NMR Measurement of Perfusion Using Arterial Spin Labeling Without Saturation of Macromolecular Spins

When measuring perfusion by arterial spin labeling, saturation of tissue macromolecular spins during arterial spin labeling greatly decreases tissue water magnetization, reducing the sensitivity of the technique. In this work, a theory has been developed for perfusion measurement by arterial spin labeling without saturation of macromolecular spins. A two-coil system was used to achieve arterial spin labeling without saturation of brain tissue macromolecular spins for NMR measurement of rat cerebral perfusion. The effects of crossrelaxation on the measurement of perfusion have been studied in the absence of macromolecular spin saturation, and it is demonstrated that at 4.7 Tesla, perfusion is underestimated by approximately 17% when the effect of cross-relaxation is neglected in the calculation of perfusion. However, assuming water to be a freely diffusable tracer, the effect of cross-relaxation is predicted to be flow independent, and it can, thus, be accounted for in the calculation of perfusion. The theory and experiments are presented to estimate tissue perfusion, magnetization transfer rate constants, and spin-lattice relaxation times of water and macromolecular spins in rat brain.     

Perfusion imaging using dynamic arterial spin labeling (DASL).

Recently, a technique based on arterial spin labeling, called dynamic arterial spin labeling (DASL (Magn Reson Med 1999;41:299-308)), has been introduced to measure simultaneously the transit time of the labeled blood from the labeling plane to the exchange site, the longitudinal relaxation time of the tissue, and the perfusion of the tissue. This technique relies on the measurement of the tissue magnetization response to a time varying labeling function. The analysis of the characteristics of the tissue magnetization response (transit time, filling time constant, and perfusion) allows for quantification of the tissue perfusion and for transit time map computations. In the present work, the DASL scheme is used in conjunction with echo planar imaging at 4.7 T to produce brain maps of perfusion and transit time in the anesthetized rat, under graded hypercapnia. The data obtained show the variation of perfusion and transit time as a function of arterial pCO2. Based on the data, CO2 reactivity maps are computed. Published 2001 Wiley-Liss, Inc.     

Multi-Slice MRI of Rat Brain Perfusion During Amphetamine Stimulation Using Arterial Spin Labeling

When a single coil is used to measure perfusion by arterial spin labeling, saturation of macromolecular protons occurs during the labeling period. Induced magnetization transfer contrast (MTC) effects decrease tissue water signal intensity, reducing the sensitivity of the technique. In addition, MTC effects must be properly accounted for in acquiring a control image. This forces the image to a single slice centered between the labeling plane and the control plane. In this work, a two-coil system is presented as a way to avoid saturation of macromolecular spins during arterial spin labeling. The system consists of one small surface coil for labeling the arterial water spins, and a head coil for MRI, actively decoupled from the labeling coil by using PIN diodes. It is shown that no signal loss occurs due to MTC effects when the two-coil system is used for MRI of rat brain perfusion, enabling three-dimensional perfusion imaging. Using the two-coil system, a multi-slice MRI sequence was used to study the regional effects of amphetamine on brain perfusion. Amphetamine causes significant increases in perfusion in many areas of the brain including the cortex, cingulate, and caudate putamen, in agreement with previous results using deoxyglucose uptake to monitor brain activation.     

Estimation of water extraction fractions in rat brain using magnetic resonance measurement of perfusion with arterial spin labeling

The model used for calculating perfusion by MRI techniques that use endogenous water as a tracer assumes that arterial water is a freely diffusible tracer. Evidence shows that this assumption is not valid in the brain at high blood flow rates, at which movement of water into and out of the microvasculature becomes limited by diffusion across the blood-brain barrier. In this work, the arterial spin-labeling technique is used to show that fraction of arterial water that is dependent on blood flow rate remains in the vasculature and does not exchange with brain tissue water. By using perfusion measurements without and with magnetization transfer (MT) effects, one can distinguish arterial label that exchanges into tissue because blood has much smaller MT than brain tissue. Using this technique, the extraction fraction for water is measured in the rat brain at various cerebral blood flow rates. At high flow rates (-5 ml/g/min), the extraction fraction for water is found to be about 45% in rat brain. Disruption of the blood-brain barrier with D-mannitol caused an increase in the extraction fraction for water. It was possible to form an image related to the extraction fraction for water. The ability to estimate the amount of vascular water exchanging with tissue water by MRI may represent a noninvasive approach to detect the integrity of the blood-brain barrier.     

