Accounting for pharmacokinetic differences in dual-tracer receptor density imaging.

Dual-tracer molecular imaging is a powerful approach to quantify receptor expression in a wide range of tissues by using an untargeted tracer to account for any nonspecific uptake of a molecular-targeted tracer. This approach has previously required the pharmacokinetics of the receptor-targeted and untargeted tracers to be identical, requiring careful selection of an ideal untargeted tracer for any given targeted tracer. In this study, methodology capable of correcting for tracer differences in arterial input functions, as well as binding-independent delivery and retention, is derived and evaluated in a mouse U251 glioma xenograft model using an Affibody tracer targeted to epidermal growth factor receptor (EGFR), a cell membrane receptor overexpressed in many cancers. Simulations demonstrated that blood, and to a lesser extent vascular-permeability, pharmacokinetic differences between targeted and untargeted tracers could be quantified by deconvolving the uptakes of the two tracers in a region of interest devoid of targeted tracer binding, and therefore corrected for, by convolving the uptake of the untargeted tracer in all regions of interest by the product of the deconvolution. Using fluorescently labeled, EGFR-targeted and untargeted Affibodies (known to have different blood clearance rates), the average tumor concentration of EGFR in four mice was estimated using dual-tracer kinetic modeling to be 3.9 ± 2.4 nM compared to an expected concentration of 2.0 ± 0.4 nM. However, with deconvolution correction a more equivalent EGFR concentration of 2.0 ± 0.4 nM was measured.

An investigation of changes in regional gray matter volume in cardiovascular disease patients, pre and post cardiovascular rehabilitation.

Cognitive function decline secondary to cardiovascular disease has been reported. However, little is known about the impact of coronary artery disease (CAD) on the aging brain macrostructure or whether exercise training, in the context of cardiovascular rehabilitation, can affect brain structure following a coronary event. This study employed voxel-based morphometry of high resolution structural MRI images to investigate; 1) changes in regional gray matter volume (GMV) in CAD patients compared to age-matched controls, and 2) the effects of a six-month exercise-based cardiovascular rehabilitation program on CAD-related GMV decline. Compared to controls, significant decreases in regional GMV were found in the superior, medial and inferior frontal gyrus; superior and inferior parietal gyrus; middle and superior temporal gyrus and in the posterior cerebellum of CAD patients. Cardiovascular rehabilitation was associated with the recovery of regional GMV in the superior frontal gyrus, superior temporal gyrus and posterior cerebellum of the CAD patients as well as the increase in GMV in the supplementary motor area. Total and regional GMV correlated with fitness level, defined by the maximal oxygen consumption (VO2max), at baseline but not after cardiovascular rehabilitation. This study demonstrates that cardiovascular disease can adversely affect age-related decline in GMV; and that these disease-related effects could be mitigated by moderate levels of exercise training as part of cardiovascular rehabilitation.

3D ultrasound system to investigate intraventricular hemorrhage in preterm neonates.

Intraventricular hemorrhage (IVH) is a common disorder among preterm neonates that is routinely diagnosed and monitored by 2D cranial ultrasound (US). The cerebral ventricles of patients with IVH often have a period of ventricular dilation (ventriculomegaly). This initial increase in ventricle size can either spontaneously resolve, which often shows clinically as a period of stabilization in ventricle size and eventual decline back towards a more normal size, or progressive ventricular dilation that does not stabilize and which may require interventional therapy to reduce symptoms relating to increased intracranial pressure. To improve the characterization of ventricle dilation, we developed a 3D US imaging system that can be used with a conventional clinical US scanner to image the ventricular system of preterm neonates at risk of ventriculomegaly. A motorized transducer housing was designed specifically for hand-held use inside an incubator using a transducer commonly used for cranial 2D US scans. This system was validated using geometric phantoms, US/MRI compatible ventricle volume phantoms, and patient images to determine 3D reconstruction accuracy and inter- and intra-observer volume estimation variability. 3D US geometric reconstruction was found to be accurate with an error of <0.2%. Measured volumes of a US/MRI compatible ventricle-like phantom were within 5% of gold standard water displacement measurements. Intra-class correlation for the three observers was 0.97, showing very high agreement between observers. The coefficient of variation was between 1.8-6.3% for repeated segmentations of the same patient. The minimum detectable difference was calculated to be 0.63 cm(3) for a single observer. Results from ANOVA for three observers segmenting three patients of IVH grade II did not show any significant differences (p > 0.05) for the measured ventricle volumes between observers. This 3D US system can reliably produce 3D US images of the neonatal ventricular system. There is the potential to use this system to monitor the progression of ventriculomegaly over time in patients with IVH.

Kinetic model optimization for characterizing tumour physiology by dynamic contrast-enhanced near-infrared spectroscopy.

