Using microbubbles as an MRI contrast agent for the measurement of cerebral blood volume

The susceptibility differences at the gas–liquid interface of microbubbles (MBs) allow their use as an intravascular susceptibility contrast agent for in vivo MRI. However, the characteristics of MBs are very different from those of the standard gadolinium‐diethylenetriaminepentaacetic acid (Gd‐DPTA) contrast agent, including the size distribution and hemodynamic properties, which could influence MRI outcomes. Here, we investigate quantitatively the correlation between the relative cerebral blood volume (rCBV) derived from Gd‐DTPA (rCBV_Gd) and the MB‐induced susceptibility effect (ΔR₂*_MB) by conventional dynamic susceptibility contrast MRI (DSC‐MRI). Custom‐made MBs had a mean diameter of 0.92 µm and were capable of inducing 4.68 ± 3.02% of the maximum signal change (MSC). The MB‐associated ΔR₂*_MB was compared with rCBV_Gd in 16 rats on 4.7‐T MRI. We observed a significant effect of the time to peak (TTP) on the correlation between ΔR₂*_MB and rCBV_Gd, and also found a noticeable dependence between TTP and MSC. Our findings suggest that MBs with longer TTPs can be used for the estimation of rCBV by DSC‐MRI, and emphasize the critical effect of TTP on MB‐based contrast MRI. Copyright © 2013 John Wiley & Sons, Ltd.     

Measurements of cerebral blood volume using quantitative susceptibility mapping,R2* relaxometry,and ferumoxytol‐enhanced MRI

Ferumoxytol‐enhanced MRI holds potential for the non‐invasive assessment of vascular architecture using estimates of cerebral blood volume (CBV). Ferumoxytol specifically enables steady‐state imaging with extended acquisition times, for substantial improvements in resolution and contrast‐to‐noise ratio. With such data, quantitative susceptibility mapping (QSM) can be used to obtain images of local tissue magnetic susceptibility and hence estimate the increase in blood susceptibility after administration of a contrast agent, which in turn can be correlated to tissue CBV. Here, we explore the use of QSM for CBV estimation and compare it with R₂* (1/T₂*)‐based results. Institutional review board approval was obtained, and all subjects provided written informed consent. For this prospective study, MR images were acquired on a 3.0 T scanner in 19 healthy subjects using a multiple‐echo T₂*‐weighted sequence. Scanning was performed before and after the administration of two doses of ferumoxytol (1 mg FE/kg and 4 mg FE/kg). Different QSM approaches were tested on numerical phantom simulations. Results showed that the accuracy of magnetic susceptibility measurements improved with increasing image resolution and decreasing vascular density. In vivo changes in magnetic susceptibility were measured after the administration of ferumoxytol utilizing QSM, and significantly higher QSM‐based CBV was measured in gray matter compared with white matter. QSM‐ and R₂*‐based CBV estimates correlated well, with similar average values, but a larger variance was found in QSM‐based estimates.     

Longitudinal mapping of mouse cerebral blood volume with MRI

MRI estimations of cerebral blood volume (CBV), useful in mapping brain dysfunction, typically require intravenous (IV) injections of contrast agents. Transgenically engineered mice have emerged as the dominant animal model with which to investigate disorders of the brain and novel therapeutic agents. The difficulty in gaining IV access in mice prohibits repeated administration of contrast in the same animal, limiting the ability to map CBV changes over time. Here we address this limitation by first optimizing an approach for estimating CBV that relies on intraperitoneal (IP) rather than IV injections of the contrast agent gadodiamide. Next, we show that CBV maps generated with IP or IV injections are quantitatively comparable. Finally, we show that CBV maps generated with IP gadodiamide can be acquired repeatedly, reliably and safely over time. Although this approach has certain limitations, estimating CBV with IP injections is well-suited for mapping the spatiotemporal pattern of brain dysfunction in mice models of disease, and for testing pharmacological agents.     

