Transverse Relaxation Rate Research Articles

Mo1233 Functional Evidence for the “Purse String Morphology” of the External Anal Sphincter

tion, in C57Bl6 mice. In vivo water T2 was not different between the NASH mouse model (MCD) and controls (MCS), however, the T2 of liver lipids as well as lipid fractions were significantly elevated in the MCD mice. Ex vivo metabolite profiles could be separated using principle component analysis (PCA) from HR-MAS MRS tissue data. Peaks identified to contribute to the separation of the MCD and the MCS mice, were found to have significant correlations to peaks associated with fatty acids. Our results indicate that non-invasive MRS is a usefull tool in diagnosis NAS as liver-derived lipid transverse relaxation rate values could discriminate the MCD mice from the MCS mice in vivo. The ex vivo HR-MAS results suggested that this could be due to subtle differences in the lipid profiles between the MCD and MCS groups. In conclusion, we report non-invasive in vivo diagnostic approach to NASH in mice. Our results promise translational value for MRS imaging in investigating disparities in lipid profiles in NASH.

Abstract 5037: Intrinsic susceptibility magnetic resonance imaging identifies tumors with ALKF1174L mutation in transgenic murine models of high-risk neuroblastoma.

Abstract In neuroblastoma, mutations in the anaplastic lymphoma kinase (ALK) tyrosine kinase gene have been identified in 8-10 % of primary tumors. The most common and potent ALK mutation, ALKF1174L, leads to the constitutive activation of the ALK protein and is associated preferentially with MYCN amplification, a markedly poorer prognosis, and confers resistance to the promising ALK inhibitor crizotinib. The development of more efficacious ALK inhibitors will benefit from non-invasive imaging strategies for the rapid identification of children with high-risk ALK-expressing or mutated neuroblastoma. Intrinsic susceptibility magnetic resonance imaging (IS-MRI) data was acquired from tumors arising in TH-ALKF1174L/TH-MYCN and TH-MYCN mice, two genetically engineered mouse model of high-risk neuroblastoma. The native MRI transverse relaxation rate R2*, an imaging biomarker sensitive to the concentration of paramagnetic deoxyhemoglobin, and changes in R2* induced with 100% oxygen inhalation, were quantified. Tumors in the TH-ALKF1174L/TH-MYCN mice demonstrated significantly (p<0.0001) slower native R2* rates (61 ± 3s−1, n=23) than tumors in the TH-MYCN mice (101 ± 6s−1, n=21). With hyperoxic challenge, the TH-ALKF1174L/TH-MYCN mice demonstrated a significantly (p<0.0001) lower and negligible ΔR2*oxygen-air (-3 ± 1s−1, n=10) compared with tumors in TH-MYCN mice (-26 ± 3s−1, n=12). A sensitivity of 90% and a specificity of 81% for native R2*, and a sensitivity of 90% and a specificity of 94% for hyperoxia-induced ΔR2* was determined. Histological correlates revealed a significantly (p<0.05) higher uptake of the perfusion marker Hoechst 33342, and the presence of large hemorrhagic blood lakes filled with stagnant deoxygenated erythrocytes, in tumors within the TH-MYCN mice, but not the TH-ALKF1174L/TH-MYCN model. Together these corroborate the IS-MRI findings (relatively fast native R2* and significant ΔR2*, indicative of vascular instability, in tumors in the TH-MYCN mice). IS-MRI provides a robust method to discriminate and identify TH-MYCN transgenic mice harboring the ALKF1174L mutation based on a stark differential vascular phenotype, which may impact on impaired drug delivery. IS-MRI is suitable for the scanning of young children, and quantitation of native R2* easily incorporated into existing pediatric clinical imaging protocols. This approach could provide a robust and rapid indicator of ALK genotypic status of the tumor, enabling the early identification of children with ultra high-risk neuroblastoma at the time of diagnosis. Citation Format: Yann Jamin, Laura Glass, Albert Hallsworth, Rani E. George, Dow-Mu Koh, Andrew D.J. Pearson, Louis Chesler, Simon P. Robinson. Intrinsic susceptibility magnetic resonance imaging identifies tumors with ALKF1174L mutation in transgenic murine models of high-risk neuroblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5037. doi:10.1158/1538-7445.AM2013-5037

Abstract 4459: Evaluating imaging biomarkers of acquired resistance to targeted EGFR therapy in xenograft models of human squamous cell carcinoma of the head and neck (SCCHN).

