Apparent diffusion coefficients of 31P metabolites in the human calf muscle at 7 T.

PURPOSE: In this study, we aimed to measure the apparent diffusion coefficients (ADCs) of major phosphorous metabolites in the human calf muscle at 7 T with a diffusion-weighted (DW)-STEAM sequence. METHODS: A DW-STEAM sequence with bipolar gradients was implemented at 7 T, and DW MR spectra were acquired in three orthogonal directions in the human calf muscle of six healthy volunteers (TE/TM/TR = 15 ms/750 ms/5 s) at three b-values (0, 800, and 1200 s/mm2). Frequency and phase alignments were applied prior to spectral averaging. Averaged DW MR spectra were analyzed with LCModel, and ADCs of 31P metabolites were estimated. RESULTS: Four metabolites (phosphocreatine (PCr), adenosine triphosphate (ATP), inorganic phosphate (Pi) and glycerol phosphorylcholine (GPC)) were quantified at all b-values with mean CRLBs below 10%. The ADC values of PCr, ATP, Pi, and GPC were (0.24 ± 0.02, 0.15 ± 0.04, 0.43 ± 0.14, 0.40 ± 0.09) × 10-3 mm2/s, respectively. CONCLUSION: The ADCs of four 31P metabolites were successfully measured in the human calf muscle at 7 T, among which those of ATP, Pi and GPC were reported for the first time in humans. This study paves the way to investigate 31P metabolite diffusion properties in health and disease on the clinical MR scanner.

Estimation of intravoxel incoherent motion (IVIM) parameters in vertebral bone marrow: a comparative study of five algorithms.

OBJECTIVES: To access the performances of different algorithms for quantification of Intravoxel incoherent motion (IVIM) parameters D, f, [Formula: see text] in Vertebral Bone Marrow (VBM). MATERIALS AND METHODS: Five algorithms were studied: four deterministic algorithms (the One-Step and three segmented methods: Two-Step, Three-Step, and Fixed-[Formula: see text] algorithm) based on the least-squares (LSQ) method and a Bayesian probabilistic algorithm. Numerical simulations and quantification of IVIM parameters D, f, [Formula: see text] in vivo in vertebral bone marrow, were done on six healthy volunteers. The One-way repeated-measures analysis of variance (ANOVA) followed by Bonferroni's multiple comparison test (p value = 0.05) was applied. RESULTS: In numerical simulations, the Bayesian algorithm provided the best estimation of D, f, [Formula: see text] compared to the deterministic algorithms. In vivo VBM-IVIM, the values of D and f estimated by the Bayesian algorithm were close to those of the One-Step method, in contrast to the three segmented methods. DISCUSSION: The comparison of the five algorithms indicates that the Bayesian algorithm provides the best estimation of VBM-IVIM parameters, in both numerical simulations and in vivo data.

Avoiding data loss: Synthetic MRIs generated from diffusion imaging can replace corrupted structural acquisitions for freesurfer-seeded tractography.

Magnetic Resonance Imaging (MRI) motion artefacts frequently complicate structural and diffusion MRI analyses. While diffusion imaging is easily 'scrubbed' of motion affected volumes, the same is not true for T1w or T2w 'structural' images. Structural images are critical to most diffusion-imaging pipelines thus their corruption can lead to disproportionate data loss. To enable diffusion-image processing when structural images are missing or have been corrupted, we propose a means by which synthetic structural images can be generated from diffusion MRI. This technique combines multi-tissue constrained spherical deconvolution, which is central to many existing diffusion analyses, with the Bloch equations that allow simulation of MRI intensities for given scanner parameters and magnetic resonance (MR) tissue properties. We applied this technique to 32 scans, including those acquired on different scanners, with different protocols and with pathology present. The resulting synthetic T1w and T2w images were visually convincing and exhibited similar tissue contrast to acquired structural images. These were also of sufficient quality to drive a Freesurfer-based tractographic analysis. In this analysis, probabilistic tractography connecting the thalamus to the primary sensorimotor cortex was delineated with Freesurfer, using either real or synthetic structural images. Tractography for real and synthetic conditions was largely identical in terms of both voxels encountered (Dice 0.88-0.95) and mean fractional anisotropy (intrasubject absolute difference 0.00-0.02). We provide executables for the proposed technique in the hope that these may aid the community in analysing datasets where structural image corruption is common, such as studies of children or cognitively impaired persons.

