Manganese‐enhanced MRI optic nerve tracking: effect of intravitreal manganese dose on retinal toxicity

The aim of this study was to provide data on the dose dependence of manganese‐enhanced MRI (MEMRI) in the visual pathway of experimental rats and to study the toxicity of MnCl₂ to the retina. Sprague–Dawley rats were intravitreally injected with 2 μL of 0, 10, 25, 50, 75, 100, 150 and 300 mm MnCl₂, respectively_. The contrast‐to‐noise ratio (CNR) of MEMRI for optic nerve enhancement was measured at different concentrations of MnCl₂. Simultaneously, the toxicity of manganese was evaluated by counting retinal ganglion cells and by retinal histological examination using light microscopy and transmission electron microscopy. The CNR increased with increasing concentration of MnCl₂ up to 75 mm . Retinal ganglion cell densities were reduced significantly when the concentration of MnCl₂ in the intravitreal injection was equal to or greater than 75 mm . Increasing numbers of ribosomes in retinal ganglion cells were first detected at 25 mm of MnCl₂. The retinal toxicity of MnCl₂ at higher concentration also included mitochondrial pathology and cell disruption of retinal ganglion cells, as well as abnormalities of photoreceptor and retinal pigment epithelium cells. It can be concluded that intravitreal injection of MnCl₂ induces retinal cell damage that appears to start from 25 mm . The concentration of MnCl₂ should not exceed 25 mm through intravitreal injection for visual pathway MEMRI in the rat. Copyright © 2012 John Wiley & Sons, Ltd.     

Manganese‐enhanced MRI (MEMRI) via topical loading of Mn2+ significantly impairs mouse visual acuity: a comparison with intravitreal injection

Manganese‐enhanced MRI (MEMRI) with topical loading of MnCl₂ provides optic nerve enhancement comparable to that seen by intravitreal injection. However, the impact of this novel and non‐invasive Mn²⁺ loading method on visual function requires further assessments. The objective of this study is to determine the optimal topical Mn²⁺ loading dosage for MEMRI and to assess visual function after MnCl₂ loading. Intravitreal administration was performed to compare the two approaches of MnCl₂ loading. Twenty‐four hours after topical loading of 0, 0.5, 0.75, and 1 M MnCl₂, T₁‐weighted, T2‐weighted, diffusion tensor imaging and visual acuity (VA) assessments were performed to determine the best topical loading dosage for MEMRI measurements and to assess the integrity of retinas and optic nerves. Mice were perfusion fixed immediately after in vivo experiments for hematoxylin and eosin and immunohistochemistry staining. Topical loading of 1 M MnCl₂ damaged the retinal photoreceptor layer with no detectable damage to retina ganglion cell layers or prechiasmatic optic nerves. For the topical loading, 0.75 M MnCl₂ was required to see sufficient enhancement of the optic nerve. At this concentration the visual function was significantly affected, followed by a slow recovery. Intravitreal injection (0.25 μL of 0.2 M MnCl₂) slightly affected VA, with full recovery a day later. To conclude, intravitreal MnCl₂injection provides more reproducible results with less adverse side‐effects than topical loading. Copyright © 2014 John Wiley & Sons, Ltd.     

Manganese‐enhanced MRI visualizes V1 in the non‐human primate visual cortex

MRI at 7 Tesla has been used to investigate the accumulation of manganese in the occipital cortex of common marmoset monkeys (Callithrix jacchus) after administering four fractionated injections of 30 mg/kg MnCl₂ · 4H₂O in the tail vein. We found a statistically significant decrease in T₁ in the primary (V1) and secondary (V2) areas of the visual cortex caused by an accumulation of manganese. The larger T₁ shortening in V1 (ΔT₁ = 640 ms) relative to V2 (ΔT₁ = 490 ms) allowed us to robustly detect the V1/V2 border in vivo using heavily T₁‐weighted MRI. Furthermore, the dorso‐medial (DM) and middle‐temporal (MT) areas of the visual pathway could be identified by their T₁‐weighted enhancement. We showed by comparison to histological sections stained for cytochrome oxidase (CO) activity that the extent of V1 is accurately identified throughout the visual cortex by manganese‐enhanced MRI (MEMRI). This provides a means of visualizing functional cortical regions in vivo and could be used in longitudinal studies of phenomena such as cortical plasticity, and for non‐destructive localization of cortical regions to guide in the implementation of functional techniques. Published in 2009 by John Wiley & Sons, Ltd.     

