Water Proton Longitudinal Relaxation Research Articles

Magnetic Resonance Imaging Correlates of Dichotic Listening Performance in Multiple Sclerosis

Multiple sclerosis (MS) pathology can cause disruptions in central auditory processing. Here, we applied quantitative magnetic resonance imaging (MRI) techniques to investigate the impact of global neurodegenerative processes on dichotic listening performance in MS. We studied 28 subjects with clinically definite MS and 26 healthy controls using 3T MRI and a dichotic digits task (DDT) performed in the scanner. Subjects with MS displayed increased white matter lesions, prolonged water proton longitudinal relaxation time constants in normal appearing white matter, reduced gray matter volumes, and reduced corpus callosum areas compared with controls. No group differences were found for any of the DDT performance measures. In subjects with MS, corpus callosum area was strongly correlated with DDT performance. This relationship remained present after controlling for other measures of neuropathology, suggesting that callosal atrophy directly impacts dichotic listening performance in MS.

1H-NMR analysis of water mobility in cultured phototrophic biofilms

The present work reports on the first attempt to study water mobility in phototrophic biofilms, applying the 1H-NMR relaxometry technique to closely monitored microbial communities grown in a microcosm under controlled ambient conditions. Longitudinal water proton relaxation times exhibited a bi-exponential behavior in all biofilm samples, indicating two types of water molecules with diverging dynamic properties, confined to different compartments of the biofilm. The fast-relaxing component can be attributed to water molecules tightly bound to the intracellular matrix, while the slow-relaxing component could reflect the behavior of water embedded in the biopolymer matrix, confined into matrix pores and channels. The results are discussed with respect to a possible key role of exopolysaccharides and uronic acids in water binding in phototrophic biofilms.

Water-Soluble MnO Nanocolloid for a Molecular T1 MR Imaging: A Facile One-Pot Synthesis, In vivo T1 MR Images, and Account for Relaxivities

A facile one-pot synthesis of a water-soluble MnO nanocolloid (i.e., D-glucuronic acid-coated MnO nanoparticle) is presented. The MnO nanoparticle in the MnO nanocolloid was coated with a biocompatible and hydrophilic D-glucuronic acid, and its particle diameter was nearly monodisperse and ranged from 2 to 3 nm. The average hydrodynamic diameter of the MnO nanocolloid was estimated to be 5 nm. The MnO nanoparticle was nearly paramagnetic down to T=3 K. The MnO nanocolloid showed a high longitudinal water proton relaxivity of r1=7.02 s(-1) mM(-1) with the r2/r1 ratio of 6.83 due to five unpaired S-state electrons of Mn(II) ion (S=5/2) as well as a high surface to volume ratio of the MnO nanoparticle. High contrast in vivo T1 MR images were obtained for various organs, showing the capability of the MnO nanocolloid as a sensitive T1 MRI contrast agent. The suggested three key-parameters which control the r1 and r2 relaxivities of nanocolloids (i.e., the S value of a metal ion, the spin structure, and the surface to volume ratio of a nanoparticle) successfully accounted for the observed r1 and r2 relaxivities of the MnO nanocolloid.

Design, Synthesis, and Evaluation of 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic Acid Derived, Redox-Sensitive Contrast Agents for Magnetic Resonance Imaging

The design and synthesis of three 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) derivatives bearing linkers with terminal thiol groups and a preliminary evaluation of their potential for use in assembling redox-sensitive magnetic resonance imaging contrast agents are reported. The linkers were selected on the basis of computational docking with a crystal structure of human serum albumin (HSA). Gd(III)-DO3A and Eu(III)-DO3A complexes were synthesized, and the structure of one complex was established by X-ray crystallographic analysis. The binding to HSA of a Gd(III)-DO3A complex bearing a thiol-terminated 3,6-dioxanonyl chain was competitively inhibited by homocysteine and by the corresponding Eu chelate. Binding to HSA was abolished when the terminal thiol group of this complex was absent. The longitudinal water-proton relaxivities (r(1)) of the three Gd(III)-DO3A complexes and of two Gd(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexes were measured in saline at 7 T. The DO3A complexes exhibited smaller r(1) values, in both bound and free states, than the DOTA complexes.