Voxel-based mapping of five MR biomarkers in the wrist bone marrow.

OBJECTIVE: MRI is a reliable and accurate technique to characterize rheumatoid arthritis. The aim of this study was to provide voxel-by-voxel 3D maps of the proton density fat fraction (PDFF), the T1 of water (T1W), the T1 of fat (T1F), the T2* of water (T2*W), the T2* of fat (T2*F) in the wrist bone marrow. MATERIALS AND METHODS: The experiments were conducted on 14 healthy volunteers (mean age: 24 ± 4). The data were acquired at 1.5 T using two optimized four-echo 3D 1.2 × 1.2 × 1.2 mm3-isotropic spoiled gradient sequences. A repeatability study was carried out. The measurements were done using a homemade parametric viewer software. RESULTS: The inter-volunteer results were, on average: PDFF = 86 ± 3%, T1W = 441 ± 113 ms, T1F = 245 ± 19 ms, T2*W = 6 ± 1 ms and T2*F = 16 ± 3 ms. The coefficients of variation were for fat based biomarkers CVPDFF < 5%, CVT1F < 15% and CVT2*F < 10% in the repeatability study. DISCUSSION: The protocol and quantification tool proposed in this study provide high-resolution voxel-by-voxel 3D maps of five biomarkers in the wrist in less than 4 min of acquisition.

Confounding factors in multi-parametric q-MRI protocol: A study of bone marrow biomarkers at 1.5 T.

OBJECT: The MRI tissue characterization of vertebral bone marrow includes the measurement of proton density fat fraction (PDFF), T1 and T2* relaxation times of the water and fat components (T1W, T1F, T2*W, T2*F), IVIM diffusion D, perfusion fraction f and pseudo-diffusion coefficient D*. However, the measurement of these vertebral bone marrow biomarkers (VBMBs) is affected with several confounding factors. In the current study, we investigated these confounding factors including the regional variation taking the example of variation between the anterior and posterior area in lumbar vertebrae, B1 inhomogeneity and the effect of fat suppression on f. MATERIALS AND METHODS: A fat suppressed diffusion-weighted sequence and two 3D gradient multi-echo sequences were used for the measurements of the seven VBMBs. A turbo flash B1 map sequence was used to estimate B1 inhomogeneities and thus, to correct flip angle for T1 quantification. We introduced a correction to perfusion fraction f measured with fat suppression, namely fPDFF. RESULTS: A significant difference in the values of PDFF, f and fPDFF, T1F, T2*W and D was observed between the anterior and posterior region. Although, little variations of flip angle were observed in this anterior-posterior direction in one vertebra but larger variations were observed in head-feet direction from L1 to L5 vertebrae. DISCUSSION: The regional difference in PDFF, fPDFF and T2*W can be ascribed to differences in the trabecular bone density and vascular network within vertebrae. The regional variation of VBMBs shows that care should be taken in reproducing the same region-of-interest location along a longitudinal study. The same attention should be taken while measuring f in fatty environment, and measuring T1. Furthermore, the MRI-protocol presented here allows for measurements of seven VBMBs in less than 6 min and is of interest for longitudinal studies of bone marrow diseases.

Comparison of 18F-Choline PET/CT and MRI functional parameters in prostate cancer.