Regional specificity of manganese accumulation and clearance in the mouse brain: implications for manganese‐enhanced MRI

Manganese‐enhanced MRI has recently become a valuable tool for the assessment of in vivo functional cerebral activity in animal models. As a result of the toxicity of manganese at higher dosages, fractionated application schemes have been proposed to reduce the toxic side effects by using lower concentrations per injection. Here, we present data on regional‐specific manganese accumulation during a fractionated application scheme over 8 days of 30 mg/kg MnCl₂, as well as on the clearance of manganese chloride over the course of several weeks after the termination of the whole application protocol supplying an accumulative dose of 240 mg/kg MnCl₂. Our data show most rapid accumulation in the superior and inferior colliculi, amygdala, bed nucleus of the stria terminalis, cornu ammonis of the hippocampus and globus pallidus. The data suggest that no ceiling effects occur in any region using the proposed application protocol. Therefore, a comparison of basal neuronal activity differences in different animal groups based on locally specific manganese accumulation is possible using fractionated application. Half‐life times of manganese clearance varied between 5 and 7 days, and were longest in the periaqueductal gray, amygdala and entorhinal cortex. As the hippocampal formation shows one of the highest T₁‐weighted signal intensities after manganese application, and manganese‐induced memory impairment has been suggested, we assessed hippocampus‐dependent learning as well as possible manganese‐induced atrophy of the hippocampal volume. No interference of manganese application on learning was detected after 4 days of Mn²⁺ application or 2 weeks after the application protocol. In addition, no volumetric changes induced by manganese application were found for the hippocampus at any of the measured time points. For longitudinal measurements (i.e. repeated manganese applications), a minimum of at least 8 weeks should be considered using the proposed protocol to allow for sufficient clearance of the paramagnetic ion from cerebral tissue. Copyright © 2012 John Wiley & Sons, Ltd.     

Monitoring dynamic alterations in calcium homeostasis by T1‐mapping manganese‐enhanced MRI (MEMRI) in the early stage of small intestinal ischemia–reperfusion injury

Manganese‐enhanced MRI studies have proven to be useful in monitoring physiological activities associated with calcium ions (Ca²⁺) due to the paramagnetic property of the manganese ion (Mn²⁺), which makes it an excellent probe of Ca²⁺. In this study, we developed a method in which a Mn²⁺‐enhanced T₁‐map MRI could enable the monitoring of Ca²⁺ influx during the early stages of intestinal ischemia–reperfusion (I/R) injury. The Mn²⁺ infusion protocol was optimized by obtaining dose‐dependent and time‐course wash‐out curves using a Mn²⁺‐enhanced T₁‐map MRI of rabbit abdomens following an intravenous infusion of 50 mmol/l MnCl₂ (5–10 nmol/g body weight (BW)). In the rabbit model of intestinal I/R injury, T₁ values were derived from the T₁ maps in the intestinal wall region and revealed a relationship between the dose of the infused MnCl₂ and the intestinal wall relaxation time. Significant Mn²⁺ clearance was also observed over time in control animals after the infusion of Mn²⁺ at a dose of 10 nmol/g BW. This technique was also shown to be sensitive enough to monitor variations in calcium ion homeostasis in vivo after small intestinal I/R injury. The T₁ values of the intestinal I/R group were significantly lower (P < 0.05) than that of the control group at 5, 10, and 15 min after Mn²⁺ infusion. Our data suggest that MnCl₂ has the potential to be an MRI contrast agent that can be effectively used to monitor changes in intracellular Ca²⁺ homeostasis during the early stages of intestinal I/R injury. Copyright © 2015 John Wiley & Sons, Ltd.     