New MRI method with contrast based on the macromolecular characteristics of tissues.

A new MRI method with a contrast that is derived from the macromolecular composition and spin dynamics in the tissue is described and demonstrated on excised mouse brain and rat spinal cord. In the method, magnetization is selectively excited in the macromolecules by using a double quantum filter and subsequently transferred to water. The new imaging method differs from previous methods that rely on magnetization transfer contrast (MTC) in that it enables a separate and independent control of the effect of the macromolecule characteristics, chemical exchange, and water-related parameters on the images.     

Quantitative studies of hydrodynamic effects and cross-relaxation in protein solutions and tissues with proton and deuteron longitudinal relaxation times

Longitudinal relaxation times T1 of water protons were measured in 5% protein solutions at different static magnetic fields (0.47, 2, and 7 T), for proteins with molecular weight ranging between 1.4 and 480 kDa and in solvents of varying degrees of deuteration. T1 values were also obtained for rat liver soaked with Krebs-Ringer solutions of varying degrees of deuteration at the above fields. For the samples containing D2O, T1 for deuterium was also measured at fields 2 and 7 T. The deuterium measurements were used to estimate water rotational correlation times which were in turn used to estimate the contribution of so-called "hydrodynamic effects" of macromolecules to proton relaxation. The proton relaxation rates at full deuteration were compared with those in protonated solvent (water) to obtain a second, direct measurement of this effect. Both measurements provide quantitation of the hydrodynamic effects, free from the contributions of other effects that are transparent to deuteration, and results from both measurements agree with each other reasonably well. The cross-relaxation rate between solute and solvent protons, and the contribution of paramagnetic impurities in the samples were also obtained from the proton T1 studies. The experimental results show that the hydrodynamic effects (intramolecular and intermolecular water-water interactions) are about the same magnitude in all the proteins studied as well as in rat liver. However, the cross-relaxation rate generally increases with increasing protein molecular weight. Measurements in soaked rat liver indicate that the cross-relaxation rate per unit mass of solute is much higher in tissues than in simple solutions of proteins of similar mean molecular weight. The results challenge the prevailing concept that the relaxation properties of biological tissues may be treated as a simple superposition of the properties of their constituents.     

Regional effects of magnetization dispersion on quantitative perfusion imaging for pulsed and continuous arterial spin labeling

Most experiments assume a global transit delay time with blood flowing from the tagging region to the imaging slice in plug flow without any dispersion of the magnetization. However, because of cardiac pulsation, nonuniform cross‐sectional flow profile, and complex vessel networks, the transit delay time is not a single value but follows a distribution. In this study, we explored the regional effects of magnetization dispersion on quantitative perfusion imaging for varying transit times within a very large interval from the direct comparison of pulsed, pseudo‐continuous, and dual‐coil continuous arterial spin labeling encoding schemes. Longer distances between tagging and imaging region typically used for continuous tagging schemes enhance the regional bias on the quantitative cerebral blood flow measurement causing an underestimation up to 37% when plug flow is assumed as in the standard model. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc.     

