Theragnostics for tumor and plaque angiogenesis with perfluorocarbon nanoemulsions.

Molecular imaging agents are extending the potential of noninvasive medical diagnosis from basic gross anatomical descriptions to complicated phenotypic characterizations based upon the recognition of unique cell-surface biochemical signatures. Although originally the purview of nuclear medicine, "molecular imaging" is now studied in conjunction with all clinically relevant imaging modalities. Of the myriad of particles that have emerged as prospective candidates for clinical translation, perfluorocarbon nanoparticles offer great potential for combining targeted imaging with drug delivery, much like the "magic bullet" envisioned by Paul Ehrlich 100 years ago. Perfluorocarbon nanoparticles, once studied in Phase III clinical trials as blood substitutes, have found new life for molecular imaging and drug delivery. The particles have been adapted for use with all clinically relevant modalities and for targeted drug delivery. In particular, their intravascular constraint due to particle size provides a distinct advantage for angiogenesis imaging and antiangiogenesis therapy. As perfluorocarbon nanoparticles have recently entered Phase I clinical study, this review provides a timely focus on the development of this platform technology and its application for angiogenesis-related pathologies.

Occult cardiac contractile dysfunction in dystrophin-deficient children revealed by cardiac magnetic resonance strain imaging.

BACKGROUND: Duchenne muscular dystrophy (DMD) is an inherited disease characterized by early onset of skeletal muscle degeneration and progressive weakness. Although dilated cardiomyopathy may occur during adolescence, it is often undetected early in its course because of physical inactivity and generalized debilitation. The purpose of this study was to apply the technique of cardiac magnetic resonance (CMR) tagging to detect occult cardiac dysfunction in young subjects with DMD by measuring myocardial strain and torsion. METHODS AND RESULTS: Thirteen DMD pediatric subjects without clinically apparent heart disease and 9 age-matched healthy males were recruited. Each was scanned on a 1.5-T clinical scanner to acquire contiguous short-axis planes from the apex to the mitral valve plane and then 3 tagged images at base, midventricle, and apex. Global and segmental myocardial net twist and circumferential strain were computed with the use of 2D homogeneous strain analysis. Ventricular torsion was computed by normalizing net twist by the distance from apex to mitral valve plane. DMD patients exhibited normal left ventricular volumes and ejection fractions but manifested reduced midventricular and basal cross-sectional global circumferential strain compared with the reference group (P<0.005). These alterations also appeared in segmental analyses in the septal, anterior, lateral, and inferior walls (P<0.05). CONCLUSIONS: In patients predisposed to cardiomyopathies because of dystrophinopathy, occult regional cardiac dysfunction can be diagnosed with CMR tagging. This method of strain imaging analysis may offer a sensitive approach for delineating the presence and progression of cardiovascular disease and for assessing therapies designed to modulate the onset and course of heart failure.

Effects of pulmonary blood flow on the fractal nature of flow heterogeneity in sheep lungs.

The spatial heterogeneity of pulmonary blood flow can be described by the relative dispersion (RD) of weight-flow histograms (RD = SD/mean). Glenny and Robertson (J. Appl. Physiol. 69: 532-545, 1990) showed that RD of flow in the lung is fractal in nature, characterized by the fractal dimension (D) and RD for the smallest realizable volume element (RDref). We studied the effects of increasing total pulmonary blood flow on D and RDref. In eight in situ perfused sheep lung preparations, 15-microns radio-labeled microspheres were injected into the pulmonary artery at five different blood flows ranging, in random order, from 1.5 to 5.0 l/m. The lungs were in zone 2 at the lower flows and in zone 3 at the higher flows. The lungs were removed, dried, cut into 2 x 2 x 2-cm3 pieces, weighed, and then counted for microsphere radioactivity. Fractal plots of log(weight) vs. log(RD) were constructed by iteratively combining neighboring pieces and then calculating RD with the increasingly larger portion size. D, which is one minus the slope of the fit through this plot, was 1.14 +/- 0.09 and did not change as blood flow increased. However, RDref decreased significantly (P < 0.01) as total flow increased. We conclude that the fractal nature of pulmonary blood flow distribution is not altered by changes in overall flow.

Effects of flow heterogeneity on the measurement of capillary exchange in the lung.