Abstract Overexpression of EGFR has been identified as a negative prognostic factor in squamous cell carcinoma of the head and neck (SCCHN). Patients with SCCHN who respond to EGFR-targeted tyrosine kinase inhibitors (TKIs) eventually develop acquired resistance. Colocalization of EGFR expression and tumor hypoxia in SCCHN is associated with poor outcome, suggesting a role for hypoxia in drug resistance. Non-invasive imaging strategies to accurately identify and monitor patients whose tumors have become resistant to EGFR-TKI therapy would have clinical value. As part of a pre-clinical multiparametric imaging study, we have investigated EGFR-TKI resistance using intrinsic susceptibility magnetic resonance imaging (IS-MRI), which relies on the dependence of the MRI transverse relaxation rate R2* on the ratio of oxy- to deoxyhemoglobin in blood. Given its relationship to blood oxygen saturation and pO2 in and around blood vessels, R2* and hyperoxia-induced ΔR2* are being investigated as imaging biomarkers of tumor oxygenation. IS-MRI was performed on size-matched xenografts derived from the EGFR TKI sensitive SCCHN cell line CAL27 and an isogenic subline resistant to multiple TKIs (gefitinib, erlotinib, and afatinib). Tumor-bearing mice were administered the hypoxia marker pimonidazole, and baseline R2* quantified from resistant (n=8) or sensitive (n=7) tumors whilst the host breathed air. Gas delivery was then switched to 100% O2, and tumour R2* measured again. Finally, mice were administered the perfusion marker Hoechst 33342. The extent of functional tumor vasculature and hypoxia were quantified ex vivo using fluorescence microscopy. Resistant tumors revealed regions of fast R2* (functional, deoxygenated vasculature) restricted primarily to the tumor periphery, while sensitive tumors exhibited a more heterogeneous distribution of fast R2* throughout. There was no significant difference in baseline R2* between the two cohorts (64 ± 4s-1 and 76 ± 5s-1, p=0.07). Hyperoxia resulted in a significantly smaller ΔR2* in the resistant tumors (-2.4 ± 1.4s-1) compared to sensitive tumors (-9.1 ± 2s-1, p<0.05). Resistant tumors had significantly lower Hoechst 33342 uptake (9.5 ± 1.3%, p<0.01) and increased pimonidazole adducts (21 ± 2%, p<0.01) compared to sensitive tumors (19.2 ± 3% and 10.4 ± 2% respectively). Tumor regions of fast R2* and hyperoxic-induced ΔR2* were spatially associated with Hoechst 33342 uptake. Tumors with resistance to EGFR-TKIs exhibited a reduced hemodynamic MRI response that was associated with decreased vessel perfusion and increased tumor hypoxia. IS-MRI informs on phenotypic differences in tumor blood vessel distribution, functionality and oxygenation associated with EGFR-TKI resistance and sensitivity, affording useful non-invasive imaging biomarkers for investigating EGFR drug resistance and tumor hypoxia. Citation Format: Lauren CJ Baker, Carol Box, Arti Sikka, Gary Box, Suzanne A. Eccles, Simon P. Robinson. Evaluating imaging biomarkers of acquired resistance to targeted EGFR therapy in xenograft models of human squamous cell carcinoma of the head and neck (SCCHN). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4459. doi:10.1158/1538-7445.AM2013-4459

Generating Accurate Contact Maps of Transient Long-Range Interactions in Intrinsically Disordered Proteins by Paramagnetic Relaxation Enhancement

Generating Accurate Contact Maps of Transient Long-Range Interactions in Intrinsically Disordered Proteins by Paramagnetic Relaxation Enhancement

Is R2* a New MRI Biomarker for the Progression of Parkinson’s Disease? A Longitudinal Follow-Up

