DOI: 10.1148/radiol.2433052077
(Radiology 2007;243:796-803.)
© RSNA, 2007
Low Spin-Lock Field T1 Relaxation in the Rotating Frame as a Sensitive MR Imaging Marker for Gene Therapy Treatment Response in Rat Glioma1
Mikko I. Kettunen, PhD,
Alejandra Sierra, PhD,
M. Johanna Närväinen, PhD2,
Piia K. Valonen, PhD,
Seppo Ylä-Herttuala, MD, PhD,
Risto A. Kauppinen, MD, PhD, and
Olli H. J. Gröhn, PhD
1 From the Departments of Biotechnology and Molecular Medicine (M.I.K., P.K.V., S.Y.) and Neurobiology (M.J.N., O.H.J.G.), A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Kuopio, Finland; Laboratorio de Imagen y Espectroscopia por Resonancia Magnética, Instituto de Investigaciones Biomédicas "Alberto Sols" Consejo Superior De Investigaciones Cientificas/Universidad Autonoma De Madrid, Madrid, Spain (A.S.); and School of Sport and Exercise Sciences, University of Birmingham, Birmingham, England (R.A.K.). Received December 20, 2005; revision requested February 15, 2006; revision received April 28; accepted May 31; final version accepted September 13. Supported by the Academy of Finland, the Sigrid Juselius Foundation, the Finnish Cancer Foundation, the Finnish Cultural Foundation, and the Research Foundation of Leiras.
Address correspondence to M.I.K., Department of Biochemistry, University of Cambridge, Old Addenbrookes Site, 80 Tennis Court Rd, Cambridge CB2 1GA, England (e-mail: mik21{at}mole.bio.cam.ac.uk).
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ABSTRACT
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Purpose: To prospectively assess the effectiveness of T1 relaxation in the rotating frame (T1
) dispersion and the low spin-lock radiofrequency field (B1) T1 magnetic resonance (MR) imaging relaxation time in noninvasive monitoring of gene therapy response in BT4C glioma in rats.
Materials and Methods: All animal studies were approved by the ethical committee of the National Laboratory Animal Center. Rats with BT4C gliomas (n = 9) were treated with herpes simplex virus thymidine kinase gene therapy and were compared with untreated rats (n = 5). Absolute T1 at a B1 range of 2.0 x 10–6 to 1.4 x 10–4 T, T1, T2, and apparent diffusion constant were measured at 4.7 T during treatment. Statistical significance was tested by using repeated-measures analysis of variance.
Results: A significant (P < .05) lengthening of T1 was observed beginning on the 4th day of treatment, and T1 values increased to be approximately 80% higher than values observed before treatment. These changes preceded T1 and T2 changes and resembled those of water diffusion. The T1 was associated with a treatment-induced decrease in cell density; this was the only measured MR imaging property that provided significant (P < .05) Pearson correlation with cell density in the tumor border. T1 relaxation dispersion, however, did not offer additional benefits over those offered in one B1 experiment in the early phase of treatment.
Conclusion: T1 with low B1 is an excellent MR imaging marker of early gene therapy response in gliomas. The low B1 approach is not limited by specific absorption rate restrictions; this finding suggests that spin-lock methods could be applicable in clinical settings.
© RSNA, 2007
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INTRODUCTION
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Gene therapy in patients with gliomas has reached the point where the first successful attempts at glioma treatment have been reported (1). Gene therapy could potentially be tailored for each patient, in which case early noninvasive detection of the treatment response would be beneficial. To this end, magnetic resonance (MR) imaging performed with multiple endogenous contrast techniques is likely to be an efficient solution. In particular, diffusion-weighted MR contrast has shown great promise as a surrogate treatment marker (2–4).