Mean cerebral blood flow measurements using phase contrast MRI in the first year of life

Alterations in cerebral blood flow (CBF) are believed to be linked to many of the neurological pathologies that affect neonates and small infants. CBF measurements are nonetheless often difficult to perform in this population, as many techniques rely on radioactive tracers or other invasive methods. In this study, mean global CBF was measured in 21 infants under the age of one, using non-invasive MRI techniques adapted to the neonatal population. Mean CBF was computed as the ratio of blood flow delivered to the brain (measured using phase contrast MRI) and brain volume (computed by segmenting anatomical MR images). Tests in adult volunteers and repeated measurements showed the flow measurements using the proposed method to be both accurate and reproducible. It was also found that cardiac gating need not be employed in infants with no known cardiac pathology. The developed technique can easily be appended to a neonatal MRI examination to provide rapid, robust, and non-invasive estimates of mean CBF, thus providing a means to monitor developmental or pathology-related alterations in cerebral perfusion and the impact of different treatment courses. In the imaged cohort, mean CBF and flow to the brain were found to rapidly increase during the first year of life (from approx. 25 to 60 ml blood/100 ml tissue/min), in good agreement with literature from other modalities where available. Mean CBF also showed a significant correlation with arterial oxygen saturation level and heart rate, but no significant correlation was found between CBF and the hematocrit or body temperature.     

Regional changes in cerebral blood volume during mental activity

Summary Ten human subjects were injected intravenously with a non-diffusible gamma-emitting isotope. At steady state, 8 collimated scintillation detectors, placed laterally to the subject's head, measured the activity in 8 hemisphere regions. During various types of psychological tests, regional variations in the gamma radiation were recorded. Different patterns of changes were seen during reception of visual impulses, and during various cognitive tasks. These patterns probably represent changes in cerebral blood volume, which are caused by regional metabolic and circulatory events, mainly in the cerebral cortex, and which have a relation to mental activity. Previously demonstrated changes in regional cerebral blood flow during mentation highly support this interpretation. The untraumatic method used in the present study permits, for the first time, continuous extracranial measurements of regional cerebral circulatory events related to mentation.This investigation was aided by grants from the Swedish Medical Research Council (contracts No. B 67-21x-84-03) and from the Wallenherg Foundation, Stockholm.     

Measurement of absolute arterial cerebral blood volume in human brain without using a contrast agent

Arterial cerebral blood volume (CBV_a) is a vital indicator of tissue perfusion and vascular reactivity. We extended the recently developed inflow vascular‐space‐occupancy (iVASO) MRI technique, which uses spatially selective inversion to suppress the signal from blood flowing into a slice, with a control scan to measure absolute CBV_a using cerebrospinal fluid (CSF) for signal normalization. Images were acquired at multiple blood nulling times to account for the heterogeneity of arterial transit times across the brain, from which both CBV_a and arterial transit times were quantified. Arteriolar CBV_a was determined separately by incorporating velocity‐dependent bipolar crusher gradients. Gray matter (GM) CBV_a values (n = 11) were 2.04 ± 0.27 and 0.76 ± 0.17 ml blood/100 ml tissue without and with crusher gradients (b = 1.8 s/mm²), respectively. Arterial transit times were 671 ± 43 and 785 ± 69 ms, respectively. The arterial origin of the signal was validated by measuring its T₂, which was within the arterial range. The proposed approach does not require exogenous contrast agent administration, and provides a non‐invasive alternative to existing blood volume techniques for mapping absolute CBV_a in studies of brain physiology and neurovascular diseases. Copyright © 2011 John Wiley & Sons, Ltd.     

Dynamic susceptibility contrast MRI in advanced pancreatic cancer: semi‐automated analysis to predict response to chemotherapy