PurposeTo study changes of iron content in basal ganglia in Parkinson’s disease (PD) through a three-year longitudinal follow-up of the effective transverse relaxation rate R2*, a validated MRI marker of brain iron content which can be rapidly measured under clinical conditions.MethodsTwenty-seven PD patients and 26 controls were investigated by a first MRI (t0). Longitudinal analysis was conducted among the 18 controls and 14 PD patients who underwent a second MRI (t1) 3 years after. The imaging protocol consisted in 6 gradient echo images obtained at different echo-times for mapping R2*. Quantitative exploration of basal ganglia was performed by measuring the variation of R2* [R2*(t1) – R2*(t0)] in several regions of interest.ResultsDuring the three-year evolution of PD, R2* increased in Substantia nigra (SN) (by 10.2% in pars compacta, p = 0.001, and 8.1% in pars reticulata, p = 0.013) and in the caudal putamen (11.4%, p = 0.011), without significant change in controls. Furthermore, we showed a positive correlation between the variation of R2* and the worsening of motor symptoms of PD (p = 0.028).ConclusionSignificant variation of R2* was longitudinally observed in the SN and caudal putamen of patients with PD evolving over a three-year period, emphasizing its interest as a biomarker of disease progression. Our results suggest that R2* MRI follow-up could be an interesting tool for individual assessment of neurodegeneration due to PD, and also be useful for testing the efficiency of disease-modifying treatments.

Evaluation of Folate Conjugated Superparamagnetic Iron Oxide Nanoparticles for Scintigraphic/Magnetic Resonance Imaging

The physical and chemical properties of the nanoparticles influence their pharmacokinetics and ability to accumulate in tumors. In this paper we report a facile method to conjugate folic acid molecule to iron oxide nanoparticles to increase the specific uptake of these nanoparticles by the tumor, which will be useful in targeted imaging of the tumor. The iron oxide nanoparticles were synthesized by alkaline co precipitation method and were surface modified with dextranto make them stable. The folic acid is conjugated to the dextran modified iron oxide nanoparticles by reductive amination process after the oxidation of the dextran with periodate. The synthesized folic acid conjugated nanoparticles were characterized for size, phase, morphology and magnetization by using various physicochemical characterization techniques such as transmission electron microscopy, X-ray diffraction, fourier transform infrared spectroscopy, vibrating sample magnetometry, dynamic light scattering and zetasizer etc. The quantification of the generated carbonyl groups and folic acid conjugated to the surface of the magnetic nanoparticles was done by colorimetric estimations using UV-Visible spectroscopy. The in vitro MR studies were carried out over a range of concentrations and showed significant shortening of the transverse relaxation rate, showing the ability of the nanoconjugate to act as an efficient probe for MR imaging. The biodistribution studies and the scintigraphy done by radiolabeling the nanoconjugate with 99mTc show the enhanced uptake at the tumor site showing its enhanced specificity.

The effect of temperature induced phase transitions in aqueous solutions of triblock copolymers and Triton X-100 on the EPR, magnetic relaxation and luminescent characteristics of Gd(III) and Eu(III) ions

The present report is inspired by the idea to develop novel spectroscopy based techniques to detect the phase transitions in solutions of triblock copolymers with the use of Gd(III) and Eu(III) ions as probes. The choice of (PEO)13(PPO)30(PEO)13 (L64), (PPO)14(PEO)24(PPO)14 (17R4), (PPO)8(PEO)22(PPO)8 (10R5) and Triton X-100 is conditioned by their phase transitions occurring in mild conditions. The cloud point extraction (CPE) data reveal the conditions (pH and chelating agent) where the binding of lanthanides with surfactant rich phase of triblock copolymers and Triton X-100 occurs. The effect of phase transitions in solutions of triblock copolymers on the temperature resolved line widths in EPR spectra of Gd(III) aqua ions and transverse relaxation rates of Gd(III) inner-sphere water protons depends on the architecture of triblock copolymers and pH conditions. The steady state luminescence of Eu(III) complexes with phosphine oxide in aqueous solutions of triblock copolymers and TX-100 is influenced by the temperature induced aggregation and phase separation in solutions of reverse triblock copolymers 17R4 and 10R5, while the effect of the aggregation is insignificant for L64.