AIM: 18F-Choline (FCH) uptake parameters are strong indicators of aggressive disease in prostate cancer. Functional parameters derived by magnetic resonance imaging (MRI) are also correlated to aggressive disease. The aim of this work was to evaluate the relationship between metabolic parameters derived by FCH PET/CT and functional parameters derived by MRI. MATERIALS AND METHODS: Fourteen patients with proven prostate cancer who underwent FCH PET/CT and multiparametric MRI were enrolled. FCH PET/CT consisted in a dual phase: early pelvic list-mode acquisition and late whole-body acquisition. FCH PET/CT and multiparametric MRI examinations were registered and tumoral volume-of-interest were drawn on the largest lesion visualized on the apparent diffusion coefficient (ADC) map and projected onto the different multiparametric MR images and FCH PET/CT images. Concerning the FCH uptake, kinetic parameters were extracted with the best model selected using the Akaike information criterion between the one- and two-tissue compartment models with an imaging-derived plasma input function. Other FCH uptake parameters (early SUVmean and late SUVmean) were extracted. Concerning functional parameters derived by MRI scan, cell density (ADC from diffusion weighting imaging) and vessel permeability (Ktrans and Ve using the Tofts pharmakinetic model from dynamic contrast-enhanced imaging) parameters were extracted. Spearman's correlation coefficients were calculated to compare parameters. RESULTS: The one-tissue compartment model for kinetic analysis of PET images was selected. Concerning correlation analysis between PET parameters, K1 was highly correlated with early SUVmean (r = 0.83, p < 0.001) and moderately correlated with late SUVmean (r = 0.66, p = 0.010) and early SUVmean was highly correlated with late SUVmean (r = 0.90, p < 0.001). No significant correlation was found between functional MRI parameters. Concerning correlation analysis between PET and functional MRI parameters, K1 (from FCH PET/CT imaging) was moderately correlated with Ktrans (from perfusion MR imaging) (r = 0.55, p = 0.041). CONCLUSIONS: No significant correlation was found between FCH PET/CT and multiparametric MRI metrics except FCH influx which is moderately linked to the vessel permeability in prostate cancer.

Measurements of Diffusion and Perfusion in Vertebral Bone Marrow Using Intravoxel Incoherent Motion (IVIM) With Multishot, Readout-Segmented (RESOLVE) Echo-Planar Imaging.

BACKGROUND: A limited number of studies have used the intravoxel incoherent motion (IVIM) approach on bone marrow. In none of the previous studies were the effects of fat suppression on the IVIM parameters investigated. PURPOSE: To measure the water diffusion coefficient and the perfusion fraction in vertebral bone marrow using IVIM with multishot, readout-segmented (RESOLVE) echo-planar imaging and to assess the effects of different fat suppression techniques on the measurement of the IVIM parameters. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Six healthy volunteers (24.2 ± 4.3 years). FIELD STRENGTH/SEQUENCE: 1.5T, RESOLVE. ASSESSMENT: Four experiments were performed: 1) RESOLVE imaging without fat suppression, 2) with fat saturation (FS), 3) with spectral attenuated inversion recovery (SPAIR), and 4) with short-tau inversion recovery (STIR). The water diffusion coefficient D, pseudo-diffusion coefficient D*, and the perfusion fraction f were assessed in the vertebral bodies of the lumbar vertebrae. STATISTICAL TESTS: One-way repeated-measures analysis of variance (ANOVA) followed by Bonferroni's multiple comparison test. RESULTS: The RESOLVE IVIM protocol allowed for measurement of D, D*, and f in all volunteers. The signal of lipid protons affected the quantification of the IVIM diffusion coefficient: D = 0.24 ± 0.10 (×10-3 mm2 /s), no FS; D = 0.43 ± 0.07 (×10-3 mm2 /s), FS; D = 0.42 ± 0.07 (×10-3 mm2 /s), SPAIR; D = 0.35 ± 0.10 (×10-3 mm2 /s), STIR; and IVIM perfusion fraction f = 7.5 ± 1.9% no FS, f = 14.5 ± 5.4%, FS; f = 12.5 ± 2.6%, SPAIR; f = 18.1 ± 6.1%, STIR. No significant effect (P = 0.36) was found on the quantification of D*. DATA CONCLUSION: An IVIM-MRI protocol using the RESOLVE sequence was implemented for measurements of vertebral bone marrow diffusion and the perfusion. The comparison between the protocols with and without fat suppression indicates that the lipid signal results in an underestimation of both D and f. LEVEL OF EVIDENCE: Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;49:768-776.