Sensitivity calibration with a uniform magnetization image to improve arterial spin labeling perfusion quantification

Quantification of perfusion with arterial spin labeling MRI requires a calibration of the imaging sensitivity to water throughout the imaged volume. Since this sensitivity is affected by coil loading and other interactions between the subject and the scanner, the sensitivity must be calibrated in the subject at the time of scan. Conventional arterial spin labeling perfusion quantification assumes a uniform proton density and acquires a proton density reference image to serve as the calibration. This assumption, in the form of an assumed constant brain‐blood partition coefficient, incorrectly adds inverse proton density weighting to the perfusion image. Here, a sensitivity calibration is proposed by generating a uniform magnetization image whose intensity is highly independent of brain tissue type. It is shown that such a uniform magnetization image can be achieved, and brain tissue perfusion values quantified with the sensitivity calibration agree with those quantified with a proton density image when segmentation of brain tissues is performed and appropriate partition coefficients are assumed. Quantification of brain tissue water density is also demonstrated using this sensitivity calibration. This approach can improve and simplify quantification of arterial spin labeling perfusion and may have broader applications to measurement of edema and sensitivity calibration for parallel imaging. Magn Reson Med, 2011. © 2011 Wiley Periodicals, Inc.     

Transit time, trailing time, and cerebral blood flow during brain activation: measurement using multislice, pulsed spin-labeling perfusion imaging.

Transit time and trailing time in pulsed spin-labeling perfusion imaging are likely to be modulated by local blood flow changes, such as those accompanying brain activation. The majority of transit/trailing time is due to the passage of the tagged blood bolus through the arteriole/capillary regions, because of lower blood flow velocity in these regions. Changes of transit/trailing time during activation could affect the quantification of CBF in functional neuroimaging studies, and are therefore important to characterize. In this work, the measurement of transit and trailing times and CBF during sensorimotor activation using multislice perfusion imaging with pulsed arterial spin-labeling is described. While CBF elevated dramatically ( thick similar80.7%) during the sensorimotor activation, sizable reductions of transit time ( thick similar0.11 sec) and trailing time ( thick similar0.26 sec) were observed. Transit and trailing times were dependent on the distances from the leading and trailing edges of the tagged blood bolus to the location of the imaging slices. The effects of transit/trailing time changes on CBF quantification during brain activation were analyzed by simulation studies. Significant errors can be caused in the estimation of CBF if such changes of transit/trailing time are not taken into account.     

Reduced resolution transit delay prescan for quantitative continuous arterial spin labeling perfusion imaging

Arterial spin labeling perfusion MRI can suffer from artifacts and quantification errors when the time delay between labeling and arrival of labeled blood in the tissue is uncertain. This transit delay is particularly uncertain in broad clinical populations, where reduced or collateral flow may occur. Measurement of transit delay by acquisition of the arterial spin labeling signal at many different time delays typically extends the imaging time and degrades the sensitivity of the resulting perfusion images. Acquisition of transit delay maps at the same spatial resolution as perfusion images may not be necessary, however, because transit delay maps tend to contain little high spatial resolution information. Here, we propose the use of a reduced spatial resolution arterial spin labeling prescan for the rapid measurement of transit delay. Approaches to using the derived transit delay information to optimize and quantify higher resolution continuous arterial spin labeling perfusion images are described. Results in normal volunteers demonstrate heterogeneity of transit delay across different brain regions that lead to quantification errors without the transit maps and demonstrate the feasibility of this approach to perfusion and transit delay quantification.     

Perfusion imaging with compensation for asymmetric magnetization transfer effects

The effects of off-resonance radio-frequency irradiation on the intensity of the MR signal from water protons in the cat brain are asymmetric around the chemical shift of the water signal. This asymmetry, which could arise from a shift in the magnetization transfer spectrum ?1.5 ppm upfield from the solvent water signal, must be taken into account to compensate for magnetization transfer effects inherent in arterial spin tagging approaches that use a single radio-frequency coil. Two approaches that either correct for, or circumvent, the apparent upfield shift of the magnetization transfer spectrum are presented, and a perfusion image of the cat brain, using flow-induced adiabatic inversion of arterial water protons, is presented. Other problems in obtaining quantitative cerebral blood flow values using the arterial spin tagging approach are discussed.     