An R1ρ expression for a spin in chemical exchange between two sites with unequal transverse relaxation rates

An analytical expression is derived for the rotating frame relaxation rate, R(1ρ), of a spin exchanging between two sites with different transverse relaxation times. A number of limiting cases are examined, with the equation reducing to formulae derived previously under the assumption of equivalent relaxation rates at each site. The measurement of a pair off-resonance R(1ρ) values, with the carrier displaced equally on either side of the observed correlation, forms the basis of one of the approaches for obtaining signs of chemical shift differences, Δω, of exchanging nuclei. The results presented here establish that this method is relatively insensitive to differential transverse relaxation rates between the exchaning states, greatly simplifying the calculation of optimal parameters in R(1ρ) based experiments that are used for measurement of signs of Δω.

The effect of magnetically induced linear aggregates on proton transverse relaxation rates of aqueous suspensions of polymer coated magnetic nanoparticles

It has been recently reported that for some suspensions of magnetic nanoparticles the transverse proton relaxation rate, R(2), is dependent on the time that the sample is exposed to an applied magnetic field. This time dependence has been linked to the formation of linear aggregates or chains in an applied magnetic field via numerical modeling. It is widely known that chain formation occurs in more concentrated ferrofluids systems and that this has an affect on the ferrofluid properties. In this work we examine the relationships between colloidal stability, the formation of these linear structures, and changes observed in the proton transverse relaxation rate of aqueous suspensions of magnetic particles. A series of iron oxide nanoparticles with varying stabilizing ligand brush lengths were synthesized. These systems were characterized with dynamic light scattering, transmission electron microscopy, dark-field optical microscopy, and proton transverse relaxation rate measurements. The dark field optical microscopy and R(2) measurements were made in similar magnetic fields over the same time scale so as to correlate the reduction of the transverse relaxivity with the formation of linear aggregates. Our results indicate that varying the ligand length has a direct effect on the colloidal arrangement of the system in a magnetic field, producing differences in the rate and size of chain formation, and hence systematic changes in transverse relaxation rates over time. With increasing ligand brush length, attractive inter-particle interactions are reduced, which results in slower aggregate formation and shorter linear aggregate length. These results have implications for the stabilization, characterization and potentially the toxicity of magnetic nanoparticle systems used in biomedical applications.

Fast hydrogen exchange affects 15N relaxation measurements in intrinsically disordered proteins

Unprotected amide protons can undergo fast hydrogen exchange (HX) with protons from the solvent. Generally, NMR experiments using the out-and-back coherence transfer with amide proton detection are affected by fast HX and result in reduced signal intensity. When one of these experiments, (1)H-(15)N HSQC, is used to measure the (15)N transverse relaxation rate (R2), the measured R2 rate is convoluted with the HX rate (kHX) and has higher apparent R2 values. Since the (15)N R2 measurement is important for analyzing protein backbone dynamics, the HX effect on the R2 measurement is investigated and described here by multi-exponential signal decay. We demonstrate these effects by performing (15)N R 2 (CPMG) experiments on α-synuclein, an intrinsically disordered protein, in which the amide protons are exposed to solvent. We show that the HX effect on R 2 (CPMG) can be extracted by the derived equation. In conclusion, the HX effect may be pulse sequence specific and results from various sources including the J coupling evolution, the change of steady state water proton magnetization, and the D2O content in the sample. To avoid the HX effect on the analysis of relaxation data of unprotected amides, it is suggested that NMR experimental conditions insensitive to the HX should be considered or that intrinsic R 2 (CPMG) values be obtained by methods described herein.

Use of contrast agents in oncological imaging: magnetic resonance imaging

Magnetic resonance plays a leading role in the management of oncology patients, providing superior contrast resolution and greater sensitivity compared with other techniques, which enables more accurate tumor identification, characterization and staging. Contrast agents are widely used in clinical magnetic resonance imaging; approximately 40–50% of clinical scans are contrast enhanced. Most contrast agents are based on the paramagnetic gadolinium ion Gd3+, which is chelated to avoid the toxic effects of free gadolinium. Multiple factors such as molecule structure, molecule concentration, dose, field strength and temperature determine the longitudinal and transverse relaxation rates (R1 and R2, respectively) and thus the T1- and T2-relaxivities of these chelates. These T1- and T2-relaxivities, together with their pharmacokinetic properties (i.e. distribution and concentration in the area of interest), determine the radiologic efficacy of the gadolinium-based contrast agents.