Spin-lock contrast, which is mainly governed by the T1 relaxation in the rotating frame (T1) constant, might also be a valuable tool in the early assessment of successful gene therapy with current clinical magnetic field settings. In evaluation with spin-lock contrast, the excitation pulse is immediately followed by a second radiofrequency pulse that locks the magnetization in the transverse plane. The magnetization then relaxes longitudinally along the magnetic field component of the radiofrequency field (B1). T1 closely resembles T1 relaxation in the weak magnetic field and enables measurement of low-frequency fluctuations caused by slow molecular motion in the tissue while maintaining the high signal intensity provided by the main magnetic field. T1 has been shown to improve tumor detection at magnetic field strengths of 0.1–4 T (5–9). Study findings have indicated that T1 is also a sensitive and early MR imaging marker of tumor cell death at high main magnetic field strengths with relatively high spin-lock fields (10–12). In these studies, changes in T1 were observed earlier than changes in T1 or T2 and, in some cases, before diffusion changes.
T1 imaging has been successfully applied in human cartilage (13) and in brain tissue at 1.5 T (14) and 4 T (15), indicating that use of the spin-lock method is feasible in clinical settings. Clinical use of spin-lock techniques can be restricted by safety limits because of the specific absorption rate (SAR), as long spin-lock pulses could potentially lead to tissue heating. SAR can be minimized by using fast MR image acquisition protocols, such as echo-planar imaging, and other methods that lower the number of spin-lock pulses needed (16). Still, one would want to minimize exposure to radiofrequency pulses by using the lowest possible spin-lock B1. As it was shown that contrast resembling T1 (conceptually approaching low B1 T1 [17]) can be acheived with Carr-Purcell T2 techniques (12), spin-lock experiments with low B1 amplitude could potentially be used to detect treatment response to glioma gene therapy. The dependency of spin-lock contrast on the amplitude of B1 (ie, T1 relaxation dispersion) (5) could also be useful in improving the detection of therapy response. T1 dispersion has been shown to improve tumor characterization at low magnetic field strengths (5,6). Results of studies of T1 dispersion in cerebral ischemia at 4.7 T have shown similar improvements and implied that dispersion analysis may also offer additional information on tissue status that is not detected with diffusion weighting or with use of other relaxation times (18–20).
The purpose of our study was to prospectively assess the effectiveness of T1 dispersion and the low spin-lock B1 T1 MR imaging relaxation time in noninvasive monitoring of gene therapy response in BT4C glioma in rats.
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MATERIALS AND METHODS
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Animals
The ethical committee of the National Laboratory Animal Center at the University of Kuopio in Finland approved all animal studies. The BT4C gliomas were induced by implanting 10 000 herpes simplex virus thymidine kinase–positive cells into the corpus callosum of 14 female BDIX rats (National Laboratory Animal Center, Kuopio, Finland), as described previously (11,12,21). (Implantation was performed by a research technician.) Tumors were allowed to grow for 3–4 weeks before treatment started. At the beginning of treatment, the average tumor size was 80 mm3 ± 20. Rats in the treatment group (n = 9; the number of animals needed was based on the behavior of MR properties reported in previous studies [11,12]) were injected twice daily with ganciclovir (25 mg per kilogram of body weight) for the duration of the study (8 days). Animals in the control group (n = 5) were injected with saline. MR data were collected every 2 days. During MR imaging, the animals were anesthetized with halothane (maintenance level of 1%) in a 25%:75% mixture of O2 and N2O and fixed in a custom head holder with a teeth bar and ear pins.
MR Imaging
MR imaging was performed with a 4.7-T horizontal magnet (Magnex Scientific, Yarnton, England) equipped with actively shielded gradients interfaced to a Unity Inova (Varian, Palo Alto, Calif) console. A quadrature half-volume coil (Highfield Imaging, Minneapolis, Minn) with a loop diameter of 28 mm was used in the transmit-receive mode. T1-weighted (repetition time msec/echo time msec, 100/6; field of view, 35 x 35 mm; matrix, 128 x 64; section thickness, 1 mm) coronal pilot images were acquired, and a transverse section through the tumor was selected for relaxation measurements. On-resonance T1 dispersion data were acquired by using a nonselective spin-lock pulse consisting of a 4-msec adiabatic half passage, a variable-length rectangular pulse (four spin-lock times between 11 and 95 msec), and a 4-msec reverse adiabatic half passage returning magnetization to the positive z-axis before a crusher gradient in front of the fast spin-echo imaging pulse sequence (2500/6; 16 echoes; echo space, 10 msec; field of view, 35 x 35 mm; matrix, 128 x 64; section thickness, 1.5 mm). While measurements were obtained, the maximum B1 of adiabatic half passage was kept constant at 4.0 x 10–5 T, while the amplitude of rectangular pulse varied from 2.0 x 10–6 to 1.4 x 10–4 T in 14 steps (15). In addition, T1 (repetition time msec/echo time msec/inversion time msec, 5000/6/5, 500, 1500, 2000) and T2 (2500/12, 24, 48, 96) were measured with the same pulse sequence. T2 was measured with a double spin-echo preparation block that consisted of an adiabatic half passage, two hyperbolic secant pulses, a reverse adiabatic half passage, and a crusher gradient before the imaging sequence. Apparent diffusion constant was measured by using a spin-echo sequence with a series of bipolar gradients along all axes (1500/53, three b values between approximately 0 and 1057 sec/mm2), yielding the trace of the diffusion tensor within one examination (22).