The purpose of this study was to assess whether dynamic susceptibility contrast magnetic resonance imaging (DSC‐MRI) can predict response to chemotherapy in advanced pancreatic cancer. DSC‐MRI was performed using gradient‐echo echo‐planar imaging after bolus injection of contrast material. Fifty‐four patients with advanced pancreatic cancer who were scheduled for chemotherapy were enrolled. ΔR2* was calculated using semi‐automated computer analysis capable of tracking moving lesions during DSC‐MRI. Pre‐treatment maximum ΔR2* and clinical factors including gender, age, tumor stage (UICC III/IV), initial tumor size, and chemotherapy regimen were compared between patients with progressive disease and patients with stable disease as was determined at 3‐month follow‐up, and between patients with progressive disease and patients with stable disease as was determined at 6‐month follow‐up. Receiver operating characteristic (ROC) analysis and the Kaplan–Meier method with log‐rank test were used to assess the relationship between the pre‐treatment maximum ΔR2* and early progression (i.e. at 3‐month follow‐up). The pre‐treatment maximum ΔR2* of patients with disease progression at 3‐month follow‐up (10.68 ± 3.88 s^?1) was significantly different (p < 0.01) from that of patients with stable disease at 3‐month follow‐up (6.94 ± 3.12 s^?1). Pre‐treatment maximum ΔR2* of patients with disease progression at 6‐month follow‐up was not significantly different from that of patients with stable disease at 6‐month follow‐up, although a trend was noted (p = 0.08). Pre‐treatment clinical factors were not significantly different between progressive and stable patients at 3‐ and 6‐month follow‐up. Tumor progression rate was significantly higher in patients with a higher pre‐treatment maximum ΔR2* than in those with a lower pre‐treatment maximum ΔR2* (median progression time, 38 vs 138 days, p < 0.01, using a cut‐off value of 8.13 s^?1 as determined by ROC analysis). In conclusion, DSC‐MRI may predict early progression in patients with advanced pancreatic cancer undergoing chemotherapy. Copyright © 2009 John Wiley & Sons, Ltd.     

Regional blood volume changes of the lungs in response to the vegetative nerves stimulation

Significant regional differences in the values of blood volume change response within one lobe of the lung upon the cervic sympathetic and parasympathetic nerves electrical stimulation have been demonstrated through the use of regional lung electroplethysmography method under the conditions of a minimal surical trauma in dogs, cats, and rabbits kept in a supine position. The vascular component of the reaction has been isolated.It consists in blood volume increase in the lungs during the vagus stimulation and blood volume decrease during the sympathetic nerves stimulation. This response is very well manifested in central portions of the lung lobes and decreases progressively in peripheral direction.Blood volume changes due to different body positions relative to the gravitation direction have been demonstrated.Mechanisms of regional differences in blood volume changes have been discussed. The gravitation factor has been suggested to be also responsible for the formation of the neurogenic vasomotoric reaction in lungs.     

Regional brain activation by bicuculline visualized by functional magnetic resonance imaging. Time-resolved assessment of bicuculline-induced changes in local cerebral blood volume using an intravascular contrast agent

Functional magnetic resonance imaging (fMRI) has been applied to study rat focal brain activation induced by intravenous administration of the GABA(A) antagonist bicuculline. Using magnetite nanoparticles as a blood pool contrast agent, local changes in cerebral blood volume (CBV) were assessed with high temporal (10 s) and spatial (0.35 x 0.6 mm(2)) resolutions. Upon infusion of the bicuculline region-specific increases in CBV have been observed, suggesting CBV to reflect brain activity. During the first 2 min, the signal increases were predominant in the cortex, followed by increases in other brain areas, such as the caudate putamen, thalamus and cerebellum. Ten minutes after the start of infusion, a dominant response was observed in the thalamus, while in the caudate putamen a biphasic response pattern was seen. The magnitude of the signal responses in all brain regions was dependent on the dose of bicuculline and, in general, matched the known distribution of GABA(A) binding sites. This study suggests that pharmacological fMRI, displaying brain function at the highly specific level of drug-receptor interaction, should foster our understanding of normal and pathological brain function.     

Quantitative measurement of spinal cord blood volume in humans using vascular-space-occupancy MRI

Although perfusion is of major interest for many spinal cord disorders, there is no established, reproducible technique for evaluating blood flow or blood volume of the spinal cord in humans. Here the first report of in vivo measurement of human spinal cord blood volume (scBV) is presented. An FDA-approved contrast agent, Gd-DTPA, was used as an intravascular agent for the cord parenchyma, and pre-/post-contrast vascular-space-occupancy (VASO) MRI experiments were performed to obtain a quantitative estimation of scBV in mL blood/100 mL tissue. VASO MRI was used because it does not rely on knowledge of an arterial input function, it avoids the imaging artifacts of single-shot echo planar imaging approaches, and it requires only relatively simple and direct calculations for scBV quantification. Preliminary tests at 1.5 T and 3 T gave mean +/- SD scBV values of 4.3 +/- 0.7 ml/100 mL tissue (n = 6) and 4.4 +/- 0.7 ml/100 mL tissue (n = 4), respectively, consistent with the expectation that the scBV values would not be field-dependent.     