?Longitudinal Water Proton Relaxivities of Ultra Small 3d and 4f Transition Metal Oxide Nanoparticles

We report the longitudinal water proton relaxivities (r1) of several 3d and 3f transition metal oxide nanoparticles. These include ultrasmall iron oxide, manganese oxide, europium oxide, gadolinium oxide, and dysprosium oxide nanoparticles. The nanoparticles ranged from 1.0 to 3.0 nm in diameter. Ultrasmall metal oxide nanoparticles with metal ions of high and pure S-state electron magnetic moments showed high r1 relaxivities. The measured relaxivities indicate that ultrasmall gadolinium oxide nanoparticles with a high r1 relaxivity of 12.6 mM −1s−1 may be suitable for use as a sensitive T1 MRI contrast agent.

Assessment of Blood Hemodynamics by USPIO-Induced R 1 Changes in MRI of Murine Colon Carcinoma

The objective of this study is to assess whether ultrasmall superparamagnetic iron oxide (USPIO)-induced changes of the water proton longitudinal relaxation rate (R 1) provide a means to assess blood hemodynamics of tumors. Two types of murine colon tumors (C26a and C38) were investigated prior to and following administration of USPIO blood-pool contrast agent with fast R 1 measurements. In a subpopulation of mice, R 1 was measured following administration of hydralazine, a well-known blood hemodynamic modifier. USPIO-induced R 1 increase in C38 tumors (ΔR 1 = 0.072 ± 0.0081 s−1) was significantly larger than in C26a tumors (ΔR 1 = 0.032 ± 0.0018 s−1, N = 9, t test, P < 0.001). This was in agreement with the immunohistochemical data that showed higher values of relative vascular area (RVA) in C38 tumors than in C26a tumors (RVA = 0.059 ± 0.015 vs. 0.020 ± 0.011; P < 0.05). Following administration of hydralazine, a decrease in R 1 value was observed. This was consistent with the vasoconstriction induced by the steal effect mechanism. In conclusion, R 1 changes induced by USPIO are sensitive to tumor vascular morphology and to blood hemodynamics. Thus, R 1 measurements following USPIO administration can give novel insight into the effects of blood hemodynamic modifiers, non-invasively and with a high temporal resolution.

Nuclear Relaxometry Helps Designing Systems for Solution DNP on Proteins

The measurement of water proton longitudinal relaxation rates in aqueous solutions of paramagnetic compounds (radicals, paramagnetic metal ions) as a function of magnetic field (relaxometry) provides two important pieces of information for predicting the efficacy of dynamic nuclear polarization (DNP) to be ultimately achieved on protein nuclei: the correlation time for the electron–nuclear interaction and the actual water proton relaxation rate at any magnetic field of interest. Likewise, relaxometry measurements on protein protons themselves, which can be performed in D2O solutions, provide information on the polarization loss occurring on protein protons in DNP-shuttling experiments during the shuttling of the sample from the electron paramagnetic resonance to the nuclear magnetic resonance field. A collection of water proton and protein proton relaxometry profiles, recently obtained in the course of the DNP Design Study project, is here reported, and the relevant parameters are discussed.

Organophosphonate Functionalized Gd@C82 as a Magnetic Resonance Imaging Contrast Agent

A new magnetic resonance imaging contrast agent containing organophosphonate functional groups was synthesized in high yield by a simple synthesis procedure. This molecule exhibits much higher longitudinal water proton relaxivity (37.0 mM−1 s−1) than commercial Omniscan (Gd-DTPA BMA, 5.7 mM−1 s−1) at 0.35 T. Notably, the relaxivity is larger than that of carboxylated Gd@C82 (16.0 mM−1 s−1) under the same conditions, indicating that the functional groups have an important role on the image contrast enhancement. In addition, the introduction of phosphonate substituents may provide bone-targeting MRI contrast agents.