Histologic Analysis
After MR imaging, animals were sacrificed with CO2, and transcardiac perfusion was performed with 0.9% NaCl for 10 minutes (30 mL/min) followed by 4% paraformaldehyde in 0.1 mol/L phosphate buffer (pH 7.4) for 10 minutes (30 mL/min). The fixed brain was removed from the skull, rinsed in phosphate-buffered saline, and cryoprotected (immersed for 24 hours in 20% glycerol in 0.02 mol/L potassium phosphate–buffered saline) for cryosectioning. Histologic slices were stained with the Nissl method, in which one stains the RNA within the cell body, rough endoplasmic reticulum, and nucleus, thereby allowing cell counting and assessment of cytoarchitecture. Cell counting was performed in the tumor border (outer third of the tumor) and tumor center (inner two-thirds of the tumor) by using Stereo Investigator software (MicroBrightField, Colchester, Vt) on a NeuroLucidia morphometry system (MicroBrightField). Only cells with intact well-defined margins were included. Histologic analysis and cell counting were performed by a research technician with 2 years of experience in brain pathology.
Data Analysis
Maps of relaxation times and diffusion were calculated by using monoexponential formulas on a pixel-by-pixel basis. Relative spin density was calculated as the ratio between spin densities obtained from T2 calculations and corrected for T1 relaxation effects in tumor and contralateral brain tissue. Regions of interest (ROIs) that covered the whole tumor were selected on T2-weighted images. ROI size varied from 298 to 1055 pixels, which corresponded to a size of 33–118 mm3, and depended on the stage and type of the treatment. ROIs were selected by an author (M.I.K.) with 9 years of experience in MR imaging of brain diseases. For reference, brain tissue and cerebrospinal fluid data were also analyzed in the contralateral frontoparietal cortex (average ROI size, 20 mm3) and lateral ventricles (average ROI size, 0.8 mm3), respectively. Changes in untreated tumors (day 0) were calculated for all MR imaging properties. Since the response to therapy may vary in different regions of a tumor, MR data were analyzed with two different approaches: First, the histogram was analyzed, and the percentage of pixels with values above or below 2 standard deviations of the mean value in untreated tumors was calculated for each day of treatment. Second, as in histologic analysis, the changes in MR properties were analyzed separately for the border and center regions of the tumor.
The effect of B1 on T1 was estimated by calculating relative T1 ratios (T1R) with B1 values of (a) 2.0 x 10–6 and 1.5 x 10–5 T and (b) 2.0 x 10–5 and 1.4 x 10–4 T with the following equation:
 | (1) |
where T1H is T1 with a high B1 (either 1.5 x 10–5 T or 1.4 x 10–4 T) and T1L is T1 with a low B1 (either 2.0 x 10–6 T or 2.0 x 10–5 T).
In addition, T1 data from the whole B1 range were fitted to an empirical equation suggested by Gröhn et al (18):
 | (2) |
where a is the fitted parameter, which was interpreted as the dispersion amplitude, b is a fitted parameter, e is Euler number, and b minus a yielded an estimate of T1 in the low end of the B1 range. Relative dispersion was estimated by dividing dispersion amplitude by T1 in the low end of the B1 range. All data were analyzed by an author (M.I.K.).