Correlation between cerebral blood volume and cerebral blood flow in the cat

Summary Blood flow and blood volume were measured simultaneously in the same cerebral region in anaesthetized cats with controlled respiration. The measurements were made with the same scintillation-detector, using the freely diffusible indicator ¹³³ Xenon for flow determinations and the intra-vascular indicator RISA (¹³¹I) for volume recordings. A very high correlation was found between volume and flow changes (r = .96, p < 0.001). This finding indicates that variations of regional cerebral blood volume are accompanied by proportional blood flow changes.Attaché de recherche au C.N.R.S., Laboratoire de Neurophysiologie, Hopital Henri Rouselle, Paris, France.     

Laser speckle contrast imaging of cerebral blood flow

Laser speckle contrast imaging (LSCI) has emerged over the past decade as a powerful, yet simple, method for imaging of blood flow dynamics in real time. The rapid adoption of LSCI for physiological studies is due to the relative ease and low cost of building an instrument as well as the ability to quantify blood flow changes with excellent spatial and temporal resolution. Although measurements are limited to superficial tissues with no depth resolution, LSCI has been instrumental in pre-clinical studies of neurological disorders as well as clinical applications including dermatological, neurosurgical and endoscopic studies. Recently a number of technical advances have been developed to improve the quantitative accuracy and temporal resolution of speckle imaging. This article reviews some of these recent advances and describes several applications of speckle imaging.     

Mapping of the cerebral vascular response to hypoxia and hypercapnia using quantitative perfusion MRI at 3 T

Changes in breathing change the concentration of oxygen and carbon dioxide in arterial blood resulting in changes in cerebral blood flow (CBF). This mechanism can be described by the cerebral vascular response (CVR), which has been shown to be altered in different physiological and pathophysiological states. CBF maps of grey matter (GM) were determined with a pulsed arterial spin labelling technique at 3 T in a group of 19 subjects under baseline conditions, hypoxia, and hypercapnia. Experimental conditions allowed a change in either arterial oxygen (hypoxia) or carbon dioxide (hypercapnia) concentration compared with the baseline, leaving the other variable constant, in order to separate the effects of these two variables. From these results, maps were calculated showing the regional distribution of the CVR to hypoxia and hypercapnia in GM. Maps of CVR to hypoxia showed very high intra-subject variations, with some GM regions exhibiting a positive response and others a negative response. Per 10% decrease in arterial oxygen saturation, there was a statistically significant 7.0 +/- 2.9% (mean +/- SEM) increase in GM-CBF for the group. However, 70% of subjects showed an overall positive CVR (positive responders), and the remaining 30% an overall negative CVR (negative responders). Maps of CVR to hypercapnia showed less intra-subject variation. Per 1 mm Hg increase in partial pressure of end-tidal carbon dioxide, there was a statistically significant 5.8 +/- 0.9% increase in GM-CBF, all subjects showing an overall positive CVR. As the brain is particularly vulnerable to hypoxia, a condition associated with cardiorespiratory diseases, CVR maps may help in the clinic to identify the areas most prone to damage because of a reduced CVR.     

Noninvasive cerebral blood volume measurement during seizures using multichannel near infrared spectroscopic topography

Near infrared spectroscopic topography (NIRS) is widely recognized as a noninvasive method to measure the regional cerebral blood volume (rCBV) dynamics coupled with neuronal activities. We analyzed the rCBV change in the early phase of epileptic seizures in 12 consecutive patients with medically intractable epilepsy. Seizure was induced by bemegride injection. We used eight-channel NIRS in nine cases and 24 channel in three cases. In all of the cases, rCBV increased rapidly after the seizure onset on the focus side. The increased rCBV was observed for about 30-60 s. The NIRS method can be applied to monitor the rCBV change continuously during seizures. Therefore, this method may be combined with ictal SPECT as one of the most reliable noninvasive methods of focus diagnosis.     