Determination of water permeability of paramagnetic liposomes of interest in MRI field

The water permeability of various liposome membranes has been determined at 298K by measuring the NMR longitudinal water proton relaxation rate of vesicles encapsulating the clinically approved Gd-HPDO3A complex (HPDO3A=10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid). Two basic formulations based on DPPC (dipalmitoylphosphatidylcholine) and POPC (palmitoyl-oleylphosphatidylcholine) phospholipids were selected and investigated. Furthermore, the permeability changes caused by the membrane incorporation of amphiphiles like cholesterol and/or metal complexes of interest for designing improved liposome-based MRI contrast agents, were also investigated. The incorporation of cholesterol and metal complexes bearing C18 saturated chains in POPC-based liposomes reduces the water diffusivity across the membrane bilayer. On the contrary, the incorporation of a macrocyclic metal complex bearing four C12 alkylic chains, one for each coordination arm of the ligand, considerably enhances the water permeability in DPPC-based liposomes. Finally, it is reported that the permeability of POPC-based bilayer is increased when the liposomes are subjected to an osmotic stress.

A benzene-core trinuclear GdIIIcomplex: towards the optimization of relaxivity for MRI contrast agent applications at high magnetic field

A novel ligand, H(12)L, based on a trimethylbenzene core bearing three methylenediethylenetriamine-N,N,N'',N''-tetraacetate moieties (-CH(2)DTTA(4-)) for Gd(3+) chelation has been synthesized, and its trinuclear Gd(3+) complex [Gd(3)L(H(2)O)(6)](3-) investigated with respect to MRI contrast agent applications. A multiple-field, variable-temperature (17)O NMR and proton relaxivity study on [Gd(3)L(H(2)O)(6)](3-) yielded the parameters characterizing water exchange and rotational dynamics. On the basis of the (17)O chemical shifts, bishydration of Gd(3+) could be evidenced. The water exchange rate, k(ex)(298)=9.0+/-3.0 s(-1) is around twice as high as k(ex)(298) of the commercial [Gd(DTPA)(H(2)O)](2-) and comparable to those on analogous Gd(3+)-DTTA chelates. Despite the relatively small size of the complex, the rotational dynamics had to be described with the Lipari-Szabo approach, by separating global and local motions. The difference between the local and global rotational correlation times, tau(lO)(298)=170+/-10 ps and tau(gO)(298)=540+/-100 ps respectively, shows that [Gd(3)L(H(2)O)(6)](3-) is not fully rigid; its flexibility originates from the CH(2) linker between the benzene core and the poly(amino carboxylate) moiety. As a consequence of the two inner-sphere water molecules per Gd(3+), their close to optimal exchange rate and the appropriate size and limited flexibility of the molecule, [Gd(3)L(H(2)O)(6)](3-) has remarkable proton relaxivities when compared with commercial contrast agents, particularly at high magnetic fields (r(1)=21.6, 17.0 and 10.7 mM(-1)s(-1) at 60, 200 and 400 MHz respectively, at 25 degrees C; r(1) is the paramagnetic enhancement of the longitudinal water proton relaxation rate, referred to 1 mM concentration of Gd(3+)).

Noncovalent Functionalization of Carbon Nanotubes with Amphiphilic Gd3+ Chelates: Toward Powerful T1 and T2 MRI Contrast Agents

An amphiphilic gadolinium (III) chelate (GdL) was synthesized from commercially available stearic acid. Aqueous solutions of the complex at different concentrations (from 1 mM to 1 microM) were prepared and adsorbed on multiwalled carbon nanotubes. The resulting suspensions were stable for several days and have been characterized with regard to magnetic resonance imaging (MRI) contrast agent applications. Longitudinal water proton relaxivities, r1, have been measured at 20, 300, and 500 MHz. The r1 values show a strong dependence on the GdL concentration, particularly at low field. The relaxivities decrease with increasing field as it is predicted by the Solomon-Bloembergen-Morgan theory. Transverse water proton relaxation times, T2, have also been measured and are practically independent of both the frequency and the GdL concentration. An in vivo feasibility MRI study has been performed at 300 MHz in mice. A negative contrast could be well observed after injection of a suspension of functionalized nanotubes into the muscle of the leg of the mouse.