Statistical Analysis
All data are presented as means ± standard deviations. Statistical significance between MR properties (a) of tumor and brain tissue, (b) of center and border regions of the tumor, and (c) before and during treatment was analyzed by using the paired Student t test and repeated-measures analysis of variance with the Dunnett post hoc test for multiple comparisons (level of significance, P < .05). The association between cell density and MR properties was analyzed by using the Pearson correlation coefficient.
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RESULTS
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MR Properties in Tumor, Brain, and Cerebrospinal Fluid before Treatment
Minimal contrast between tumor and brain tissue in T1-weighted images and nearly identical T1 dispersion in both tissues was observed prior to treatment (Fig 1). In comparison, T2 was 13% ± 4 shorter, T1 was 12% ± 4 longer, and apparent diffusion constant was 9% ± 8 higher (P < .01 for all MR properties) in tumors than in contralateral brain tissue (Table 1). Comparison of tumor center with tumor border indicated some inherent heterogeneity in T1 and T1, while T2 and apparent diffusion constant did not differ significantly between regions. Cerebrospinal fluid levels were higher than brain tissue values for these MR properties (Table 1), in accordance with the more mobile state of cerebrospinal fluid.
Therapy Response in Treated and Control Animals
MR properties of saline-treated animals did not change significantly during the treatment period (Fig 2), and the tumors continued to grow throughout the follow-up period. On the other hand, tumors in ganciclovir-treated animals reached maximum size on treatment day 4, and tumor size was significantly (P < .01) reduced from the maximum size by treatment day 6. At the end of the treatment period, mean tumor size was 50 mm3 ± 20 (43% ± 10 smaller than before treatment). T1 relaxation time, as analyzed over the whole tumor, had significantly (P < .05) increased throughout the studied range of B1 values by treatment day 4; however, no significant changes in T1 or T2 were observed until treatment day 8 (Fig 2, Table 2). Because of steady T1 response throughout the B1 range, the initial changes in T1 were not reflected in either the dispersion amplitude or the relative T1 ratios (Table 2). Similar to T1, diffusion was significantly (P < .05) altered by treatment day 4. Relative spin density did not change from the mean pretreatment value of 1.04 ± 0.02 during treatment, although a slight increasing trend was observed. At the end of the treatment period, apparent diffusion constant and T1 with B1 of 1.4 x 10–4 T were approximately 80% higher than their respective values before treatment (Table 2). T1 with B1 of 2.0 x 10–6 T was lengthened by approximately 40%, while T2 and T1 showed less than a 20% change. Interestingly, dispersion amplitude and relative T1 ratios increased nearly 120%, which indicated significant (P < .05) changes in dispersion during the advanced stage of treatment.
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Figure 2a: Relative responses of MR properties to gene therapy in (a, b) whole tumor and (c) border region of tumor. Data are means ± standard deviations. 1 G = 1 x 10–4 T. Error bars at day 0 show relative variability between values in rats prior to treatment. Statistically significant changes from day 0 were estimated by using analysis of variance with Dunnett post hoc test. (* indicates P < .05, ** indicates P < .01.) D av = apparent diffusion constant, dT1 = dispersion amplitude.
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Figure 2b: Relative responses of MR properties to gene therapy in (a, b) whole tumor and (c) border region of tumor. Data are means ± standard deviations. 1 G = 1 x 10–4 T. Error bars at day 0 show relative variability between values in rats prior to treatment. Statistically significant changes from day 0 were estimated by using analysis of variance with Dunnett post hoc test. (* indicates P < .05, ** indicates P < .01.) D av = apparent diffusion constant, dT1 = dispersion amplitude.
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Figure 2c: Relative responses of MR properties to gene therapy in (a, b) whole tumor and (c) border region of tumor. Data are means ± standard deviations. 1 G = 1 x 10–4 T. Error bars at day 0 show relative variability between values in rats prior to treatment. Statistically significant changes from day 0 were estimated by using analysis of variance with Dunnett post hoc test. (* indicates P < .05, ** indicates P < .01.) D av = apparent diffusion constant, dT1 = dispersion amplitude.