Dynamic contrast-enhanced (DCE) methods are widely used with magnetic resonance imaging and computed tomography to assess the vascular characteristics of tumours since these properties can affect the response to radiotherapy and chemotherapy. In contrast, there have been far fewer studies using optical-based applications despite the advantages of low cost and safety. This study investigated an appropriate kinetic model for optical applications to characterize tumour haemodynamics (blood flow, F, blood volume, V(b), and vascular heterogeneity) and vascular leakage (permeability surface-area product, PS). DCE data were acquired with two dyes, indocyanine green (ICG) and 800 CW carboxylate (IRD(cbx)), from a human colon tumour xenograph model in rats. Due to the smaller molecular weight of IRD(cbx) (1166 Da) compared to albumin-bound ICG (67 kDa), PS of IRD(cbx) was significantly larger; however, no significant differences in F and V(b) were found between the dyes as expected. Error analysis demonstrated that all parameters could be estimated with an uncertainty less than 5% due to the high temporal resolution and signal-to-noise ratio of the optical measurements. The next step is to adapt this approach to optical imaging to generate haemodynamics and permeability maps, which should enhance the clinical interest in optics for treatment monitoring.

Quantification of pain-induced changes in cerebral blood flow by perfusion MRI.

The purpose of this study was to assess if the functional activation caused by painful stimuli could be detected with arterial spin labeling (ASL), which is a non-invasive magnetic resonance imaging (MRI) technique for measuring cerebral blood flow (CBF). Because ASL directly measures blood flow, it is well suited to pain conditions that are difficult to assess with current functional MRI, such as chronic pain. However, the use of ASL in neuroimaging has been hampered by its low sensitivity. Recent improvements in MRI technology, namely increased magnetic field strengths and phased array receiver coils, should enable ASL to measure the small changes in CBF associated with pain. In this study, healthy volunteers underwent two ASL imaging sessions, during which a painful thermal stimulus was applied to the left hand. The results demonstrated that the ASL technique measured changes in regional CBF in brain regions that have been previously identified with pain perception. These included bilateral CBF changes in the insula, secondary somatosensory, and cingulate cortices, as well as the supplementary motor area (SMA). Also observed were contralateral primary somatosensory and ipsilateral thalamic CBF changes. The average change in CBF for all regions of interest was 3.68ml/100g/min, ranging from 2.97ml/100g/min in ipsilateral thalamus to 4.91ml/100g/min in contralateral insula. The average resting global CBF was 54+/-9.7ml/100g/min, and there was no change in global CBF due to the noxious thermal stimulus.

Noise reduction in multi-slice arterial spin tagging imaging.

Attenuating the static signal in arterial spin tagging (ASSIST) was initially developed for 3D imaging of cerebral blood flow. To enable the simultaneous collection of cerebral blood flow and BOLD data, a multi-slice version of ASSIST is proposed. As with the 3D version, this sequence uses multiple inversion pulses during the tagging period to suppress the static signal. To maintain background suppression in all slices, the multi-slice sequence applies additional inversion pulses between slice acquisitions. The utility of the sequence was demonstrated by simultaneously acquiring ASSIST and BOLD data during a functional task and by collecting resting-state ASSIST data over a large number of slices. In addition, the temporal stability of the perfusion signal was found to be 60% greater at 3 T compared to 1.5 T, which was attributed to the insensitivity of ASSIST to physiologic noise.

Effects of the apparent transverse relaxation time on cerebral blood flow measurements obtained by arterial spin labeling.

Previous modeling studies have predicted that a significant fraction of the signal in arterial spin labeling (ASL) experiments originates from labeled water in the capillaries. Provided that the relaxation times in blood and tissue are similar, ASL data can still be analyzed with the conventional one-compartment Kety model. Such studies have primarily focused on T1 differences and have neglected any differences in transverse relaxation times (T2 and T2*). This is reasonable for studies at lower fields; however, it may not be valid at higher fields due to the stronger susceptibility effects of deoxygenated blood. In this study a tracer kinetic model was developed that includes T2* differences between capillary blood and tissue. The model predicts that a reduction in blood T2* at higher fields will attenuate the capillary contribution to the ASL signal. This in turn causes an underestimation of CBF when ASL data are analyzed with the one-compartment Kety model. We confirmed this prediction by comparing ASL data collected at 1.5 and 4 T, and at multiple gradient echoes (19, 32, 45, and 58 ms). A decrease in resting-state CBF with echo time (TE) was observed at 4 T, but not at 1.5 T. These results suggest that at higher fields AST data should be collected using gradient-echo techniques with short TEs, or with spin-echo techniques. Furthermore, the sensitivity of the CBF measurements to venous T2* may affect the interpretation of concurrent ASL/BOLD studies.

Measuring the effects of indomethacin on changes in cerebral oxidative metabolism and cerebral blood flow during sensorimotor activation.