Optimization of temporal sampling for 18F-choline uptake quantification in prostate cancer assessment.

BACKGROUND: Suboptimal temporal sampling of time-activity curves (TAC) from dynamic 18F-fluoromethylcholine (FCH) PET images may introduce bias in quantification of FCH uptake in prostate cancer assessment. We sought to define an optimal temporal sampling protocol for dynamic FCH PET imaging. Seven different time samplings were tested: 5 × 60″, 10 × 30″, 15 × 15″-1 × 75″, 6 × 10″-8 × 30″, 12 × 5″-8 × 30″; 10 × 5″-4 × 10″-3 × 20″-5 × 30″, and 8 × 3″-8 × 12″-6 × 30″. First, the irreversible and reversible one-tissue compartment model with blood volume parameter (VB) (respectively, 1T1K+VB and 1T2k+VB, with K1 = transfer coefficient from the arterial blood to the tissue compartment and k2 = transfer coefficient from the tissue compartment to the arterial blood) were compared for 37 lesions from 32 patients who underwent FCH PET imaging for initial or recurrence assessment of prostate cancer, and the model was selected using the Akaike information criterion. To determine the optimal time sampling, K1 values extracted from 1000 noisy-simulated TAC using Monte Carlo method from the seven different time samplings were compared to a target K1 value which is the average of the K1 values extracted from the 37 lesions using an imaging-derived input function for each patient. K1 values extracted with the optimal time sampling for each tumoral lesion were compared to K1 values extracted from each of the other time samplings for the 37 lesions. RESULTS: The 1T2k + VB model was selected. The target K1 value as the objective was 0.506 mL/ccm/min (range 0.216-1.246). Results showed a significant difference between K1 values from the simulated TAC with the seven different time samplings analyzed. The closest K1 value from the simulated TAC to the target K1 value was obtained by the 12 × 5″-8 × 30″ time sampling. Concerning the clinical validation, K1 values extracted from the optimal time sampling (12 × 5″-8 × 30″) were significantly different with K1 values extracted from the other time samplings, except for the comparison with K1 values extracted from the 10 × 5″-4 × 10″-3 × 20″-5 × 30″ time sampling. CONCLUSIONS: A two-phase framing of dynamic PET reconstruction with frame durations of 5 s (blood phase) and 30 s (tissue phase) could be used to sample the TAC for uptake quantification in prostate cancer assessment.

Prostate cancer detection using quantitative T2 and T2 -weighted imaging: The effects of 5-alpha-reductase inhibitors in men on active surveillance.

BACKGROUND: T2 -weighted imaging (T2 -WI) information has been used in a qualitative manner in the assessment of prostate cancer. Quantitative derivatives (T2 relaxation time) can be generated from T2 -WI. These outputs may be useful in helping to discriminate clinically significant prostate cancer from background signal. PURPOSE/HYPOTHESIS: To investigate changes in quantitative T2 parameters in lesions and noncancerous tissue of men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo daily for 6 months. STUDY TYPE: Retrospective. POPULATION/SUBJECTS: Forty men randomized to 6 months of daily dutasteride (n = 20) or placebo (n = 20). FIELD STRENGTH/SEQUENCE: Multiparametric 3T MRI at baseline and 6 months. This included a multiecho MR sequence for quantification of the T2 relaxation times, in three regions of interest (index lesion, noncancerous peripheral [PZ] and transitional [TZ] zones). A synthetic signal contrast (T2 Q contrast) between lesion and noncancerous tissue was assessed using quantitative T2 values. Signal contrast was calculated using the T2 -weighted sequence (T2 W contrast). ASSESSMENT: Two radiologists reviewed the scans in consensus according to Prostate Imaging Reporting and Data System (PI-RADS v. 2) guidelines. STATISTICAL TESTS: Wilcoxon and Mann-Whitney U-tests, Spearman's correlation. RESULTS: When compared to noncancerous tissue, shorter T2 values were observed within lesions at baseline (83.5 and 80.5 msec) and 6 months (81.5 and 81.9 msec) in the placebo and dutasteride arm, respectively. No significant differences for T2 W contrast at baseline and after 6 months were observed, both in the placebo (0.40 [0.29-0.49] vs. 0.43 [0.25-0.49]; P = 0.881) and dutasteride arm (0.35 [0.24-0.47] vs. 0.37 [0.22-0.44]; P = 0.668). There was a significant, positive correlation between the T2 Q contrast and the T2 W contrast values (r = 0.786; P < 0.001). DATA CONCLUSION: The exposure to antiandrogen therapy did not significantly influence the T2 contrast or the T2 relaxation values in men on active surveillance for prostate cancer. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1646-1653.

