature dependence of the susceptibility shift showed dΔχGd-DTPA/dT = -0.00038 ± 0.00008 ppm/mM/°C. No additional susceptibility effect was measured upon Gd release from paramagnetic liposomes. In vivo, intravenous Gd-DTPA injection resulted in a perceived temperature change of 2.0°C ± 0.1°C at the center of the hind leg muscle. Conclusions The use of a paramagnetic MR contrast agent prior to MR-HIFU treatment may influence the accuracy of the PRFS MR thermometry. Depending on the treatment workflow, Gd-induced temperature errors ranging between -4°C and +3°C can be expected. Longer waiting time between contrast agent injection and treatment, as well as shortening the ablation duration by increasing the sonication power, will minimize the Gd influence. Compensation for the phase changes induced by the changing Gd presence is difficult as the magnetic field changes are arising nonlocally in the surroundings of the susceptibility change.