A characterization of ABL‐101 as a potential tracer for clinical fluorine‐19 MRI

The two main challenges that prevent the translation of fluorine‐19 (¹⁹F) MRI for inflammation monitoring or cell tracking into clinical practice are (i) the relatively low signal‐to‐noise ratio generated by the injected perfluorocarbon (PFC), which necessitates long scan times, and (ii) the need for regulatory approval and a high biocompatibility of PFCs that are also suitable for MRI. ABL‐101, an emulsion of perfluoro(t‐butylcyclohexane), is a third‐generation PFC that is already used in clinical trials, but has not yet been used for ¹⁹F MRI. The objective of this study was therefore to assess the performance of ABL‐101 as a ¹⁹F MRI tracer. At magnetic field strengths of 3, 9.4 and 14.1 T, the CF₃ groups of ABL‐101 generated a large well‐separated singlet with T₂/T₁ ratios of >0.27, >0.14 and > 0.05, respectively. All relaxation times decreased with the increase in magnetic field strength. The detection limit of ABL‐101 in a 0.25 mm³ voxel at 3 T, 37°C and with a 3‐minute acquisition time was 7.21mM. After intravenous injection, the clearance half‐lives of the ABL‐101 ¹⁹F MR signal in mouse (n = 3) spleen and liver were 6.85 ± 0.45 and 3.20 ± 0.35 days, respectively. These results demonstrate that ABL‐101 has ¹⁹F MR characteristics that are similar to those of PFCs developed specifically for MRI, while it has clearance half‐lives similar to PFCs that have previously been used in large doses in non‐MRI clinical trials. Overall, ABL‐101 is thus a very promising candidate tracer for future clinical trials that use ¹⁹F MRI for cell tracking or the monitoring of inflammation.     

39K and 23Na relaxation times and MRI of rat head at 21.1 T

At ultrahigh magnetic field strengths (B₀ ≥ 7.0 T), potassium (³⁹K) MRI might evolve into an interesting tool for biomedical research. However, ³⁹K MRI is still challenging because of the low NMR sensitivity and short relaxation times. In this work, we demonstrated the feasibility of ³⁹K MRI at 21.1 T, determined in vivo relaxation times of the rat head at 21.1 T, and compared ³⁹K and sodium (²³Na) relaxation times of model solutions containing different agarose gel concentrations at 7.0 and 21.1 T. ³⁹K relaxation times were markedly shorter than those of ²³Na. Compared with the lower field strength, ³⁹K relaxation times were up to 1.9‐ (T₁), 1.4‐ (T_2S) and 1.9‐fold (T_2L) longer at 21.1 T. The increase in the ²³Na relaxation times was less pronounced (up to 1.2‐fold). Mono‐exponential fits of the ³⁹K longitudinal relaxation time at 21.1 T revealed T₁ = 14.2 ± 0.1 ms for the healthy rat head. The ³⁹K transverse relaxation times were 1.8 ± 0.2 ms and 14.3 ± 0.3 ms for the short (T_2S) and long (T_2L) components, respectively. ²³Na relaxation times were markedly longer (T₁ = 41.6 ± 0.4 ms; T_2S = 4.9 ± 0.2 ms; T_2L = 33.2 ± 0.2 ms). ³⁹K MRI of the healthy rat head could be performed with a nominal spatial resolution of 1 × 1 × 1 mm³ within an acquisition time of 75 min. The increase in the relaxation times with magnetic field strength is beneficial for ²³Na and ³⁹K MRI at ultrahigh magnetic field strength. Our results demonstrate that ³⁹K MRI at 21.1 T enables acceptable image quality for preclinical research. Copyright © 2016 John Wiley & Sons, Ltd.     

Impact of contrast agent injection duration on dynamic contrast‐enhanced MRI quantification in prostate cancer

The volume transfer constant K^trans, which describes the leakage of contrast agent (CA) from vasculature into tissue, is the most commonly reported quantitative parameter for dynamic contrast‐enhanced (DCE‐) MRI. However, the variation in reported K^trans values between studies from different institutes is large. One of the primary sources of uncertainty is quantification of the arterial input function (AIF). The aim of this study is to determine the influence of the CA injection duration on the AIF and tracer kinetic analysis (TKA) parameters (i.e. K^trans, k_ep and v_e). Thirty‐one patients with prostate cancer received two DCE‐MRI examinations with an injection duration of 5 s in the first examination and a prolonged injection duration in the second examination, varying between 7.5 s and 30 s. The DCE examination was carried out on a 3.0 T MRI scanner using a transversal T₁‐weighted 3D spoiled gradient echo sequence (300 s duration, dynamic scan time of 2.5 s). Data of 29 of the 31 were further analysed. AIFs were determined from the phase signal in the left and right femoral arteries. K^trans, k_ep and v_e were estimated with the standard Tofts model for regions of healthy peripheral zone and tumour tissue. We observed a significantly smaller peak height and increased width in the AIF for injection durations of 15 s and longer. However, we did not find significant differences in K^trans, k_ep or v_e for the studied injection durations. The study demonstrates that the TKA parameters K^trans, k_ep and v_e, measured in the prostate, do not show a significant change as a function of injection duration.     