A glycosylated complex of gadolinium, a new potential contrast agent for magnetic resonance angiography?

A new low-molecular weight dendrimer-like MRI contrast agent (Gd–D1) has been synthesized and characterized in vitro by proton and oxygen-17 relaxometry. Its pharmacokinetic parameters and biodistribution patterns were evaluated on rats. Its in vitro and in vivo properties, that is, the longitudinal relaxivity (defined as the increase of the water proton longitudinal relaxation rate induced by one millimole per liter of Gd–D1) equal to 5.6 s −1 mM −1 at 20 MHz and 310 K, the elimination half-time equal to 85 min, and its low accumulation in liver and spleen, underline its potential as a blood-pool MRI contrast agent. ©2000 Elsevier Science Ltd. All rights reserved.

Magnetic field and tissue dependencies of human brain longitudinal 1H2O relaxation in vivo

Brain water proton (1H2O) longitudinal relaxation time constants (T1) were obtained from three healthy individuals at magnetic field strengths (B0) of 0.2 Tesla (T), 1.0T, 1.5T, 4.0T, and 7.0T. A 5-mm midventricular axial slice was sampled using a modified Look-Locker technique with 1.5 mm in-plane resolution, and 32 time points post-adiabatic inversion. The results confirmed that for most brain tissues, T1 values increased by more than a factor of 3 between 0.2T and 7T, and over this range were well fitted by T1 (s)=0.583(B0)0.382, T1(s)=0.857(B0)0.376, and T1(s)=1.35(B0)0.340 for white matter (WM), internal GM, and blood 1H2O, respectively. The ventricular cerebrospinal fluid (CSF) 1H2O T1 value did not change with B0, and its average value (standard deviation (SD)) across subjects and magnetic fields was 4.3 (+/-0.2) s. The tissue 1/T1 values at each field were well correlated with the macromolecular mass fraction, and to a lesser extent tissue iron content. The field-dependent increases in 1H2O T1 values more than offset the well-known decrease in typical MRI contrast reagent (CR) relaxivity, and simulations predict that this leads to lower CR concentration detection thresholds with increased magnetic field.

Redox‐sensitive contrast agents for MRI based on reversible binding of thiols to serum albumin

DOTA-based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine-34. The binding constant of the hexyl complex to HSA was measured to be 64 mM(-1) and decreased to 17, 6.1, and 3.6 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM(-1)) and decreased to 2.0, 1.5, and 0.87 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water-proton relaxivities of the hexyl and propyl complexes at 37 degrees C and 4.7 T were 2.3 and 2.9 mM(-1) s(-1), respectively, in saline. The relaxivities of the HSA-bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM(-1) s(-1), respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox-sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood-pool by MRI.

In vitro Relaxometric and Luminescence Characterization of P792 (Gadomelitol, Vistarem®), an Efficient and Rapid Clearance Blood Pool MRI Contrast Agent

AbstractP792 (Gadomelitol, Vistarem®), a hydrophilic high molecular weight (MW = 6473 g/mol) derivative of DOTA‐Gd is a rapid clearance blood pool agent (RCBPA) characterized by high proton relaxivities r1 and r2 at 310 K in the current range of clinical imaging magnetic fields. Luminescence data of the EuIII complex, as expected for this type of DOTA derivative, agree with the presence of one water molecule in the first coordination sphere of the lanthanide ion. The stability of the water proton longitudinal relaxation rate in the presence of zinc(II) and phosphate ions showed that the transmetallation by ZnII ions is negligible. The temperature dependence of the water oxygen‐17 transverse relaxation rate gave a τM smaller than 100 ns at 310 K. No significant increase of longitudinal or transverse relaxation rates in serum or HSA solution was noticed, precluding association with high molecular weight blood components. The proton Nuclear Magnetic Relaxation Dispersion (NMRD) profile of the water solution showed a maximum of longitudinal relaxivity between 20 and 40 MHz (r1 ≈ 40 s–1 mM–1 at 310 K). Fitting of the proton NMRD curve by the classical outersphere and innersphere models, including or not additional second sphere water molecules, gave a rotational correlation time of approximately 2 to 3 ns and a large value of the electronic relaxation time at low field (τSO ≈ 500 ps). (© Wiley‐VCH Verlag GmbH &amp; Co. KGaA, 69451 Weinheim, Germany, 2005)