Determination of magnetization transfer contrast in tissue: an MR imaging study of brain tumors.

OBJECTIVE. In this study, the magnetization transfer contrast (MTC) on MR images of several brain tumors and the correlation between MTC and tumors' histologic features were investigated. MTC depends on the extent of magnetization transfer, or cross-relaxation, from tissue water protons to macromolecular protons. On the basis of the known increase of the cross-relaxation rate with increasing molecular weight of protein in protein solutions, the hypothesis that changes in MTC correlate directly with the macromolecular composition of various tumors was tested. SUBJECTS AND METHODS. Preoperative MR images were obtained with a 0.1-T MR system in 40 patients with brain tumors. MTC was correlated with the histologic features and the dry weight of the tumors. The tumors studied included astrocytomas (10), acoustic schwannomas (three), meningiomas (12), pituitary adenomas (10), craniopharyngiomas (two), and hemangioblastomas (three). RESULTS. MTC was 0.43 in normal white matter and 0.42 in normal gray matter, and varied from 0.11 to 0.37 in the tumors. The mean MTC in astrocytomas (0.21 +/- 0.09) was smaller than the mean MTC in the gray matter (p = .0001) or in the other solid tumors (0.34 +/- 0.07 to 0.37 +/- 0.09, p < .002). MTC was larger in high-grade than in low-grade astrocytomas (0.28 +/- 0.05 vs 0.14 +/- 0.04, p = .0005). In meningiomas, MTC correlated with the collagen content of the tumor tissue (r = .95, p = .01). The differences in contents of solids between the solid tumor groups were not significant (p > or = .1, NS). CONCLUSION. When the previously demonstrated correlations between solid content and 1/T1 of the types of tumors studied are taken into consideration, the present results suggest a larger relative contribution from hydrodynamic vs cross-relaxation effects in astrocytomas than in benign tumors or in gray matter. The twofold difference in MTC between low- and high-grade astrocytomas probably reflects the amount of nuclear material in the tumor cells. Collagen content determined the differences in MTC among meningiomas. These results indicate that the major determinant of differences in MTC within these tumor groups is the high-molecular-weight tissue macromolecules, suggesting higher specificity for MTC than for T1 in discriminating between tissues on MR images.     

Modeling and optimization of Look-Locker spin labeling for measuring perfusion and transit time changes in activation studies taking into account arterial blood volume.

This work describes a new compartmental model with step-wise temporal analysis for a Look-Locker (LL)-flow-sensitive alternating inversion-recovery (FAIR) sequence, which combines the FAIR arterial spin labeling (ASL) scheme with a LL echo planar imaging (EPI) measurement, using a multireadout EPI sequence for simultaneous perfusion and T*(2) measurements. The new model highlights the importance of accounting for the transit time of blood through the arteriolar compartment, delta, in the quantification of perfusion. The signal expected is calculated in a step-wise manner to avoid discontinuities between different compartments. The optimal LL-FAIR pulse sequence timings for the measurement of perfusion with high signal-to-noise ratio (SNR), and high temporal resolution at 1.5, 3, and 7T are presented. LL-FAIR is shown to provide better SNR per unit time compared to standard FAIR. The sequence has been used experimentally for simultaneous monitoring of perfusion, transit time, and T*(2) changes in response to a visual stimulus in four subjects. It was found that perfusion increased by 83 +/- 4% on brain activation from a resting state value of 94 +/- 13 ml/100 g/min, while T*(2) increased by 3.5 +/- 0.5%.     

Four-phase single-capillary stepwise model for kinetics in arterial spin labeling MRI.