MRI accurately identifies early murine mammary cancers and reliably differentiates between in situ and invasive cancer: correlation of MRI with histology

MRI methods that accurately identify various stages of mouse mammary cancer could provide new knowledge that may have a direct impact on the management of breast cancer in patients. This research investigates whether we can accurately follow the progression from in situ to invasive cancer by the evaluation of in vivo and ex vivo MRI, and in comparison with histology as the gold standard for the diagnosis and staging of cancer. Six C3(1)SV40Tag virgin female mice, aged 12–16 weeks, were studied. At this age, these mice develop in situ cancer that resembles human ductal carcinoma in situ (DCIS). Fast spin‐echo images of inguinal mammary glands were acquired at 9.4 T. After in vivo MRI, mice were sacrificed; inguinal mammary glands were excised and fixed in formalin for ex vivo MRI. Three‐dimensional, volume‐rendered, in vivo and ex vivo MR images were then correlated with histology. High‐resolution ex vivo scans facilitated the comparison of in vivo scans with histology. The sizes of mammary cancers classified as in situ on the basis of histology ranged from 150 to 400 µm in largest diameter, and the average signal intensity relative to muscle was 1.40 ± 0.18 on T₂‐weighted images. Cancers classified as invasive on the basis of histology were >400 µm in largest diameter, and the average intensity relative to muscle on T₂‐weighted images was 2.34 ± 0.26. Using a cut‐off of 400 µm in largest diameter to distinguish between in situ and invasive cancers, a T₂‐weighted signal intensity of at least 1.4 times that of muscle for in situ cancer, and at least 2.3 times that of muscle for invasive cancer, 96% of in situ and 100% of invasive cancers were correctly identified on in vivo MRI, using histology as the gold standard. Precise MRI–histology correlation demonstrates that MRI reliably detects early in situ cancer and differentiates in situ from invasive cancers in the SV40Tag mouse model of human breast cancer. Copyright © 2015 John Wiley & Sons, Ltd.     

Characterization of MRI techniques to assess neonatal brain oxygenation and blood flow

There is increasing interest in applying physiological MRI in neonates, based on the premise that physiological parameters may provide an early biomarker of neonatal brain health and injury. Two commonly used techniques are oxygen extraction fraction (OEF) measurement using T₂‐relaxation‐under‐spin‐tagging (TRUST) MRI and cerebral blood flow measurement using phase‐contrast (PC) quantitative flow MRI, which collectively provide an assessment of the brain's oxygen consumption. However, prior research has only demonstrated proof of principle of these methods in neonates, without characterization or benchmarking of the techniques. This is because available time is limited in neonatal subjects, especially when scans are performed as add‐ons to clinical scans (typically less than 5 min). The work presented aims to examine the TRUST and PC MRI sequences systematically in normal neonates, through research‐dedicated scan sessions. A series of characterization and optimization studies were conducted in a total of 26 radiographically normal neonates on 3 T systems. Our results show that TRUST MRI at the superior sagittal sinus (SSS) provides an OEF measurement equivalent to that at the internal jugular vein (r = 0.80, n = 10), yet with shorter scan time. Lower resolution provided better precision in the TRUST measurement (p = 0.001, n = 9). Therefore, the preferred OEF measurement is to apply TRUST MRI at the SSS using a spatial resolution of 2.5 mm. For PC MRI, our results showed that non‐gated PC MRI yielded blood flow measurements comparable to those from the more time‐consuming gated approach in neonates (r = 0.89, n = 7). It was also found that blood flow could be overestimated by 18% when imaging resolution is larger than 0.3 mm (n = 7). Therefore, non‐gated PC MRI with a spatial resolution of 0.3 mm is recommended for neonatal applications. In conclusion, this study verifies consistency of neonatal brain oxygenation and flow measurements across acquisition schemes and points to optimal strategies in parameter selection when using these sequences.     

MRI reveals increased tumorigenesis following high fat feeding in a mouse model of triple‐negative breast cancer