Suppression of Cooperative Motions in Phospholipid Membranes by Osmotic Stress: Deuterium NMR Relaxation Study

Understanding membrane dynamics is crucial to explaining the function of membrane proteins. Phospholipids are commonly employed as model systems to investigate biological membranes. The complex dynamic organization of phospholipid membranes spans several frequency decades, starting from sub-picosecond local motions to millisecond collective dynamics [1]. Such motional frequencies can be accessed using various NMR relaxation methods. To address membrane dynamics mediated by osmotic stress, we measured 2H longitudinal (R1Z) and transverse quadrupolar echo (R2QE) relaxation rates for the liquid-crystalline phase of DMPC-d54 membrane bilayers. Osmotic stress was applied by both dehydration and osmolyte concentration [2]. The R1Z values of individual acyl segments were independent of osmotic stress while the segmental order parameters (SCD) and R1Z profiles followed a theoretical square-law functional dependence [3]. The R2QE rates were found to be sensitive to osmotic pressure as well as the acyl position, thus yielding two important observations: enhanced transverse relaxation rates with increased amount of water per lipid, and limiting lower R2QE values as we dehydrate the membrane. The R2QE rates of the acyl segments and respective SCD values tend to follow a square-law behavior [3] with increasing lipid dehydration. At higher hydration the square-law behavior is limited to those acyl segments deeper in the hydrophobic region, with a break as the head group is approached. These results clearly indicate that water enhances slow cooperative motions whereas they are suppressed by dehydration. Additional complementary Carr-Purcell-Meiboom-Gill (CPMG) dispersion measurements map the frequency dependence of relaxation rates. Such studies in presence of membrane proteins give insight into optimized lipid hydration for their biological functions.[1] A. Leftin et al. (2011) BBA 1808, 818-839.[2] K.J. Mallikarjunaiah et al. (2011) BJ100, 98-107.[3] M.F. Brown (1982) JCP77, 1576-1599.

High-Resolution MR Imaging of the Human Brainstem In vivo at 7 Tesla

The human brainstem, which comprises a multitude of axonal nerve fibers and nuclei, plays an important functional role in the human brain. Depicting its anatomy non-invasively with high spatial resolution may thus in turn help to better relate normal and pathological anatomical variations to medical conditions as well as neurological and peripheral functions. We explored the potential of high-resolution magnetic resonance imaging (MRI) at 7 T for depicting the intricate anatomy of the human brainstem in vivo by acquiring and generating images with multiple contrasts: T2-weighted images, quantitative maps of longitudinal relaxation rate (R1 maps) and effective transverse relaxation rate ( maps), magnetic susceptibility maps, and direction-encoded track-density images. Images and quantitative maps were compared with histological stains and anatomical atlases to identify nerve nuclei and nerve fibers. Among the investigated contrasts, susceptibility maps displayed the largest number of brainstem structures. Contrary to R1 maps and T2-weighted images, which showed rather homogeneous contrast, maps, magnetic susceptibility maps, and track-density images clearly displayed a multitude of smaller and larger fiber bundles. Several brainstem nuclei were identifiable in sections covering the pons and medulla oblongata, including the spinal trigeminal nucleus and the reticulotegmental nucleus on magnetic susceptibility maps as well as the inferior olive on R1, , and susceptibility maps. The substantia nigra and red nuclei were visible in all contrasts. In conclusion, high-resolution, multi-contrast MR imaging at 7 T is a versatile tool to non-invasively assess the individual anatomy and tissue composition of the human brainstem.

Quantitative multi-parameter mapping of R1, PD*, MT, and R2* at 3T: a multi-center validation