Comparison of perfusion MRI by flow-sensitive alternating inversion recovery and dynamic susceptibility contrast in rats with permanent middle cerebral artery occlusion

We compared cerebral blood flow (CBF) parameters obtained by dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with those obtained by flow-sensitive alternating inversion recovery (FAIR) in brain regions with different perfusion levels in rats with permanent middle cerebral artery (MCA) occlusion. MCA occlusion was performed in 19 rats. T2-weighted MRI, FAIR and DSC-MRI were performed within 48 h after occlusion. CBF parameters were analyzed in regions of interest with either prolonged or less prolonged mean transit time (MTT). Ratios of ipsi- vs contralateral CBF values were calculated and tested for correlation and differences between FAIR and DSC-MRI. FAIR-aCBF ratios correlated significantly with DSC-rCBF ratios. The mean FAIR-aCBF ratio was significantly lower than mean DSC-rCBF ratio in the area with prolonged MTT. In the area with less prolonged MTT, the mean FAIR-aCBF ratio and mean DSC-rCBF values did not differ significantly. We conclude that FAIR correlates with DSC-MRI if perfusion is preserved. FAIR provides lower CBF values than DSC-MRI if perfusion is reduced and MTT is prolonged. This probable underestimation of perfusion may be caused by transit delays. Care should be taken when quantifying CBF with FAIR and when comparing the results of FAIR- and DSC-MRI in areas with hypoperfusion.     

Regional blood flow in response to exercise in conscious dogs

Summary Regional blood flow was measured with the microsphere method in conscious dogs under resting conditions and during moderate exercise on the treadmill.With respect to total organ blood flow, exercise induced a marked increase in blood flow to the calf muscles and to the myocardium, and a significant decrease in the arterial blood supply to the liver. Slight changes in blood flow to the other organs under study (various skeletal muscles, skin, brain, kidneys, intestine) were not significant.Study of the blood flow distribution within the myocardium showed a slight decrease of the ratio of subendocardial to subepicardial blood flow in the left ventricular free wall in response to exercise, and within the brain there was a relative increase in the blood flow to the cerebellum.     

Sensitive MRI detection of internalized T1 contrast agents using magnetization transfer contrast

This work addresses the possibility of using Magnetization Transfer Contrast (MTC) for an improved MRI detection of T₁ relaxation agents. The need to improve the detection threshold of MRI agents is particularly stringent when the contrast agents failed to accumulate to the proper extent in targeting procedures. The herein reported approach is based on the T₁ dependence of MT contrast. It has been assessed that MT contrast can allow the detection of a Gd‐containing agent at a lower detection threshold than the one accessible by acquiring T_1W images. Measurements have been carried out either in TS/A cells or in vivo in a syngeneic murine breast cancer model. The reported data showed that in cellular experiments the MTC method displays a better sensitivity with respect to the common T_1W experiments. In particular, the reached detection threshold allowed the visualization of samples containing only 2% of Gd‐labeled cells diluted in unlabeled cells. In vivo experiments displayed a more diversified scheme. In particular, the tumor region showed two distinct behaviors accordingly with the localization of the imaging probe. The probe located in the tumor core could be detected to the same extent either by T_1w or MTC contrast. Conversely, the agent located in the tumor rim was detected with a larger sensitivity by the MTC method herein described. Copyright © 2015 John Wiley & Sons, Ltd.     

A cancer-recognizable MRI contrast agents using pH-responsive polymeric micelle

A cancer-recognizable MRI contrast agents (CR-CAs) has been developed using pH-responsive polymeric micelles. The CR-CAs with pH sensitivity were self-assembled based on well-defined amphiphilic block copolymers, consisting of methoxy poly(ethylene glycol)-b-poly(l-histidine) (PEG-p(l-His)) and methoxy poly(ethylene glycol)-b-poly(l-lactic acid)-diethylenetriaminopentaacetic acid dianhydride-gadolinium chelate (PEG-p(l-LA)-DTPA-Gd). The CR-CAs have a spherical shape with a uniform size of ∼40 nm at physiological pH (pH 7.4). However, in acidic tumoral environment (pH 6.5), the CR-CAs were destabilized due to the protonation of the imidazole groups of p(l-His) blocks, causing them to break apart into positively charged water-soluble polymers. As a result, the CR-CAs exhibit highly effective T₁ MR contrast enhancement in the tumor region, which enabled the detection of small tumors of ∼3 mm³in vivo at 1.5 T within a few minutes.