High animal fat consumption is associated with an increase in triple‐negative breast cancer (TNBC) risk. Based on previous MRI studies demonstrating the feasibility of detecting very early non‐palpable mammary cancers in simian virus 40 large T antigen (SV40TAg) mice, we examined the effect of dietary fat fed from weaning to young adulthood in this model of TNBC. Virgin female C3(1)SV40TAg mice (n = 16) were weaned at 3–4 weeks of age and then fed either a low fat diet (LFD) (n = 8, 3.7 kcal/g; 17.2% kcal from vegetable oil) or a high animal fat diet (HAFD) (n = 8, 5.3 kcal/g; 60% kcal from lard). After 8 weeks on the diet (12 weeks of age), fast spin echo MR images of inguinal mammary glands were acquired at 9.4 T. Following in vivo MRI, mice were sacrificed and inguinal mammary glands were excised and formalin fixed for ex vivo MRI. 3D volume‐rendered MR images were then correlated with mammary gland histology to assess the glandular parenchyma and tumor burden. Using in vivo MRI, an average of 3.88 ± 1.03 tumors were detected per HAFD‐fed mouse compared with an average of 1.25 ± 1.16 per LFD‐fed mouse (p < 0.007). Additionally, the average tumor volume was significantly higher following HAFD feeding (0.53 ± 0.45 mm³) compared with LFD feeding (0.20 ± 0.08 mm³, p < 0.02). Analysis of ex vivo MR and histology images demonstrated that HAFD mouse mammary glands had denser parenchyma, irregular and enlarged ducts, dilated blood vessels, increased white adipose tissue, and increased tumor invasion. MRI and histological studies of the SV40TAg mice demonstrated that HAFD feeding also resulted in higher cancer incidence and larger mammary tumors. Unlike other imaging methods for assessing environmental effects on mammary cancer growth, MRI allows routine serial measurements and reliable detection of small cancers as well as accurate tumor volume measurements and assessment of the three‐dimensional distribution of tumors over time.     

Comparison of different MRI sequences in lesion detection and early response evaluation of diffuse large B‐cell lymphoma – a whole‐body MRI and diffusion‐weighted imaging study

To compare different MRI sequences for the detection of lesions and the evaluation of response to chemotherapy in patients with diffuse large B‐cell lymphoma (DLBCL), 18 patients with histology‐confirmed DLBCL underwent 3‐T MRI scanning prior to and 1 week after chemotherapy. The MRI sequences included T₁‐weighted pre‐ and post‐contrast, T₂‐weighted with and without fat suppression, and a single‐shot echo‐planar diffusion‐weighted imaging (DWI) with two b values (0 and 800 s/mm²). Conventional MRI sequence comparisons were performed using the contrast ratio between tumor and normal vertebral body instead of signal intensity. The apparent diffusion coefficient (ADC) of the tumor was measured directly on the parametric ADC map. The tumor volume was used as a reference for the evaluation of chemotherapy response. The mean tumor volume was 374 mL at baseline, and decreased by 65% 1 week after chemotherapy (p < 0.01). The T₂‐weighted image with fat suppression showed a significantly higher contrast ratio compared with images from all other conventional MRI sequences, both before and after treatment (p < 0.01, respectively). The contrast ratio of the T₂‐weighted image with fat suppression decreased significantly (p < 0.01), and that of the T₁‐weighted pre‐contrast image increased significantly (p < 0.01), after treatment. However, there was no correlation between the change in contrast ratio and tumor volume. The mean ADC value was 0.68 × 10^–3 mm²/s at baseline; it increased by 89% after chemotherapy (p < 0.001), and the change in ADC value correlated with the change in tumor volume (r = 0.66, p < 0.01). The baseline ADC value also correlated inversely with the percentage change in ADC after treatment (r = ?0.62, p < 0.01). In conclusion, this study indicates that T₂‐weighted imaging with fat suppression is the best conventional sequence for the detection of lesions and evaluation of the efficacy of chemotherapy in DLBCL. DWI with ADC mapping is an imaging modality with both diagnostic and prognostic value that could complement conventional MRI. Copyright © 2013 John Wiley & Sons, Ltd.     

Developing quantitative MRI parameters to characterize host response and tissue ingrowth into collagen scaffolds

The in vivo evaluation of soft biomaterial implant remodeling routinely requires the surgical removal of the implant for subsequent histological assessment of tissue ingrowth and scaffold remodeling. This approach is very resource intensive, often destructive, and imposes practical limitations on how effectively these materials can be evaluated. MRI has the potential to non‐invasively monitor the remodeling of implanted collagen scaffolds in real time. This study investigated the development of a model system to characterize the cellular infiltration, void area fraction, and angiogenesis in collagen scaffold implants using T₂ relaxation time and apparent diffusion coefficient (ADC) maps along with conventional histological techniques. Initial correlations found statistically significant relationships between the MRI and histological parameters for various regions of the implanted sponges: T₂ versus cell density (r ≈ ?0.83); T₂ versus void area fraction (r ≈ +0.78); T₂ versus blood vessel density (r ≈ +0.95); ADC versus cell density (r ≈ ?0.77); and ADC versus void area fraction (r ≈ +0.84). This suggests that MRI is sensitive to specific remodeling parameters and has the potential to serve as a non‐invasive tool to monitor the remodeling of implanted collagen scaffolds, and to ultimately assess the ability of these scaffolds to regenerate the functional properties of damaged tissues such as tendons, ligaments, skin or skeletal muscle.     