The effects of flow heterogeneity on the measurement of transcapillary escape of small molecules for perfused in situ sheep lungs were evaluated. Lungs were studied at five flows (1.5-5.0 l/min) ranging from zone 1 to zone 3 conditions. At each flow, multiple indicator-dilution curves were collected using 14C-labeled urea (U) or butanediol (B) as the diffusing tracer, and radiolabeled 15-microns microspheres were injected. The lungs were removed, dried, sectioned, weighed, and counted for microsphere radioactivity. Flow heterogeneity expressed as relative dispersion, decreased with increasing flow, from 0.838 +/- 0.179 (mean +/- SD, n = 8) to 0.447 +/- 0.119 (n = 6). We applied homogeneous flow models of capillary exchange to compute permeability-surface area product (PS) and a related parameter, D1/2S, for diffusing tracers. (D is effective diffusivity of capillary exchange.) PS and D1/2S increased to a maximum with increasing flow, but the ratio of D1/2SU to D1/2SB remained constant. A new model incorporating flow heterogeneity and recruitment (the variable recruitment model) was used. The variable recruitment model described the effects of flow on capillary recruitment, but incorporating heterogeneity into the computation did not alter D1/2S values from those computed assuming homogeneous flow.

Regional measurements of pulmonary edema by using magnetic resonance imaging.

A three-dimensional magnetic resonance imaging (MRI) method to measure pulmonary edema and lung microvascular barrier permeability was developed and compared with conventional methods in nine mongrel dogs. MRIs were obtained covering the entire lungs. Injury was induced by injection of oleic acid (0.021-0.048 ml/kg) into a jugular catheter. Imaging followed for 0.75-2 h. Extravascular lung water and permeability-related parameters were measured from multiple-indicator dilution curves. Edema was measured as magnetic resonance signal-to-noise ratio (SNR). Postinjury wet-to-dry lung weight ratio was 5.30 +/- 0.38 (n = 9). Extravascular lung water increased from 2.03 +/- 1.11 to 3.00 +/- 1.45 ml/g (n = 9, P < 0.01). Indicator dilution studies yielded parameters characterizing capillary exchange of urea and butanediol: the product of the square root of equivalent diffusivity of escape from the capillary and capillary surface area (D1/2S) and the capillary permeability-surface area product (PS). The ratio of D1/2S for urea to D1/2S for butanediol increased from 0.583 +/- 0.027 to 0.852 +/- 0.154 (n = 9, P < 0.05). Whole lung SNR at baseline, before injury, correlated with D1/2S and PS ratios (both P < 0.02). By using rate of SNR change, the mismatch of transcapillary filtration flow and lymph clearance was estimated to be 0.2-1.8 ml/min. The filtration coefficient was estimated from these values. Results indicate that pulmonary edema formation during oleic acid injury can be imaged regionally and quantified globally, and the results suggest possible regional quantification by using three-dimensional MRI.

Intraventricular CSF pulsation artifact on fast fluid-attenuated inversion-recovery MR images: analysis of 100 consecutive normal studies.

BACKGROUND AND PURPOSE: CSF pulsation artifact is a pitfall of fast fluid-attenuated inversion-recovery (FLAIR) brain MR imaging. We studied ventricular CSF pulsation artifact (VCSFA) on axial FLAIR images and its relationship to age and ventricular size. METHODS: Fast FLAIR axial images were obtained on a 1.5-T unit (8000/150/2 [TR/TE/ excitations], inversion time = 2200, field of view = 24 cm, matrix = 189x256, and 5-mm interleaved sections). Two observers rated VCSFA (hyperintensity on FLAIR images) in the lateral, third, and fourth ventricles by using a three-point ordinal scale in 100 consecutive subjects (ages 20-86 years) with normal brain MR studies. Left-to-right third ventricular width was also measured. RESULTS: Seventy-two subjects had VCSFA in at least one ventricular cavity. The fourth ventricle was the most common site of VCSFA (n = 58), followed by the third ventricle (n = 47) and the lateral ventricles (n = 13). VCSFA was usually severe in the third and fourth ventricles and less severe in the lateral ventricles. Fourth ventricular VCSFA was significantly associated with third ventricular VCSFA. Increasing third ventricular size and, to a lesser extent, increasing age was significantly associated with VCSFA. Ghost pulsation of VCSFA occurred across the brain parenchyma in the phase-encoding direction. VCSFA seen in the fourth ventricle on axial FLAIR images disappeared on sagittal FLAIR images in one subject. CONCLUSION: VCSFA on axial FLAIR images represents inflow artifact caused by inversion delay and ghosting effects. VCSFA might obscure or mimic intraventricular lesions, especially in the third and fourth ventricles. Although common in adults of all ages, VCSFA is associated with advancing age and increasing ventricular size. Thus, altered CSF flow dynamics that occur with ventriculomegaly and aging contribute to VCSFA on axial FLAIR MR images.