An extended model for extracting measures of brain perfusion from pulsed arterial spin labeling (ASL) data while considering transit effects and restricted permeability of capillaries to blood water is proposed. We divided the time course of the signal difference between control and labeled images into four phases with respect to the arrival time of labeled blood water at the voxel of interest (t(A)), transit time through the arteries in the voxel (t(ex)), and duration of the bolus of labeled spins (tau). Dividing the labeled slab of blood water into many discrete segments, and adapting numerical integration methods allowed us to conveniently model restricted capillary-tissue exchange based on a modified distributed parameter model. We compared this four-phase single-capillary stepwise (FPSCS) model with models that treat water as a freely diffusible tracer, using both simulations and experimental ASL brain imaging data at 1.5T from eight healthy subjects (24-80 years old). The FPSCS model yielded less errors in the least-squares sense in fitting brain ASL data in comparison with freely diffusible tracer models of water (P = 0.055). These results imply that restricted permeability of capillaries to water should be considered when brain ASL data are analyzed.     

Mechanism of magnetization transfer during on-resonance water saturation. A new approach to detect mobile proteins, peptides, and lipids.

The mechanism of magnetization transfer (MT) between water and components of the proton spectrum was studied ex vivo in a perfused cell system and in vivo in the rat brain (n = 5). Water was selectively labeled and spectral buildup consequential to transfer of longitudinal magnetization was followed as a function of time. At short mixing time (T(m)), nitrogen-bound solvent-exchangeable protons were observed, predominantly assigned to amide groups of proteins and peptides. At longer T(m), intramolecular nuclear Overhauser enhancement (NOE) was observed in the aliphatic proton region, leading to a mobile-macromolecule-weighted spectrum that resembles typical protein spectra described in the literature. This effect on the proton spectrum is distinct from that of classical off-resonance MT, which has been shown to be due to the immobile solid-like proton pool. When studying a solution of major brain metabolites under physiological concentrations and conditions (pH), no transfer effects were observed, in line with expectations based on reduced NOE effects in rapidly tumbling molecules and the fast proton exchange rates of amino, amine, SH, and OH groups. The spectral intensities of the amide protons may serve as indicators for pH and cellular levels of mobile proteins and peptides, while the aliphatic components are representative of several types of mobile macromolecules, including proteins, peptides, and lipids.     

Evidence for the exchange of arterial spin-labeled water with tissue water in rat brain from diffusion-sensitized measurements of perfusion

The extraction fraction of vascular water in rat brain is investigated by means of diffusion measurements of arterial spin labeled water at varying cerebral blood flow (CBF) values. The apparent diffusion coefficient (ADC) of the difference of the proton magnetization signal in the brain acquired with and without continuous arterial spin labeling is modeled to provide a measure of the amount of arterial water in tissue and vasculature and thus of the extraction fraction. The tissue and vascular portion of the arterial spin labeled water are differentiated based on their diffusion characteristics in a manner analogous to the intravoxel incoherent motion (IVIM) method. The amount of labeled arterial water that exchanges with tissue water is determined by estimating the fraction of the total signal that is associated with the slow-decaying component of a biexponential fit to the normalized difference signal between the magnetization of brain tissue acquired with and without arterial spin labeling. The results indicate that, at normal CBF (1.15 ± 0.21 ml g^-1 min^-1), about 90% of the arterial spin labeled water diffuses with an ADC of (1.21 ± 0.37) 10^-3mm² s^-1), which is equal to tissue. At high CBF, an increasing fraction of the labeling water has a fast-pseudo-diffusion coefficient due to a decrease in water extraction fractions. The results also show that the contribution of vascular water to the measurement of perfusion by techniques that use endogenous water as a tracer can be efficiently eliminated by the use of diffusion sensitizing gradients with small effective b values (b ≈ 20 s/mm²), enabling these techniques to monitor true changes in tissue perfusion.     