Multi-center studies using magnetic resonance imaging facilitate studying small effect sizes, global population variance and rare diseases. The reliability and sensitivity of these multi-center studies crucially depend on the comparability of the data generated at different sites and time points. The level of inter-site comparability is still controversial for conventional anatomical T1-weighted MRI data. Quantitative multi-parameter mapping (MPM) was designed to provide MR parameter measures that are comparable across sites and time points, i.e., 1 mm high-resolution maps of the longitudinal relaxation rate (R1 = 1/T1), effective proton density (PD*), magnetization transfer saturation (MT) and effective transverse relaxation rate (R2* = 1/T2*). MPM was validated at 3T for use in multi-center studies by scanning five volunteers at three different sites. We determined the inter-site bias, inter-site and intra-site coefficient of variation (CoV) for typical morphometric measures [i.e., gray matter (GM) probability maps used in voxel-based morphometry] and the four quantitative parameters. The inter-site bias and CoV were smaller than 3.1 and 8%, respectively, except for the inter-site CoV of R2* (<20%). The GM probability maps based on the MT parameter maps had a 14% higher inter-site reproducibility than maps based on conventional T1-weighted images. The low inter-site bias and variance in the parameters and derived GM probability maps confirm the high comparability of the quantitative maps across sites and time points. The reliability, short acquisition time, high resolution and the detailed insights into the brain microstructure provided by MPM makes it an efficient tool for multi-center imaging studies.

HASH: a program to accurately predict protein Hα shifts from neighboring backbone shifts.

Chemical shifts provide not only peak identities for analyzing nuclear magnetic resonance (NMR) data, but also an important source of conformational information for studying protein structures. Current structural studies requiring H(α) chemical shifts suffer from the following limitations. (1) For large proteins, the H(α) chemical shifts can be difficult to assign using conventional NMR triple-resonance experiments, mainly due to the fast transverse relaxation rate of C(α) that restricts the signal sensitivity. (2) Previous chemical shift prediction approaches either require homologous models with high sequence similarity or rely heavily on accurate backbone and side-chain structural coordinates. When neither sequence homologues nor structural coordinates are available, we must resort to other information to predict H(α) chemical shifts. Predicting accurate H(α) chemical shifts using other obtainable information, such as the chemical shifts of nearby backbone atoms (i.e., adjacent atoms in the sequence), can remedy the above dilemmas, and hence advance NMR-based structural studies of proteins. By specifically exploiting the dependencies on chemical shifts of nearby backbone atoms, we propose a novel machine learning algorithm, called HASH, to predict H(α) chemical shifts. HASH combines a new fragment-based chemical shift search approach with a non-parametric regression model, called the generalized additive model, to effectively solve the prediction problem. We demonstrate that the chemical shifts of nearby backbone atoms provide a reliable source of information for predicting accurate H(α) chemical shifts. Our testing results on different possible combinations of input data indicate that HASH has a wide rage of potential NMR applications in structural and biological studies of proteins.

Voxel spread function method for correction of magnetic field inhomogeneity effects in quantitative gradient-echo-based MRI.

Macroscopic magnetic field inhomogeneities adversely affect different aspects of MRI images. In quantitative MRI when the goal is to quantify biological tissue parameters, they bias and often corrupt such measurements. The goal of this article is to develop a method for correction of macroscopic field inhomogeneities that can be applied to a variety of quantitative gradient-echo-based MRI techniques. We have reanalyzed a basic theory of gradient echo MRI signal formation in the presence of background field inhomogeneities and derived equations that allow for correction of magnetic field inhomogeneity effects based on the phase and magnitude of gradient echo data. We verified our theory by mapping effective transverse relaxation rate in computer simulated, phantom, and in vivo human data collected with multi-gradient echo sequences. The proposed technique takes into account voxel spread function effects and allowed obtaining virtually free from artifacts effective transverse relaxation rate maps for all simulated, phantom and in vivo data except of the edge areas with very steep field gradients. The voxel spread function method, allowing quantification of tissue specific effective transverse relaxation rate-related tissue properties, has a potential to breed new MRI biomarkers serving as surrogates for tissue biological properties similar to longitudinal and transverse relaxation rate constants widely used in clinical and research MRI.

Superparamagnetic iron oxide and drug complex-embedded acoustic droplets for ultrasound targeted theranosis