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A more modest response was observed in the tumor border than in the tumor center (Fig 2). The heterogeneous tumor response was reflected in the MR property histograms, which showed marked broadening of distributions during treatment. Interestingly, T1 and diffusion responses exhibited a shift in distribution toward larger values (Fig 3), while T2 and T1 showed a relatively symmetrical broadening of distribution around the maximum (ie, the peak in parameter distribution plots), with a minimal shift in peak value. This effect was more clearly observed by comparing the percentage of pixels with values above or below the mean pretreatment values ± 2 standard deviations. For diffusion constant and T1 in the high end of the B1 range, the average percentage of pixels with larger values increased by up to 80% (360–380 pixels; mean total number of pixels in a region of interest on treatment day 8, 470 ± 110), with slightly smaller percentage increases at low B1 fields. At the same time, the percentage of pixels with smaller values remained less than 5% (14 of 470). In contrast, T1 and T2 showed marked percentage increases in both low-value (18% ± 7 [87 of 470] and 14% ± 9 [68 of 470] for T1 and T2, respectively) and high-value (46% ± 17 [205 of 470] and 38% ± 13 [175 of 470] for T1 and T2, respectively) ratios during treatment.
Histologic Analysis
Histologic analysis revealed that the cell count in treated animals was significantly (P < .01) decreased compared with that in control animals. In the tumor center, mean cell counts were 6700 cells per square millimeter ± 4300 and 24 500 cells per square millimeter ± 4800 in treated and control animals, respectively. In the tumor border, the corresponding mean cell counts were 17 700 cells per square millimeter ± 5800 and 27 900 cells per square millimeter ± 3400. In treated animals, the cell counts differed significantly (P < .01) between the tumor center and the tumor border regions. Significant (P < .01) Pearson correlation coefficients between cell counts and MR properties were observed in central regions (Table 3). Interestingly, only T1 and dispersion values were significantly (P < .05) related to the cell count in tumor border regions.
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DISCUSSION
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Our findings show excellent association of T1 MR imaging with the early events of cell death in a glioma. T1 signal markedly increased throughout the B1 range from 2.0 x 10–6 to 1.4 x 10–4 T during tumor cell death induced by gene therapy. This indicates that cell eradication can be detected by using low B1, thus minimizing the radiofrequency deposit into tissue. The results of the current study also indicate that acquisition of a T1 dispersion curve in the B1 range used may not offer additional benefits over those offered in a single B1 experiment.
In the early stages of gene therapy, T1 was more closely associated with cell death at low B1 than either T2 or T1 and closely resembled diffusion changes (10–12). In the periphery of the tumor, where treatment response was weakest, T1 relaxation was the only measured property that was significantly associated with cell density decrease; this finding suggested that spin-lock contrast may provide complimentary information to more conventional MR imaging contrast. Diffusion changes are believed to mostly reflect loss of cells and increase of extracellular space due to cell death (4,23), and it is likely that similar processes also contribute to early T1 alterations. The observed association between cell loss and these MR properties resembled that reported by Chenevert et al (24) for diffusion; thus, it supported the previously mentioned idea. In addition to better association with cell density in some cases, spin-lock contrast might be a useful alternative for diffusion in situations where diffusion imaging is not technically feasible or is hampered by motion artifacts. On the other hand, T1 dispersion did not significantly change in the early stages of tumor eradication, as T1 response was uniform over the whole B1 range. This suggests that dispersion analysis may not offer an additional advantage compared with single B1 imaging until a later time when dispersion data show the largest effect of all MR properties quantified.
The close association of T1 with cell death may reflect the accumulation of water and alterations in the macromolecular pool because of loss of cells in the eradicating tumors. From this point of view, it is interesting to note that the change in T1, which mostly reflects alterations in water content at the high magnetic field (25), is delayed and much smaller in size than T1 response. Furthermore, in our study the relative spin density in tumors did not markedly change during the treatment period. Finally, the relative dispersion actually increases at later time points rather than approaches that of cerebrospinal fluid. Taken together, these observations imply that exchange processes that occur in the protein–water interface dominate over water accumulation per se in the early phase of cytotoxic gene therapy. The improved performance of T1 imaging compared with conventional Hahn spin-echo T2 imaging may also result from the reduced effect of diffusion in local (microscopic) susceptibility gradients to spin-lock experiments (20,26). Histogram data support this idea by showing an increased amount of pixels with short T2 after treatment, whereas no such effect is seen for T1. The shortening of T2 may reflect degraded oxygenation, hemorrhage, or both in parts of the tumor (27).