MRI findings in men on active surveillance for prostate cancer: does dutasteride make MRI visible lesions less conspicuous? Results from a placebo-controlled, randomised clinical trial.

OBJECTIVES: To investigate changes in the Apparent Diffusion Coefficient (ADC) using diffusion-weighted imaging (DWI) in men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo. METHODS: We analysed 37 men, randomised to 6 months of daily dutasteride (n = 18) or placebo (n = 19), undergoing 3T multi-parametric Magnetic Resonance Imaging (mpMRI) scans at baseline and 6 months. Images were reviewed blind to treatment allocation and clinical information. Mean ADC of peripheral (PZ) and transition (TZ) zones, and MR-suspicious lesions were compared between groups over 6 months. Conspicuity was defined as the PZ divided by tumour ADC, and its change over 6 months was assessed. RESULTS: A decrease in mean conspicuity in the dutasteride group (but not the controls) was seen over 6 months (1.54 vs 1.38; p = 0.025). Absolute changes in ADC and conspicuity were significantly different between placebo and dutasteride groups at 6 months: (-0.03 vs 0.08, p = 0.033) and (0.11 vs -0.16, p = 0.012), as were percentage changes in the same parameters: (-2.27% vs 8.56% p = 0.048) and (9.25% vs -9.89% p = 0.013). CONCLUSIONS: Dutasteride was associated with increased tumour ADC and reduced conspicuity. A lower threshold for triggering biopsy might be considered in men on dutasteride undergoing mpMRI for prostate cancer. KEY POINTS: • Dutasteride increases ADC and reduces conspicuity in small mpMRI-visible prostate cancers. • Knowledge of dutasteride exposure is important in the interpretation of prostate mpMRI. • A lower threshold for triggering biopsy may be appropriate on dutasteride.

A fast method for the quantification of fat fraction and relaxation times: Comparison of five sites of bone marrow.

PURPOSE: Bone marrow is found either as red bone marrow, which mainly contains haematopoietic cells, or yellow bone marrow, which mainly contains adipocytes. In adults, red bone marrow is principally located in the axial skeleton. A recent study has introduced a method to simultaneously estimate the fat fraction (FF), the T1 and T2* relaxation times of water (T1w, T2*w) and fat (T1f and T2*f) in the vertebral bone marrow. The aim of the current study was to measure FF, T1w, T1f, T2*w and T2*f in five sites of bone marrow, and to assess the presence of regional variations. METHODS: MRI experiments were performed at 1.5T on five healthy volunteers (31.6±15.6years) using a prototype chemical-shift-encoded 3D multi-gradient-echo sequence (VIBE) acquired with two flip angles. Acquisitions were performed in the shoulders, lumbar spine and pelvis, with acquisition times of <25seconds per sequence. Signal intensities of magnitude images of the individual echoes were used to fit the signal and compute FF, T1w, T1f, T2*w and T2*f in the humerus, sternum, vertebra, ilium and femur. RESULTS: Regional variations of fat fraction and relaxation times were observed in these sites, with higher fat fraction and longer T1w in the epiphyses of long bones. A high correlation between FF and T1w was measured in these bones (R=0.84 in the humerus and R=0.84 in the femur). In most sites, there was a significant difference between water and fat relaxation times, attesting the relevance of measuring these parameters separately. CONCLUSION: The method proposed in the current study allowed for measurements of FF, T1w, T1f, T2*w and T2*f in five sites of bone marrow. Regional variations of these parameters were observed and a strong negative correlation between the T1 of water and the fat fraction in bones with high fat fractions was found.