Use of three-dimensional MR angiography for tracking a contrast bolus in the carotid artery.

Contrast-bolus tracking in the carotid bifurcation was accomplished using an MR angiographic technique with a 3D turbo field-echo readout (TR/TE = 6/3, flip angle = 50 degrees) modified by a keyhole scheme. Optimal visibility of the contrast bolus was achieved by digital subtraction from a reference volume. This technique reliably time-resolves the carotid arteries from the jugular veins.

Inner ear volumetric measurements using high-resolution 3D T2-weighted fast spin-echo MR imaging: initial experience in healthy subjects.

BACKGROUND AND PURPOSE: Adult size is achieved in the inner ear labyrinth by approximately 25 weeks' gestation, and minimal variability in age, sex, side, and race is found after birth. In this study, we opted to determine the reproducibility of inner ear volumetric measurements generated from high-resolution heavily T2-weighted 3D fast spin-echo MR images. METHODS: The temporal bones of 23 volunteers were imaged using a heavily T2-weighted 3D fast spin-echo MR imaging technique. The images were assessed by a neuroradiologist for the presence of inner ear configurational anomalies and, most important, for complete coverage of the inner ear labyrinth. Subsequently, the volume of the fluid in the inner ear was determined by two observers using a semiautomated segmentation algorithm. The mean, SD, range, and coefficient of variation of fluid volume in the inner ear were calculated. Age-, sex-, and side-related differences in the inner ear volumetric measurements were evaluated using analysis of variance. Interrater consistency in the inner ear volumetric measurements was evaluated by comparing the calculated coefficients of reliability. RESULTS: Volumetric measurements were available from 46 inner ears in 23 volunteers. The mean volume was 227.8 mm3 (SD, 24.4 mm3), and the coefficient of variation was 10.7%. No age-, sex-, or side-related differences in the inner ear volumetric measurements were found (F ratios were 4.33, 5.04, and 0.26, respectively). Interrater consistency, as assessed by the coefficient of reliability, was 5.3%. CONCLUSION: Reproducible volumetric measurements of the inner ear labyrinth can be obtained by applying a semiautomated segmentation algorithm to a heavily T2-weighted 3D fast spin-echo MR imaging data set. These volumetric measurements may help identify patients with congenital sensorineural hearing loss and normal inner ear configuration.

Registration of three-dimensional MR and CT studies of the cervical spine.

A three-dimensional image registration technique for CT and MR studies of the cervical spine was evaluated for feasibility and efficacy. Registration by means of external fiducial markers was slightly more accurate than registration by anatomic landmarks. The interrelationships between bony (eg, neural foramina) and soft tissue structures (eg, nerve roots) in the cervical spine were more conspicuous on registered images than on conventional displays. Registration of CT and MR images may be used to examine more precisely the relationships between bony and soft tissue structures of the cervical spine.

Cervical spine: three-dimensional MR imaging with magnetization transfer prepulsed turbo field echo techniques.

In 11 volunteers, magnetic resonance (MR) imaging of the cervical spine was performed with a magnetization transfer preparatory pulse (prepulsed), three-dimensional Fourier transform, turbo field echo sequence. The effects of flip angle, number of shots, phase-encoding profile order, and magnetization transfer prepulse offset frequency on cerebrospinal fluid-to-cord contrast were evaluated. The contrast was improved by lowering the flip angle, increasing the number of shots, and implementing a magnetization transfer prepulse and linear phase-encoding profile order. Maximum myelographic effect was achieved with the magnetization prepulse (500-Hz frequency offset), 3 degrees flip angle, six shots, and linear phase-encoding profile order.

Relative quantification of pulmonary edema with noncontrast-enhanced MRI.