The usefulness of T1 in clinical settings could be limited by SAR issues and technical reasons. Human brain imaging with B1 of up to 2.0 x 10–5 T has already been performed at field strengths of 1.5 and 4 T (14,15) and has shown that it is possible to implement the needed spin-lock sequences into a clinical imager within the current SAR limits. In the current study, we obtained close association between T1 MR imaging and treatment response with B1 fields as low as 2.0 x 10–6 T. Given that SAR scales as square of spin-lock amplitude, a B1 reduction from 2.0 x 10–5 T to 2.0 x 10–6 T reduces SAR by a factor of 100 and makes this kind of low B1 approach practically unrestricted by SAR limitations. It should be noted, however, that spin-lock conditions are met only when the spin-lock field is higher than local fields; this may not be the case for all spins at the lowest spin-lock fields used in the current study. Nevertheless, these results indicate that conditions resembling spin lock are achieved with B1 fields of 2.0 x 10–6 T at 4.7 T. Furthermore, it is likely that spin-lock conditions are more easily fulfilled at 1.5 T, as the effect of local fields is much weaker at lower B0. Another aspect for applications of T1 at 1.5 T is B0 dependence of T1 (26,28), which could alter the observed response depending on the main magnetic field. In the current study, we did not measure the response at 1.5 T; however, previous reports that compared spin-lock contrast in human brain at 1.5 and 4.0 T on T1 in human brain showed a relatively small B0 dependence of T1 dispersion between spin-lock fields of 1.0 x 10–5 to 2.0 x 10–5 T (14,15), which suggested that moving to clinical B0 might not alter the contrast and effects seen in our study.
Our data indicate that T1 MR imaging performed with low B1 is more closely associated with the cytotoxic response to gene therapy than T2 or T1 and shows stronger association with cell density changes in the tumor border than diffusion MR imaging. T1 MR imaging has already been applied to clinical studies, and the described approach makes it practically unrestricted by SAR limits. These findings, together with the excellent association of low B1 T1 with cytotoxic gene therapy response, make this MR imaging contrast potentially clinically useful. Thus, T1 MR imaging may aid in the care of patients with glioma.
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ADVANCES IN KNOWLEDGE
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- T1 relaxation in the rotating frame (T1) acquired with low spin-lock field strength is shown to be an early MR imaging marker for gene therapy response in rats with BT4C glioma.
- Changes in T1 MR imaging findings are associated with tumor cell density during treatment.
- T1 relaxation dispersion (measured in the radiofrequency field range of 2.0 x 10–6 to 1.4 x 10–4 T) may not improve the detection of gene therapy response.
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ACKNOWLEDGMENTS
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The authors thank Sebastian Cerdan, PhD, for useful comments regarding the manuscript. Expert technical assistance by Ms Maarit Pulkkinen is greatly appreciated.
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FOOTNOTES
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Abbreviations: B1 = radiofrequency field • SAR = specific absorption rate • T1 = T1 relaxation in the rotating frame
2 Current address: School of Biological Sciences, University of Manchester, Manchester, England. 
Authors stated no financial relationship to disclose.
See also Science to Practice in this issue.
Author contributions: Guarantors of integrity of entire study, M.I.K., O.H.J.G.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, M.I.K., R.A.K., O.H.J.G.; experimental studies, M.I.K., A.S., M.J.N., P.K.V., O.H.J.G.; statistical analysis, M.I.K.; and manuscript editing, all authors
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D. Lindquist
Is There a Role for MR Imaging in Monitoring Gene Therapy Response?
Radiology,
June 1, 2007;
243(3):
611 - 612.
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ABSTRACT
INTRODUCTION