The Effect of Dutasteride on Magnetic Resonance Imaging Defined Prostate Cancer: MAPPED-A Randomized, Placebo Controlled, Double-Blind Clinical Trial.

PURPOSE: Dutasteride, which is licensed for symptomatic benign prostatic hyperplasia, has been associated with a lower progression rate of low risk prostate cancer. We evaluated the effect of dutasteride on prostate cancer volume as assessed by T2-weighted magnetic resonance imaging. MATERIALS AND METHODS: In this randomized, double-blind, placebo controlled trial, men with biopsy proven, low-intermediate risk prostate cancer (up to Gleason 3 + 4 and PSA up to 15 ng/ml) who had visible lesion of 0.2 ml or greater on T2-weighted magnetic resonance imaging sequences were randomized to daily dutasteride 0.5 mg or placebo for 6 months. Lesion volume was assessed at baseline, and 3 and 6 months with image guided biopsy to the lesion at study exit. The primary end point was the percent reduction in lesion volume over 6 months. This trial was registered with the European Clinical Trials register (EudraCT 2009-102405-18). RESULTS: A total of 42 men were recruited between June 2010 and January 2012. In the dutasteride group, the average volumes at baseline and 6 months were 0.55 and 0.38 ml, respectively and the average reduction was 36%. In the placebo group, the average volumes at baseline and 6 months were 0.65 and 0.76 ml, respectively, and the average reduction was -12%. The difference in percent reductions between the groups was 48% (95% CI 27.4-68.3, p <0.0001). The most common adverse event was deterioration in erectile function, which was 25% in men randomized to dutasteride and 16% in men randomized to placebo. CONCLUSIONS: Dutasteride was associated with a significant reduction in prostate cancer volume on T2-weighted magnetic resonance imaging compared to placebo.

Breath-hold MR measurements of fat fraction, T1 , and T2 * of water and fat in vertebral bone marrow.

PURPOSE: To assess the feasibility of measuring the fat fraction, T1 and T2 * relaxation times of water and fat signals in vertebral bone marrow using breath-hold magnetic resonance imaging (MRI) gradient echo images of the spine. MATERIALS AND METHODS: MRI experiments were performed at 1.5T on eight healthy volunteers (35.1 ± 15.7 years, five men and three women) using two sagittal four-echo 3D gradient echo volumetric interpolated breath-hold examination (VIBE Dixon) sequences acquired at two different flip angles (5° and 15°). The water/fat decomposition was performed in the vertebral bodies of L1 to L5 by fitting the signal to a function that depends on the echo time and the flip angle to calculate the fat fraction (FF) and T1 and T2 * relaxation times of water and fat signals. Repeatability was assessed by scanning one volunteer six times. RESULTS: The mean fat fraction over L1 to L5 was 33 ± 8%. The mean T1 and T2 * of water and fat signals were respectively T1w = 701 ± 151 msec, T2 *w = 13.7 ± 2.9 msec, T1f = 334 ± 113 msec, and T2 *f = 11.4 ± 2.7 msec. When considering each vertebra separately, the fat fraction increased from L1 to L5 and the T1w decreased from L1 to L5. The mean coefficients of variation obtained from the repeatability study were 8% (FF), 11% (T1w ), 17% (T1f ), 8% (T2 *w ), and 27% (T2 *f ). CONCLUSION: The method introduced in the current study allows for the measurement of the fat fraction and water and fat relaxation times, with a total acquisition time of less than 40 seconds. J. Magn. Reson. Imaging 2016;44:549-555.

In vivo MR spectroscopy of human breast tissue: quantification of fatty acid composition at a clinical field strength (3 T).