Cerebral blood volume estimation by ferumoxytol‐enhanced steady‐state MRI at 9.4 T reveals microvascular impact of α1‐adrenergic receptor antibodies

Cerebrovascular abnormality is frequently accompanied by cognitive dysfunctions, such as dementia. Antibodies against the α₁‐adrenoceptor (α₁‐AR) can be found in patients with Alzheimer's disease with cerebrovascular disease, and have been shown to affect the larger vessels of the brain in rodents. However, the impact of α₁‐AR antibodies on the cerebral vasculature remains unclear. In the present study, we established a neuroimaging method to measure the relative cerebral blood volume (rCBV) in small rodents with the ultimate goal to detect changes in blood vessel density and/or vessel size induced by α₁‐AR antibodies. For this purpose, mapping of R₂* and R₂ was performed using MRI at 9.4 T, before and after the injection of intravascular iron oxide particles (ferumoxytol). The change in the transverse relaxation rates (ΔR₂*, ΔR₂) showed a significant rCBV decrease in the cerebrum, cortex and hippocampus of rats (except hippocampal ΔR₂), which was more pronounced for ΔR₂* than for ΔR₂. Immunohistological analyses confirmed that the α₁‐AR antibody induced blood vessel deficiencies. Our findings support the hypothesis that α₁‐AR antibodies lead to cerebral vessel damage throughout the brain, which can be monitored by MRI‐derived rCBV, a non‐invasive neuroimaging method. This demonstrates the value of rCBV estimation by ferumoxytol‐enhanced MRI at 9.4 T, and further underlines the significance of this antibody in brain diseases involving vasculature impairments, such as dementia. Copyright © 2014 John Wiley & Sons, Ltd.     

A comparison of arterial spin labeling perfusion MRI and DCE‐MRI in human prostate cancer

Perfusion MRI has the potential to provide pathophysiological biomarkers for the evaluating, staging and therapy monitoring of prostate cancer. The objective of this study was to explore the feasibility of noninvasive arterial spin labeling (ASL) to detect prostate cancer in the peripheral zone and to investigate the correlation between the blood flow (BF) measured by ASL and the pharmacokinetic parameters K^trans (forward volume transfer constant), k_ep (reverse reflux rate constant between extracellular space and plasma) and v_e (the fractional volume of extracellular space per unit volume of tissue) measured by dynamic contrast‐enhanced (DCE) MRI in patients with prostate cancer. Forty‐three consecutive patients (ages ranging from 49 to 86 years, with a median age of 74 years) with pathologically confirmed prostate cancer were recruited. An ASL scan with four different inversion times (TI = 1000, 1200, 1400 and 1600 ms) and a DCE‐MRI scan were performed on a clinical 3.0 T GE scanner. BF, K^trans, k_ep and v_e maps were calculated. In order to determine whether the BF values in the cancerous area were statistically different from those in the noncancerous area, an independent t‐test was performed. Spearman's bivariate correlation was used to assess the relationship between BF and the pharmacokinetic parameters K^trans, k_ep and v_e. The mean BF values in the cancerous areas (97.1 ± 30.7, 114.7 ± 28.7, 102.3 ± 22.5, 91.2 ± 24.2 ml/100 g/min, respectively, for TI = 1000, 1200, 1400, 1600 ms) were significantly higher (p < 0.01 for all cases) than those in the noncancerous regions (35.8 ± 12.5, 42.2 ± 13.7, 53.5 ± 19.1, 48.5 ± 13.5 ml/100 g/min, respectively). Significant positive correlations (p < 0.01 for all cases) between BF and the pharmacokinetic parameters K^trans, k_ep and v_e were also observed for all four TI values (r = 0.671, 0.407, 0.666 for TI = 1000 ms; 0.713, 0.424, 0.698 for TI = 1200 ms; 0.604, 0.402, 0.595 for TI = 1400 ms; 0.605, 0.422, 0.548 for TI = 1600 ms). It can be seen that the quantitative ASL measurements show significant differences between cancerous and benign tissues, and exhibit strong to moderate correlations with the parameters obtained using DCE‐MRI. These results show the promise of ASL as a noninvasive alternative to DCE‐MRI. Copyright © 2014 John Wiley & Sons, Ltd.     