1H magnetic cross-relaxation between multiple solvent components and rotationally immobilized protein

Magnetic cross-relaxation spectra or Z-spectra are presented for water, acetone, methanol, dimethylsulfoxide, and acetonitrile in cross-linked bovine serum albumin gels. Each solvent studied, reports the same Z-spectrum linewidth and shape for the solid component that follows from solutions of the coupled relaxation equations. The Z-spectra demonstrate competition among solvents for specific protein binding sites. The rate of magnetization transfer in the rotationally immobilized protein environment is approximated by 1/T₂ for the solid component, which is shown to account for the observed magnetization transfer rates in the systems studied. The temperature dependence of the Z-spectra are different for water compared with the organic solvents. The cross-relaxation efficiency in the organic solvents decreases with increasing temperature because molecules bind less well at high temperature. For water, the hydrogen exchange path becomes increasingly important relative to the whole molecule path with increasing temperature, which improves the net cross-relaxation efficiency.     

An analysis of magnetic cross-relaxation between water and methylene protons in a model system

Experiments have been performed to demonstrate and quantify cross-relaxation between water and methylene resonances in a simple model system. Inversion recovery experiments on aqueous solutions of polyethylene glycol produce a transient nuclear Overhauser effect that alters the recovery of the methylene resonance. The relevant equations and parameters that describe this effect are identified and their values are explicitly quantified by analyzing the experimental results. It is shown that cross-relaxation is measurable and significant in this system even though there are no strong hydrophilic interactions available to immobilize water. In studies of dog bile, the water and lipid resonances behave in a qualitatively similar fashion, lending support to the contention that cross-relaxation cannot be neglected in solutions of biological macromolecules.     

Improved perfusion-weighted MRI by a novel double inversion with proximal labeling of both tagged and control acquisitions.

A novel pulsed arterial spin labeling (PASL) technique for multislice perfusion-weighted imaging is proposed that compensates for magnetization transfer (MT) effects without sacrificing tag efficiency, and balances transient magnetic field effects (eddy currents) induced by pulsed field gradients. Improved compensation for MT is demonstrated using a phantom. Improvement in perfusion measurement was compared to other PASL techniques by acquiring perfusion images from 13 healthy volunteers (nine women and four men; age range 29-64 years; mean age 45 +/- 14 years) and second-order image texture analysis. The main improvements with the new method were significantly higher image contrast, higher mean signal intensity, and better signal uniformity across slices. In conclusion, this new PASL method should provide improved accuracy in measuring brain perfusion.     

Perfusion magnetic resonance imaging with continuous arterial spin labeling: methods and clinical applications in the central nervous system.

Several methods are now available for measuring cerebral perfusion and related hemodynamic parameters using magnetic resonance imaging (MRI). One class of techniques utilizes electromagnetically labeled arterial blood water as a noninvasive diffusible tracer for blood flow measurements. The electromagnetically labeled tracer has a decay rate of T1, which is sufficiently long to allow perfusion of the tissue and microvasculature to be detected. Alternatively, electromagnetic arterial spin labeling (ASL) may be used to obtain qualitative perfusion contrast for detecting changes in blood flow, similar to the use of susceptibility contrast in blood oxygenation level dependent functional MRI (BOLD fMRI) to detect functional activation in the brain. The ability to obtain blood flow maps using a non-invasive and widely available modality such as MRI should greatly enhance the utility of blood flow measurement as a means of gaining further insight into the broad range of hemodynamically related physiology and pathophysiology. This article describes the biophysical considerations pertaining to the generation of quantitative blood flow maps using a particular form of ASL in which arterial blood water is continuously labeled, termed continuous arterial spin labeling (CASL). Technical advances permit multislice perfusion imaging using CASL with reduced sensitivity to motion and transit time effects. Interpretable cerebral perfusion images can now be reliably obtained in a variety of clinical settings including acute stroke, chronic cerebrovascular disease, degenerative diseases and epilepsy. Over the past several years, the technical and theoretical foundations of CASL perfusion MRI techniques have evolved from feasibility studies into practical usage. Currently existing methodologies are sufficient to make reliable and clinically relevant observations which complement structural assessment using MRI. Future technical improvements should further reduce the acquisition times for CASL perfusion MRI, while increasing the slice coverage, resolution and stability of the images. These techniques have a broad range of potential applications in clinical and basic research of brain physiology, as well as in other organs.