OBJECTIVE: To evaluate the feasibility of in vivo measurement of the fatty acid (FA) composition of breast adipose tissue by MRS on a clinical platform. MATERIAL AND METHODS: MRS experiments were performed at 3 T, using a STEAM sequence, on 25 patients diagnosed with breast cancer. MR spectra, acquired on healthy breast tissue, were analysed with the LCModel. RESULTS: The measured values of the saturated fatty acid (SFA), mono-unsaturated fatty acid (MUFA) and poly-unsaturated fatty acid (PUFA) fractions were 23.8 ± 7.1%, 55.4 ± 6.8% and 20.8 ± 4.4%, respectively. The values of SFA, MUFA and PUFA observed in the current study are in the same range as those found in two previous studies performed at 7 T. CONCLUSION: The results of the current study show that it is possible to quantify the fatty acid composition of breast tissue in vivo in a clinical setting (3 T).

A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator SRT2104 in elderly volunteers.

BACKGROUND: SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD(+)-dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers. METHODS: Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity. RESULTS: SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2-4 hours with elimination half-life of 15-20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation. CONCLUSIONS: SRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00964340.

Characterization of tumor vasculature in mouse brain by USPIO contrast-enhanced MRI.

Detailed characterization of the tumor vasculature provides a better understanding of the complex mechanisms associated with tumor development and is especially important to evaluate responses to current therapies which target the tumor vasculature. Magnetic resonance imaging (MRI) studies of tumors have been mostly performed using gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) contrast-enhanced imaging, which relies on Gd-DTPA leakage from hyperpermeable tumor vessels and subsequent accumulation in the tumor interstitium. In certain tumor types, especially diffuse glioma in the brain, incorporated tumor vessels are not necessarily leaky, complicating effective diagnosis via Gd-DTPA contrast-enhanced MRI. Another class of contrast agents, based on superparamagnetic ultrasmall iron oxide particles (USPIO), allows for non-invasive assessment of vascular volume within the tumor. Vascular volume can be obtained by calculating the change in water proton transverse relaxation rate (R (2) or R (2)) following USPIO administration. This allows for an objective comparison between vascular volumes of different tumors and also allows to perform longitudinal studies in order to assess, for example, treatment efficacy. Moreover, since the USPIO T (2) relaxivity is up to 20 times that of Gd-DTPA, USPIO provides a highly sensitive marker for alterations in vascular volume among tissues; this characteristic might be exploited for tumor detection. Thus, USPIO imaging may be a very attractive alternative to the most commonly used Gd-DTPA imaging and will at least have added value, especially for detection and delineation of diffuse infiltrative brain tumors.

Assessment of Blood Hemodynamics by USPIO-Induced R(1) Changes in MRI of Murine Colon Carcinoma.

The objective of this study is to assess whether ultrasmall superparamagnetic iron oxide (USPIO)-induced changes of the water proton longitudinal relaxation rate (R(1)) provide a means to assess blood hemodynamics of tumors. Two types of murine colon tumors (C26a and C38) were investigated prior to and following administration of USPIO blood-pool contrast agent with fast R(1) measurements. In a subpopulation of mice, R(1) was measured following administration of hydralazine, a well-known blood hemodynamic modifier. USPIO-induced R(1) increase in C38 tumors (DeltaR(1) = 0.072 +/- 0.0081 s(-1)) was significantly larger than in C26a tumors (DeltaR(1) = 0.032 +/- 0.0018 s(-1), N = 9, t test, P < 0.001). This was in agreement with the immunohistochemical data that showed higher values of relative vascular area (RVA) in C38 tumors than in C26a tumors (RVA = 0.059 +/- 0.015 vs. 0.020 +/- 0.011; P < 0.05). Following administration of hydralazine, a decrease in R(1) value was observed. This was consistent with the vasoconstriction induced by the steal effect mechanism. In conclusion, R(1) changes induced by USPIO are sensitive to tumor vascular morphology and to blood hemodynamics. Thus, R(1) measurements following USPIO administration can give novel insight into the effects of blood hemodynamic modifiers, non-invasively and with a high temporal resolution.

Radiation effects in the rat spinal cord: evaluation with apparent diffusion coefficient versus T2 at serial MR imaging.