Pulmonary edema is a debilitating effect of acute respiratory distress syndrome. The ability to measure it noninvasively with high sensitivity and in three dimensions could be useful in not only detection but also in assessment and guidance of treatment. To this end, a three-dimensional MRI pulse sequence to measure the formation of edema was developed and tested. Another sequence was tested to measure blood flow in distal pulmonary arteries. Pulmonary edema was induced in nine dogs via venous injections of oleic acid. Edema was verified by wet-to-dry weight ratio (5.30 +/- .38) and extra-vascular lung water at baseline (2.03 +/- 1.12 ml/g dry lung weight) versus postinjury (3.00 +/- 1.45 ml/g) (P < .005). The signal-to-noise ratio within the lungs increased from 5.47 +/- 1.00 at baseline to 7.51 +/- 1.96 (P < .005), and the time course of edema formation was resolved. Results from MR phase-contrast blood flow measurements were variable. The authors conclude that the three-dimensional scan provides a sensitive relative quantification of pulmonary edema formation without the use of contrast agents or ionizing radiation.

MR imaging of the hippocampus: measurement of T2 with four dual-echo techniques.

PURPOSE: To assess the effect of cerebrospinal fluid (CSF) signal nulling and different magnetic resonance (MR) imaging read-out implementations on the precision of T2 measurements in the hippocampus. MATERIALS AND METHODS: Oblique coronal MR imaging was performed in 12 healthy volunteers by using four dual-echo MR sequences: conventional spin-echo (SE), fast SE, gradient-echo and SE (GRASE), and fast fluid-attenuated inversion-recovery (FLAIR) imaging. T2 measurements were obtained from T2 maps derived from regions of interest within the head of both hippocampi. T2 measurements obtained with the four MR sequences were compared, as were differences in T2 between right and left hippocampi. Interrater and test-retest consistency were determined. RESULTS: Fast FLAIR imaging provided the smallest normal range and SD of T2 measurements. Fast FLAIR and fast SE imaging provided the smallest coefficients of variation. GRASE imaging provided a lower coefficient of variation than that of conventional SE. The mean difference between left and right hippocampi was smallest at fast FLAIR imaging. CONCLUSION: Use of a CSF-nulling inversion prepulse, fast SE read-out, or GRASE read-out MR sequence helps improve the precision of the hippocampal T2 measurements in comparison with use of conventional SE imaging. T2 measurements obtained at dual-echo fast FLAIR imaging may help detect subtle hippocampal abnormalities.

Black-blood MR angiography with GRASE: measurement of flow-induced signal attenuation.

We investigated the feasibility of performing black-blood MR angiography (MRA) with the gradient and spin-echo (GRASE) pulse sequence. Phantom experiments and human testing were conducted, and the results were compared with those of turbo spin-echo (TSE). We demonstrated that both techniques are able to produce signal suppression of flowing fluid to background level. With fewer radiofrequency (RF)-refocusing pulses, GRASE pulse sequences could serve as an alternative black-blood technique of reduced RF power exposure and shorter scan time. These relative advantages of GRASE may become useful when high-resolution images are taken.

Voxel sensitivity function description of flow-induced signal loss in MR imaging: implications for black-blood MR angiography with turbo spin-echo sequences.

The conditions in which the image intensity of vessels transporting laminar flow is attenuated in black-blood MR angiography (BB-MRA) with turbo spin-echo (TSE) and conventional spin-echo (CSE) pulse sequences are investigated experimentally with a flow phantom, studied theoretically by means of a Bloch equation-voxel sensitivity function (VSF) formalism, and computer modeled. The experiments studied the effects of: a) flow velocity, b) imaging axes orientation relative to the flow direction, and c) phase encoding order of the TSE train. The formulated Bloch equation-VSF theory describes flow effects in two-dimensional (2D)- and 3D-Fourier transform magnetic resonance imaging. In this theoretical framework, the main attenuation mechanism instrumental to BB-MRA, i.e., transverse magnetization dephasing caused by flow in the presence of the imaging gradients, is described in terms of flow-induced distortions of the individual voxel sensitivity functions. The computer simulations predict that the intraluminal homogeneity and extent of flow-induced image intensity attenuation increase as a function of decreasing vessel diameter, in support of the superior image quality achieved with TSE-based BB-MRA in the brain.