Low-field NMR water proton longitudinal relaxation in ultrahighly diluted aqueous solutions of silica-lactose prepared in glass material for pharmaceutical use

Low-field (0.02–4 MHz) proton nuclear magnetic resonance (NMR) longitudinal relaxometry was applied to ultrahighly diluted aqueous solutions in order to detect physical modifications induced in the solvent by the dilution process. A mixture of silica-lactose (1.67·10−5 M silica, 2.92·10−2 M lactose) was initially solubilized in water or in saline, then submitted to eighteen iterative centesimal dilutions in water or in saline under vigorous vortex agitation and rigorously controlled atmospheric conditions, and compared to similarly treated pure water and saline as controls. Several independent series of samples were measured according to a blind protocol (total of 140 code-labelled samples). A slight frequency dispersion (about 4%) was found within the 0.02–4 MHz range, centered around 0.55 MHz, and ascribed to combined effects of silica and trace paramagnetic contaminants, both concentrated and in a reduced motion at the borosilicate wall tube interface. The iterative dilution-agitation process in pure water and saline induced no significant effect on relaxivity. Slightly increased relaxivity compared to solvent was found in the initial silica-lactose dilution (especially in saline, about 4%), which vanished unexpectedly slowly upon dilution, as adjusted to an arbitrary log-linear model. Statistical analysis was applied to succeed in discriminating solutions from their solvents beyond the 10−12 level of dilution. No clear explanation emerged, but post-experiment chemical analysis revealed high amounts (6 ppm) of released silica from the glass material used, with excess in silicalactose samples, and lower amounts of trace paramagnetic contaminants in highly diluted silica-lactose samples, which could provide a clue.

Cartilage calcification studied by proton nuclear magnetic resonance microscopy.

A three-dimensional (3D) mineralizing culture system using hollow fiber bioreactors has been developed to study the early stages of endochondral ossification by proton nuclear magnetic resonance (NMR) microscopy. Chondrocytes harvested from the cephalic half of the sterna from 17-day-old chick embryos were terminally differentiated with 33 nM of retinoic acid for 1 week and mineralization was initiated by the addition of 1% beta-glycerophosphate to the culture medium. Histological sections taken after 6 weeks of development in culture confirmed calcification of the cartilage matrix formed in bioreactors. Calcium to phosphorus ratios (1.62-1.68) from X-ray microanalysis supported electron diffraction of thin tissue sections showing the presence of a poorly crystalline hydroxyapatite mineral phase in the cultures. After 4 weeks of culture, quantitative proton NMR images showed water proton magnetization transfer rate constants (km) were higher in premineralized cartilage compared with uncalcified cartilage, a result suggesting collagen enrichment of the matrix. Notably after 5 weeks mineral deposits formed in bioreactors principally in the collagen-enriched zones of the cartilage with increased km values. This caused marked reductions in water proton longitudinal (T1) and transverse (T2) relaxation times and water diffusion coefficients (D). These results support the hypothesis that mineralization proceeds in association with a collagen template. After 6 weeks of culture development, the water proton T2 values decreased by 13% and D increased by 7% in uncalcified areas, compared with the same regions of tissue examined 1 week earlier. These changes could be attributed to the formation of small mineral inclusions in the cartilage, possibly mediated by matrix vesicles, which may play an important role in cartilage calcification. In summary, NMR images acquired before and after the onset of mineralization of the same tissue provide unique insights into the matrix events leading to endochondral mineral formation.