PURPOSE: To prospectively determine whether apparent diffusion coefficients (ADCs) are more sensitive to radiation-induced changes in the rat spinal cord than T2 relaxation times. MATERIALS AND METHODS: The study was approved by the institutional ethical committee on animal welfare. One centimeter of the thoracolumbar spinal cord of six rats was irradiated with 36 Gy. For 3-6 months after irradiation, five 7.0-T magnetic resonance (MR) imaging measurements were performed in each rat until motor impairment developed. Six age-matched rats were examined as controls. Measurements were performed by using diffusion-weighted imaging with five b values and a spin-echo sequence with 20 echoes. ADC and T2 values were calculated, and the spatiotemporal evolution of the radiation-induced lesions was determined semiautomatically. The final MR measurements were compared with the histologic findings. RESULTS: Shortly before the neurologic signs appeared, the first radiation effects manifested as well-circumscribed white matter (WM) lesions with a low longitudinal ADC and normal or high T2. WM lesions with high T2 correlated with confluent necrosis at histologic analysis, whereas WM lesions with normal T2 correlated with focal necrosis and demyelination. In the gray matter (GM), lesions with diffusely high T2 were present and were attributed to edema. T2 changes in the GM preceded T2 and ADC changes in the WM. CONCLUSION: In the WM, longitudinal ADC was more sensitive for the detection of radiation damage than T2, but in the GM, T2 was more sensitive.

Noninvasive magnetic resonance imaging of the development of individual colon cancer tumors in rat liver.

Monitoring tumor development is essential for the understanding of mechanisms involved in tumor progression and to determine efficacy of therapy. One of the evolving approaches is longitudinal noninvasive magnetic resonance imaging (MRI) of tumors in experimental models. We applied high-resolution MRI at 7 Tesla to study the development of colon cancer tumors in rat liver. MRI acquisition was triggered to the respiratory cycle to minimize motion artifacts. A special radio frequency (RF) coil was designed to acquire detailed T1-weighted and T2-weighted images of the liver. T2-weighted images identified hyperintense lesions representing tumors with a minimum diameter of 2 mm, enabling the determination of growth rates and morphological aspects of individual tumors. It is concluded that high-resolution MRI using a dedicated RF coil and triggering to the respiratory cycle is an excellent tool for quantitative and morphological analysis of individual diffusely distributed tumors throughout the liver. However, at present, MRI requires expensive equipment and expertise and is a time-consuming methodology. Therefore, it should preferably be used for dedicated applications rather than for high-throughput assessment of total tumor load in animals.

Magnetic resonance imaging-based detection of glial brain tumors in mice after antiangiogenic treatment.

Proper delineation of gliomas using contrast-enhanced magnetic resonance imaging (CE-MRI) poses a problem in neuro-oncology. The blood brain barrier (BBB) in areas of diffuse-infiltrative growth may be intact, precluding extravasation and subsequent MR-based detection of the contrast agent gadolinium diethylenetriaminepenta-acetic acid (Gd-DTPA). Treatment with antiangiogenic compounds may further complicate tumor detection as such compounds can restore the BBB in angiogenic regions. The increasing number of clinical trials with antiangiogenic compounds for treatment of gliomas calls for the development of alternative imaging modalities. Here we investigated whether CE-MRI using ultrasmall particles of iron oxide (USPIO, Sinerem) as blood pool contrast agent has additional value for detection of glioma in the brain of nude mice. We compared conventional T1-weighted Gd-DTPA-enhanced MRI to T2*-weighted USPIO-enhanced MRI in mice carrying orthotopic U87 glioma, which were either or not treated with the antiangiogenic compound vandetanib (ZD6474, ZACTIMA). In untreated animals, vessel leakage within the tumor and a relatively high tumor blood volume resulted in good MRI visibility with Gd-DTPA- and USPIO-enhanced MRI, respectively. Consistent with previous findings, vandetanib treatment restored the BBB in the tumor vasculature, resulting in loss of tumor detectability in Gd-DTPA MRI. However, due to decreased blood volume, treated tumors could be readily detected in USPIO-enhanced MRI scans. Our findings suggest that Gd-DTPA MRI results in overestimation of the effect of antiangiogenic therapy of glioma and that USPIO-MRI provides an important complementary diagnostic tool to evaluate response to antiangiogenic therapy of these tumors.