Diffusion‐weighted MRI of the prostate without susceptibility artifacts: Undersampled multi‐shot turbo‐STEAM with rotated radial trajectories

The aim of this study was to develop and evaluate a clinically feasible approach to diffusion‐weighted (DW) MRI of the prostate without susceptibility‐induced artifacts. The proposed method relies on an undersampled multi‐shot DW turbo‐STEAM sequence with rotated radial trajectories and a multi‐step inverse reconstruction with denoised multi‐shot phase maps. The total acquisition time was below 6 min for a resolution of 1.4 × 1.4 × 3.5 mm³ and six directions at b = 600 s mm^?2. Studies of eight healthy subjects and two patients with prostate cancer were performed at 3 T employing an 18‐channel body‐array coil and elements of the spine coil. The method was compared with conventional DW echo‐planar imaging (EPI) of the prostate. The results confirm that DW STEAM MRI avoids geometric distortions and false image intensities, which were present for both single‐shot EPI (ssEPI) and readout‐segmented EPI, particularly near the intestinal wall of the prostate. Quantitative accuracy of the apparent diffusion coefficient (ADC) was validated with use of a numerical phantom providing ground truth. ADC values in the central prostate gland of healthy subjects were consistent with those measured using ssEPI and with literature data. Preliminary results for patients with prostate cancer revealed a correct anatomical localization of lesions with respect to T₂‐weighted MRI in both mean DW STEAM images and ADC maps. In summary, DW STEAM MRI of the prostate offers clinically relevant advantages for the diagnosis of prostate cancer compared with state‐of‐the‐art EPI‐based approaches. The method warrants extended clinical trials.     

Manganese threonine chelate—a new enteric contrast agent for MRI: a pilot study on rats

Enteric contrast agents are important in gastrointestinal MRI. However, no currently available agent is well established as the standard of care. In this study, in vitro relaxivities of manganese threonine chelate (Mn‐Thr), a common nutritional food supplement, were measured at 1.5 T and 3 T with further investigation of its efficacy and safety in vivo as an enteric contrast agent. According to the calculated relaxivities, T₁W and T₂W TSE sequences of Mn‐Thr solutions at different concentrations were acquired, and the optimal concentration for dark lumen imaging on both T₁W and T₂W images was determined in vitro. To validate the optimal concentration in vivo, eight Sprague‐Dawley rats were randomly divided into two groups. Each group received rectal injection of either 2.00 g/L (about 3.80 mM) Mn‐Thr or saline as an enteric contrast agent and underwent MRI. After a time interval of one week, the same procedures were repeated with the alternative contrast agent. Animals were sacrificed after the second MRI. Tissue manganese quantification and histopathological examination were obtained. Qualitative MR image quality assessments were performed and compared between Mn‐Thr and saline. Measured T₁ and T₂ relaxivities of Mn‐Thr were significantly higher than those of MnCl₂ in vitro (p < 0.05). At the concentration of 2.00 g/L (about 3.80 mM), Mn‐Thr produced a dark lumen on T₁W and T₂W images both in vitro and in vivo. Compared with saline, Mn‐Thr showed significantly more homogenous luminal signal and increased bowel wall conspicuity in image quality assessments. Tissue manganese concentrations were not significantly different between two groups. Histopathological examinations were normal in both groups. Our data suggest that Mn‐Thr possesses favorable paramagnetic properties and can create a homogenous dark lumen on T₁W and T₂W images without obvious side effects in healthy rats. As a commercially available nutritional food supplement, Mn‐Thr appears to be a promising enteric contrast agent for MRI.     