Sequential changes in MR water proton relaxation time detect the process of rat brain myelination during maturation

For better understanding of the behavior of water molecules in the animal brain, changes in magnetic resonance water proton relaxation processes were studied in the rat during maturation. Midbrains of male Wistar rats were removed at various time points ranging from 2 to 70 days after birth. Changes in relaxation time (water proton longitudinal relaxation time by the inversion recovery, and water proton transverse relaxation time by the spin echo and the Carr–Purcell–Meiboom–Gill pulse sequence (CPMG)) and water content were then determined for various stages of brain development. During maturation both water proton longitudinal relaxation time and water proton transverse relaxation time values decreased and this finding paralleled the decline in water content. Using the CPMG pulse sequence, the transverse relaxation time values were observed to separate into two components after 21 days. Morphologically, the most prominent change at the matured stage of midbrain development in the rat is myelination. Water proton relaxation time, which can be estimated using the CPMG pulse sequence, showed a close correlation with myelination in the central nervous system.

Response of engineered cartilage tissue to biochemical agents as studied by proton magnetic resonance microscopy.

To test the hypothesis that magnetic resonance imaging (MRI) results correlate with the biochemical composition of cartilage matrix and can therefore be used to evaluate natural tissue development and the effects of biologic interventions. Chondrocytes harvested from day-16 chick embryo sterna were inoculated into an MRI-compatible hollow-fiber bioreactor. The tissue that formed over a period of 2-4 weeks was studied biochemically, histologically, and with MRI. Besides natural development, the response of the tissue to administration of retinoic acid, interleukin-1beta (IL-1beta), and daily dosing with ascorbic acid was studied. Tissue wet and dry weight, glycosaminoglycan (GAG) content, and collagen content all increased with development time, while tissue hydration decreased. The administration of retinoic acid resulted in a significant reduction in tissue wet weight, proteoglycan content, and cell number and an increase in hydration as compared with controls. Daily dosing with ascorbic acid increased tissue collagen content significantly compared with controls, while the administration of IL-1beta resulted in increased proteoglycan content. The water proton longitudinal and transverse relaxation rates correlated well with GAG and collagen concentrations of the matrix as well as with tissue hydration. In contrast, the magnetization transfer value for the tissue correlated only with total collagen. Finally, the self-diffusion coefficient of water correlated with tissue hydration. Parameters derived from MR images obtained noninvasively can be used to quantitatively assess the composition of cartilage tissue generated in a bioreactor. We conclude that MRI is a promising modality for the assessment of certain biochemical properties of cartilage in a wide variety of settings.

Relaxometric Determination of the Exchange Rate of the Coordinated Water Protons in a Neutral GdIII Chelate

AbstractThe exchange rate of the coordinated water molecule in the neutral complex [Gd(DTPA‐BBA)(H2O)] (DTPA‐BBA = 1,7‐bis[(N‐benzylcarbamoyl)methyl]‐1,4,7‐triazaheptane‐1,4,7‐triacetate or diethylenetriaminopentaacetate N,N′‐bis(benzylamide)) is slower than in the parent complex [Gd(DTPA)(H2O)]2‐. From the analysis of the temperature dependence of the solvent 17O NMR transverse relaxation time in an aqueous solution of the paramagnetic complex, a value of 4.5 × 105 s‐1 (at 298 K) is obtained for the exchange rate of the coordinated water molecule. This rate constant does not vary in the pH range 7–12. Conversely, over the same pH range and at 298 K and 20 MHz, the longitudinal water proton relaxivity increases from 4.8 to 6.5 s‐1 mM‐1. The analysis of the dependence of the longitudinal water proton relaxation rate on magnetic field and temperature at pH 7 and pH 12 shows that the increase in relaxivity at basic pH has to be assigned to the contribution of the prototropic exchange at the water molecule in the inner coordination sphere of the metal ion. This exchange process is catalyzed by OH‐ ions (kP = 1.7 × 109 M‐1 s‐1 at 298 K) and causes an increase in the observed relaxivity when it occurs at a rate larger than the exchange rate of the entire water molecule. At pH 12 the limiting effect of the slow exchange rate for the coordinated water molecule is removed, and the longitudinal water proton relaxivity measured at this pH then represents the maximum value attainable for this complex.