Glucose exchange parameters in a subset of physiological conditions.

The chemical exchange of labile protons of the hydroxyl groups can be exploited in a variety of magnetic resonance experiments to gain information about the groups and their physicochemical environment. The exchangeable -OH protons provide important contributions to the T2 of water signals thus contributing to the T2-weighted contrast of MRI images. This exchange can be exploited more specifically and sensitively in chemical exchange saturation transfer (CEST) or longitudinal rotating frame relaxation (T1,ρ) experiments. Since glucose is omnipresent in living organisms, it may be seen as a rather universal probe. Even though the potential was first recognized many years ago, practical use has remained scarce due to numerous challenges. The major limitation is the rather low glucose concentration in most tissues. The other obstacles are related to multiple dependencies of the exchange parameters, such as temperature, pH, and concentration of various ions that are not known in sufficient detail for glucose. Thus, we embarked on evaluating the exchange parameters of a model that included every relevant chemical site for all -OH protons in both dominant enantiomers of glucose. We have (1) obtained conventional one-dimensional proton NMR spectra of glucose solutions in suitable temperature ranges, (2) we have iterated through several exchange models with various degrees of freedom determined by the number of distinguishable -OH proton sites and compared their performance, (3) we extrapolated the parameters of the best model of physiological temperature and (4) we demonstrated the use of the parameters in virtual experiments. As the main results, (1) we have obtained the temperature dependence of exchange parameters with reliable confidence intervals in three different pH values, with two of them reaching physiological temperature, and (2) we show how the parameters can be used in virtual experiments, helping to develop new applications for glucose as an NMR/MRI probe.

Quantitative Three-Dimensional Assessment of the Pharmacokinetic Parameters of Intra- and Peri-tumoural Tissues on Breast Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

We aimed to assess the feasibility of three-dimensional (3D) segmentation and to investigate whether semi-quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters are associated with traditional prognostic factors for breast cancer. In addition, we evaluated whether both intra-tumoural and peri-tumoural DCE parameters can differentiate the breast cancers that are more aggressive from those that are less aggressive. Consecutive patients with newly diagnosed invasive breast cancer and structural breast MRI (3.0 T) were included after informed consent. Fifty-six patients (mean age, 57 years) with mass lesions of > 7 mm in diameter were included. A semi-automatic image post-processing algorithm was developed to measure 3D pharmacokinetic information from the DCE-MRI images. The kinetic parameters were extracted from time-signal curves, and the absolute tissue contrast agent concentrations were calculated with a reference tissue model. Markedly, higher intra-tumoural and peri-tumoural tissue concentrations of contrast agent were found in high-grade tumours (n = 44) compared to low-grade tumours (n = 12) at every time point (P = 0.006-0.040), providing positive predictive values of 90.6-92.6% in the classification of high-grade tumours. The intra-tumoural and peri-tumoural signal enhancement ratios correlated with tumour grade, size, and Ki67 activity. The intra-observer reproducibility was excellent. We developed a model to measure the 3D intensity data of breast cancers. Low- and high-grade tumours differed in their intra-tumoural and peri-tumoural enhancement characteristics. We anticipate that pharmacokinetic parameters will be increasingly used as imaging biomarkers to model and predict tumour behavior, prognoses, and responses to treatment.

Adiabatic rotating frame relaxation of MRI reveals early cartilage degeneration in a rabbit model of anterior cruciate ligament transection.