The work presented here uses combined blood oxygenation level-dependent (BOLD) and arterial spin tagging (AST) approaches to study the effect of indomethacin on cerebral blood flow (CBF) and oxygen consumption (CMRO(2)) increases during motor activation. While indomethacin reduced the CBF increase during activation, it did not significantly affect the CMRO(2) increase during activation. The ratio of the activation-induced CBF increase in the presence and absence of indomethacin was 0.54 +/- 0.08 (+/-SEM, n = 8, P < 0.001), while the ratio of the CMRO(2) increase in the presence and absence of the drug was 1.02 +/- 0.08 (+/-SEM, N = 8, ns). Potential difficulties in estimating CMRO(2) changes from combined BOLD/AST data are discussed.

Effect of restricted water exchange on cerebral blood flow values calculated with arterial spin tagging: a theoretical investigation.

Arterial spin tagging techniques originally used the one-compartment Kety model to describe the dynamics of tagged water in the brain. The work presented here develops a more realistic model that includes the contribution of tagged water in the capillary bed and accounts for the finite time required for water to diffuse across the blood-brain barrier. The new model was used to evaluate potential errors in cerebral blood flow values calculated using the one-compartment Kety model. The results predict that if the one-compartment Kety model is used to analyze arterial spin tagging data the observed grey matter cerebral blood flow values should be relatively insensitive to restricted diffusion of water across the capillary bed. For instance, the observed grey matter cerebral blood flow should closely approximate the true cerebral blood flow and not the product of the extraction fraction and the cerebral blood flow. This prediction is in agreement with recent experimental arterial spin tagging results.

Spatial localization combining projection presaturation with a two-dimensional excitation pulse.

Single-shot spatial localization of short T1 nuclei was achieved by outer volume suppression with projection presaturation followed by selective excitation of the desired volume with a two-dimensional (2D) pulse. After the projection, presaturation with a 2D pulse avoided signal contamination from magnetization regrowth in the outer volume, whereas preceding the 2D pulse with projection presaturation reduced any unwanted excitation in the outer volume caused by the 2D pulse. The improvement in outer volume suppression achieved by combining these two techniques was demonstrated by images collected after the application of projection presaturation alone, a 2D pulse alone, and the two combined.

An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: I. Theoretical derivation.

Using the adiabatic approximation, which assumes that the tracer concentration in parenchymal tissue changes slowly relative to that in capillaries, we derived a time-domain, closed-form solution of the tissue homogeneity model. This solution, which is called the adiabatic solution, is similar in form to those of two-compartment models. Owing to its simplicity, the adiabatic solution can be used in CBF experiments in which kinetic data with only limited time resolution or signal-to-noise ratio, or both, are obtained. Using computer simulations, we investigated the accuracy and the precision of the parameters in the adiabatic solution for values that reflect 2H-labeled water (D2O) clearance from the brain (see Part II). It was determined that of the three model parameters, (1) the vascular volume (Vi), (2) the product of extraction fraction and blood flow (EF), and (3) the clearance rate constant (kadb), only the last one could be determined accurately, and therefore CBF must be determined from this parameter only. From the error analysis of the adiabatic solution, it was concluded that for the D2O clearance experiments described in Part II, the coefficient of variation of CBF was approximately 7% in gray matter and 22% in white matter.

An adiabatic approximation to the tissue homogeneity model for water exchange in the brain: II. Experimental validation.

A frequently reported limitation to using water as a tracer for measuring CBF has been the dependence of the CBF estimate on the experimental time (referred to as the falling flow phenomenon, FFP). To eliminate the FFP, we have developed the adiabatic solution of the tissue homogeneity model to replace the solution of the single-compartment Kety model. In Part I, the derivation of the adiabatic solution was presented. In this second part, the adiabatic solution was applied to measure CBF in rabbits using nuclear magnetic resonance spectroscopy and the tracer deuterium oxide. It was shown that the FFP, observable when the 2H clearance data were analyzed with the Kety equation, was significantly reduced when the same data were analyzed with the adiabatic solution of the tissue homogeneity model. By concurrently measuring CBF with radioactive microspheres, it was determined that the CBF estimates from the adiabatic solution were accurate for true blood flow values less than 60 mL x 100 g(-1) x min(-1). Above this value the CBF estimate was progressively underestimated, which was attributed to the diffusion limitation of water in the brain.

A simplified method for measuring cerebral blood flow with xenon-enhanced computed tomography.

The measurement of cerebral blood flow using the xenon-enhanced computed tomography (XECT) technique requires that the build-up of xenon in both brain tissue and end-tidal expired air be determined as a function of time. Monitoring of the former is carried out using CT scanning and the latter, most often, using a thermoconductivity analyser or mass spectrometer. This paper examines the possibility of greatly simplifying the XECT technique by eliminating the need for either thermoconductivity analyser or mass spectrometer. In the proposed approach, the patient's expired air is channelled through the scan field using a flexible plastic tube and sampled by the CT scanner in conjunction with the build-up of xenon in brain tissue. Phantom measurements have demonstrated the ability of the CT scanner to detect variations in the xenon concentration in expired air while computer simulations have shown that errors arising as a result of the proposed methodology are small compared to other inherent sources in the XECT technique.