Ultrasound-triggered acoustic droplet vaporization (ADV) has been reported as a mechanical and chemical theranostic strategy for tumor treatment. However, targeting of sufficient amounts of droplets to solid tumors to direct effective mechanical force toward tumor cells remains a major challenge. In this study, we incorporated superparamagnetic iron oxide (SPIO) nanoparticles into acoustic droplets to allow both magnetism-assisted targeting and magnetic resonance (MR)-guided ultrasound-triggered ADV. The multi-functionality of these droplets was further increased by co-encapsulation of the chemotherapeutic drug doxorubicin (DOX) and surface conjugation of anti-vascular endothelial growth factor receptor 2 antibody, to serve as an additional targeting moiety. Maximum loading capacities of 7.69 mg SPIO and 1.53 mg DOX per mL were achieved, and magnetic properties were characterized by determination of magnetic hysteresis curves and transverse relaxation rates. In vitro and in vivo MR imaging demonstrated the feasibility of dual modal imaging of SPIO-embedded droplets. Finally, a vessel-mimicking phantom model with live C6 glioma cells was used to demonstrate a 5.4-fold improvement in targeting efficacy by magnetism-assisted targeting of the SPIO-embedded droplets, and effective disruption of cells by insonation-induced ADV, suggesting the potential of developing this system for future clinical applications.

Higher iron in the red nucleus marks Parkinson's dyskinesia

Dopamine cell loss and increased iron in the substantia nigra (SN) characterize Parkinson's disease (PD), with cerebellar involvement increasingly recognized, particularly in motor compensation and levodopa-induced dyskinesia (LID) development. Because the red nucleus (RN) mediates cerebellar circuitry, we hypothesized that RN iron changes might reflect cerebellum-related compensation, and/or the intrinsic capacity for LID development. We acquired high resolution magnetic resonance images from 23 control and 38 PD subjects (12 with PD and history of LID [PD+DYS]) and 26 with PD and no history of LID (PD−DYS). Iron content was estimated from bilateral RN and SN transverse relaxation rates (R2*). PD subjects overall displayed higher R2* values in both the SN and RN. RN R2* values correlated with off-drug Unified Parkinson's Disease Rating Scale-motor scores, but not disease duration or drug dosage. RN R2* values were significantly higher in PD+DYS compared with control and PD−DYS subjects; control and PD−DYS subjects did not differ. The association of higher RN iron content with PD-related dyskinesia suggests increased iron content is involved in, or reflects, greater cerebellar compensatory capacity and thus increased likelihood of LID development.

Brain iron deposition in white matter hyperintensities: a 3-T MRI study

Iron accumulation has been implicated in the pathogenesis of demyelinating diseases. Therefore, we hypothesized that abnormal high cerebral iron deposition may be involved in the development of white matter hyperintensities (WMHs). We used R2* relaxometry to assess whether iron levels in different brain regions correlate with the severity of WMHs. This technique has been recently validated in a postmortem study to demonstrate in vivo brain iron accumulation in a quantitative manner. Fifty-two consecutive WMH patients and 30 healthy controls with 3-T magnetic resonance imaging (MRI) were reviewed in this study. We measured WMH volume (as a marker of the severity of WMHs) on MRI, and the transverse relaxation rate R2*, as an estimate of iron content in seven brain regions. We found that R2* in globus pallidus was associated with WMH volume after adjusting for sociodemographic variables (partial correlation coefficient = 0.521, P < 0.001) and in a multivariate analysis adjusted for common vascular risk factors (partial correlation coefficient = 0.572, P = 0.033). Regional R2* in globus pallidus was also significantly higher in WMHs than in controls (P = 0.042). Iron content in globus pallidus, as assessed by R2* relaxometry, is independently linked to the severity of WMHs in our cohort of patients, suggesting that iron deposition in the brain may play a role in the pathogenesis of WMHs. This may provide prognostic information on patients with WMHs and may have implications for therapeutic interventions in WMHs.

Voxel-based Relaxometry of transverse relaxation rate with gradient echo R2(*) in patients with multiple system atrophy.

To explore the transverse relaxation rate with gradient echo R2(*) changes in patients with Parkinsonian variant of multiple system atrophy (MSA-P) with a voxel-based analysis of R2(*) map. Whole brain structural images and multi-echo T2(*) weighted image were acquired in 27 patients with probable MSA-P and 24 healthy individuals. R2(*) maps of the MSA-P were compared with the controls by voxel-based methods. Compared with the controls, MSA-P patients showed significant R2(*) decrease bilaterally in brain stem, cerebellar hemispheres, insular lobe, temporal lobes, caudate nucleus, and corpus callosum (P<0.005). R2(*) can reveal the significant brain involvements of MSA-P. The introduction of gradient echo may increase the sensitivity, although the susceptible artifact may interfere the detection efficiency of R2(*).