OBJECTIVE: To investigate the sensitivity of seven quantitative magnetic resonance imaging (MRI) parameters (adiabatic T1ρ, adiabatic T2ρ, continuous wave (CW) T1ρ, relaxation along a fictitious field (RAFF), T2 measured with adiabatic double echo (DE) and Carr-Purcell-Meiboom-Gill (CPMG) sequence, and T1 during off-resonance saturation [magnetization transfer (MT)]) to detect early osteoarthritic changes in a rabbit model of anterior cruciate ligament transection (ACLT). METHODS: ACLT was unilaterally induced in the knees of New Zealand White rabbits (n = 8) while contralateral joints served as controls. Femoral condyles of the joints were harvested 4 weeks post-ACLT. MRI was performed at 9.4 T. For reference, quantitative histology, Mankin grading and biomechanical measurements were conducted. RESULTS: Reference methods demonstrated early, superficial cartilage degeneration in the ACLT group, including significant loss of proteoglycans in both medial and lateral compartments, increased collagen fibril anisotropy in the lateral condyle and decreased biomechanical properties at both medial and lateral compartments. CW-T1ρ was prolonged in the lateral compartment of ACLT joints while adiabatic T1ρ and T2ρ detected degenerative changes in tissue in both lateral and medial condyles (P < 0.05). DE-T2 was significantly (P < 0.05) elevated only in the lateral compartment while CPMG-T2, MT or RAFF did not show a statistically significant difference between the groups. CONCLUSIONS: Adiabatic T1ρ and T2ρ relaxation times detected most sensitively early degenerative changes in cartilage 4 weeks post-ACLT in a rabbit model.

T1rho and T2rho MRI in the evaluation of Parkinson's disease.

Prior work has shown that adiabatic T(1rho) and T(2rho) relaxation time constants may have sensitivity to cellular changes and the presence of iron, respectively, in Parkinson's disease (PD). Further understanding of these magnetic resonance imaging (MRI) methods and how they relate to measures of disease severity and progression in PD is needed. Using T(1rho) and T(2rho) on a 4T MRI scanner, we assessed the substantia nigra (SN) of nine non-demented moderately affected PD and ten gender- and age-matched control participants. When compared to controls, the SN of PD subjects had increased T(1rho) and reduced T(2rho). We also found a significant correlation between asymmetric motor features and asymmetry based on T(1rho). This study provides additional validation of T(1rho) and T(2rho) as a means to separate PD from control subjects, and T(1rho) may be a useful marker of asymmetry in PD.

SPECT/CT imaging of baculovirus biodistribution in rat.

Non-invasive imaging provides essential information regarding the biodistribution of gene therapy vectors and it can also be used for the development of targeted vectors. In this study, we have utilized micro Single-photon emission computed tomography to visualize biodistribution of a (99m)Tc-polylys-ser-DTPA-biotin-labelled avidin-displaying baculovirus, Baavi, after intrafemoral (i.f.), intraperitoneal (i.p.), intramuscular (i.m.) and intracerebroventricular (i.c.v.) administration. The imaging results suggest that the virus can spread via the lymphatic network after different administration routes, also showing accumulation in the nasal area after systemic administration. Extensive expression in the kidneys and spleen was seen after i.p. administration, which was confirmed by reverse transcriptase-polymerase chain reaction and immunohistochemistry. Additionally, transduction of kidneys was seen with i.m. and i.f. administrations. We conclude that baculovirus may be beneficial for the treatment of kidney diseases after i.p. administration route.

Magnetic resonance imaging of viral particle biodistribution in vivo.

We describe here a technique for the visualization of viral vector delivery by magnetic resonance imaging (MRI) in vivo. By conjugating avidin-coated baculoviral vectors (Baavi) with biotinylated ultra-small superparamagnetic iron oxide particles (USPIO), we are able to produce vector-related MRI contrast in the choroid plexus cells of rat brain in vivo over a period of 14 days. Ten microlitres of 2.5 x 10(10) PFU/ml nuclear-targeted LacZ-encoding Baavi with bUSPIO coating was injected into rat brain ventricles and visualized by MRI at 4.7 T. As baculoviruses exhibit restricted cell-type specificity in the rat brain, altered MRI contrast was detected in the choroid plexus of the injected ventricles. No specific signal loss was detected when wild-type baculoviruses or intact biotinylated USPIO particles were injected into the lateral ventricles. Cryosectioned brains were stained for nuclear-targeted beta-galactosidase gene expression, which was found to colocalize with MRI contrast. This study provides the first proof of principle for robust and non-invasive viral vector MRI by using avidin-displaying viruses in vivo. Considering the widespread use of MRI in current medical imaging, the approach is likely to provide numerous future applications in imaging of therapeutic gene transfer.