Dynamic contrast-enhanced CEST MRI using a low molecular weight dextran

Natural and synthetic sugars have great potential for developing highly biocompatible and translatable chemical exchange saturation transfer (CEST) MRI contrast agents. In this study, we aimed to develop the smallest clinically available form of dextran, Dex1 (molecular weight, MW ~ 1 kDa), as a new CEST agent. We first characterized the CEST properties of Dex1 in vitro at 11.7 T and showed that the Dex1 had a detectable CEST signal at ~1.2 ppm, attributed to hydroxyl protons. In vivo CEST MRI studies were then carried out on C57BL6 mice bearing orthotopic GL261 brain tumors (n = 5) using a Bruker BioSpec 11.7 T MRI scanner. Both steady-state full Z-spectral images and single offset (1.2 ppm) dynamic dextran-enhanced (DDE) images were acquired before and after the intravenous injection of Dex1 (2 g/kg). The steady-state Z-spectral analysis showed a significantly higher CEST contrast enhancement in the tumor than in contralateral brain (∆MTR_asym^{1.2 ppm} = 0.010 ± 0.006 versus 0.002 ± 0.008, P = 0.0069) at 20 min after the injection of Dex1. Pharmacokinetic analyses of DDE were performed using the area under the curve (AUC) in the first 10 min after Dex1 injection, revealing a significantly higher uptake of Dex1 in the tumor than in brain tissue for tumor-bearing mice (AUC[0-10 min] = 21.9 ± 4.2 versus 5.3 ± 6.4%·min, P = 0.0294). In contrast, no Dex1 uptake was foundling in the brains of non-tumor-bearing mice (AUC[0-10 min] = −1.59 ± 2.43%·min). Importantly, the CEST MRI findings were consistent with the measurements obtained using DCE MRI and fluorescence microscopy, demonstrating the potential of Dex1 as a highly translatable CEST MRI contrast agent for assessing tumor hemodynamics.     

Accelerated ferumoxytol‐enhanced 4D multiphase,steady‐state imaging with contrast enhancement (MUSIC) cardiovascular MRI: validation in pediatric congenital heart disease

The purpose of this work was to validate a parallel imaging (PI) and compressed sensing (CS) combined reconstruction method for a recently proposed 4D non‐breath‐held, multiphase, steady‐state imaging technique (MUSIC) cardiovascular MRI in a cohort of pediatric congenital heart disease patients. We implemented a graphics processing unit accelerated CS‐PI combined reconstruction method and applied it in 13 pediatric patients who underwent cardiovascular MRI after ferumoxytol administration. Conventional breath‐held contrast‐enhanced magnetic resonance angiography (CE‐MRA) was first performed during the first pass of ferumoxytol injection, followed by the original MUSIC and the proposed CS‐PI MUSIC during the steady‐state distribution phase of ferumoxytol. Qualities of acquired images were then evaluated using a four‐point scale. Left ventricular volumes and ejection fractions calculated from the original MUSIC and the CS‐PI MUSIC were also compared with conventional multi‐slice 2D cardiac cine MRI. The proposed CS‐PI MUSIC reduced the imaging time of the MUSIC acquisition to 4.6 ± 0.4 min from 8.9 ± 1.2 min. Computationally intensive image reconstruction was completed within 5 min without interruption of sequential clinical scans. The proposed method (mean 3.3–4.0) provided image quality comparable to that of the original MUSIC (3.2–4.0) (all P ≥ 0.42), and better than conventional breath‐held first‐pass CE‐MRA (1.1–3.3) for 13 anatomical structures (all P ≤ 0.0014) with good inter‐observer agreement (κ > 0.46). The calculated ventricular volumes and ejection fractions from both original MUSIC (r > 0.90) and CS‐PI MUSIC (r > 0.85) correlated well with 2D cine imaging. In conclusion, PI and CS were successfully incorporated into the 4D MUSIC acquisition to further reduce scan time by approximately 50% while maintaining highly comparable image quality in a clinically practical reconstruction time.     

An extended reference region model for DCE‐MRI that accounts for plasma volume

The reference region model (RRM) for dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) provides pharmacokinetic parameters without requiring the arterial input function. A limitation of the RRM is that it assumes that the blood plasma volume in the tissue of interest is zero, but this is often not true in highly vascularized tissues, such as some tumours. This study proposes an extended reference region model (ERRM) to account for tissue plasma volume. Furthermore, ERRM was combined with a two‐fit approach to reduce the number of fitting parameters, and this was named the constrained ERRM (CERRM). The accuracy and precision of RRM, ERRM and CERRM were evaluated in simulations covering a range of parameters, noise and temporal resolutions. These models were also compared with the extended Tofts model (ETM) on in vivo glioblastoma multiforme data. In simulations, RRM overestimated K^trans by over 10% at v_p = 0.01 under noiseless conditions. In comparison, ERRM and CERRM were both accurate, with CERRM showing better precision when noise was included. On in vivo data, CERRM provided maps that had the highest agreement with ETM, whilst also being robust at temporal resolutions as poor as 30 s. ERRM can provide pharmacokinetic parameters without an arterial input function in tissues with non‐negligible v_p where RRM provides inaccurate estimates. The two‐fit approach, named CERRM, further improves on the accuracy and precision of ERRM.