Non‐invasive diagnosis and metabolic consequences of congenital portosystemic shunts in C57BL/6 J mice

This study demonstrates the suitability of magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) for the imaging of congenital portosystemic shunts (PSS) in mice, a vascular abnormality in which mesenteric blood bypasses the liver and is instead drained directly to the systemic circulation. The non‐invasive diagnosis performed in tandem with other experimental assessments permits further characterization of liver, whole‐body and brain metabolic defects associated with PSS. Magnetic resonance measurements were performed in a 26‐cm, horizontal‐bore, 14.1‐T magnet. MRA was obtained with a three‐dimensional gradient echo sequence (GRE; in‐plane resolution, 234 × 250 × 234 μm³) using a birdcage coil. Two‐dimensional GRE MRI with high spatial resolution (in‐plane resolution, 100 × 130 μm²; slices, 30 × 0.3 mm) was performed using a surface coil. Brain‐ (dorsal hippocampus) and liver‐localized ¹H magnetic resonance spectroscopy (MRS) was also performed with the surface coil. Whole‐body metabolic status was evaluated with an oral glucose tolerance test (OGTT). Both MRA and anatomical MRI allowed the identification of hepatic vessels and the diagnosis of PSS in mice. The incidence of PSS was about 10%. Hepatic lipid content was higher in PSS than in control mice (5.1 ± 2.8% versus 1.8 ± 0.6%, p = 0.02). PSS mice had higher brain glutamine concentration than controls (7.3 ± 1.0 μmol/g versus 2.7 ± 0.6 μmol/g, p < 0.0001) and, conversely, lower myo‐inositol (4.2 ± 0.6 μmol/g versus 6.0 ± 0.4 μmol/g, p < 0.0001), taurine (9.7 ± 1.2 μmol/g versus 11.0 ± 0.4 μmol/g, p < 0.01) and total choline (0.9 ± 0.1 μmol/g versus 1.2 ± 0.1 μmol/g, p < 0.001) concentrations. Fasting blood glucose and plasma insulin were lower in PSS than in control mice (4.7 ± 0.5mM versus 8.8 ± 0.6mM, p < 0.0001; and 0.04 ± 0.03 μg/L versus 0.3 ± 0.2 μg/L, p = 0.02, respectively). Glucose clearance during OGTT was delayed and less efficient in PSS mice than in controls. Thus, given the non‐negligible incidence of PSS in inbred mice, the undiagnosed presence of PSS will, importantly, have an impact on experimental outcomes, notably in studies addressing brain, liver or whole‐body metabolism.     

Proton and phosphorus magnetic resonance spectroscopy of the healthy human breast at 7 T

In vivo water‐ and fat‐suppressed ¹H magnetic resonance spectroscopy (MRS) and ³¹P magnetic resonance adiabatic multi‐echo spectroscopic imaging were performed at 7 T in duplicate in healthy fibroglandular breast tissue of a group of eight volunteers. The transverse relaxation times of ³¹P metabolites were determined, and the reproducibility of ¹H and ³¹P MRS was investigated. The transverse relaxation times for phosphoethanolamine (PE) and phosphocholine (PC) were fitted bi‐exponentially, with an added short T₂ component of 20 ms for adenosine monophosphate, resulting in values of 199 ± 8 and 239 ± 14 ms, respectively. The transverse relaxation time for glycerophosphocholine (GPC) was also fitted bi‐exponentially, with an added short T₂ component of 20 ms for glycerophosphatidylethanolamine, which resonates at a similar frequency, resulting in a value of 177 ± 6 ms. Transverse relaxation times for inorganic phosphate, γ‐ATP and glycerophosphatidylcholine mobile phospholipid were fitted mono‐exponentially, resulting in values of 180 ± 4, 19 ± 3 and 20 ± 4 ms, respectively. Coefficients of variation for the duplicate determinations of ¹H total choline (tChol) and the ³¹P metabolites were calculated for the group of volunteers. The reproducibility of inorganic phosphate, the sum of phosphomonoesters and the sum of phosphodiesters with ³¹P MRS imaging was superior to the reproducibility of ¹H MRS for tChol. ¹H and ³¹P data were combined to calculate estimates of the absolute concentrations of PC, GPC and PE in healthy fibroglandular tissue, resulting in upper limits of 0.1, 0.1 and 0.2 mmol/kg of tissue, respectively.     

Initial investigation of glucose metabolism in mouse brain using enriched 17O‐glucose and dynamic 17O‐MRS

In this initial work, the in vivo degradation of ¹⁷O‐labeled glucose was studied during cellular glycolysis. To monitor cellular glucose metabolism, direct ¹⁷O‐magnetic resonance spectroscopy (MRS) was used in the mouse brain at 9.4 T. Non‐localized spectra were acquired with a custom‐built transmit/receive (Tx/Rx) two‐turn surface coil and a free induction decay (FID) sequence with a short TR of 5.4 ms. The dynamics of labeled oxygen in the anomeric 1‐OH and 6‐CH₂OH groups was detected using a Hankel–Lanczos singular value decomposition (HLSVD) algorithm for water suppression. Time‐resolved ¹⁷O‐MRS (temporal resolution, 42/10.5 s) was performed in 10 anesthetized (1.25% isoflurane) mice after injection of a 2.2 M solution containing 2.5 mg/g body weight of differently labeled ¹⁷O‐glucose dissolved in 0.9% physiological saline. From a pharmacokinetic model fit of the H₂¹⁷O concentration–time course, a mean apparent cerebral metabolic rate of ¹⁷O‐labeled glucose in mouse brain of CMR_Glc = 0.07 ± 0.02 μmol/g/min was extracted, which is of the same order of magnitude as a literature value of 0.26 ± 0.06 μmol/g/min reported by ¹⁸F‐fluorodeoxyglucose (¹⁸F‐FDG) positron emission tomography (PET). In addition, we studied the chemical exchange kinetics of aqueous solutions of ¹⁷O‐labeled glucose at the C1 and C6 positions with dynamic ¹⁷O‐MRS. In conclusion, the results of the exchange and in vivo experiments demonstrate that the C6‐¹⁷OH label in the 6‐CH₂OH group is transformed only glycolytically by the enzyme enolase into the metabolic end‐product H₂¹⁷O, whereas C1‐¹⁷OH ends up in water via direct hydrolysis as well as glycolysis. Therefore, dynamic ¹⁷O‐MRS of highly labeled ¹⁷O‐glucose could provide a valuable non‐radioactive alternative to FDG PET in order to investigate glucose metabolism.     

Global brain metabolic quantification with whole‐head proton MRS at 3 T

Total N‐acetyl‐aspartate + N‐acetyl‐aspartate–glutamate (NAA), total creatine (Cr) and total choline (Cho) proton MRS (¹H–MRS) signals are often used as surrogate markers in diffuse neurological pathologies, but spatial coverage of this methodology is limited to 1%–65% of the brain. Here we wish to demonstrate that non‐localized, whole‐head (WH) ¹H–MRS captures just the brain's contribution to the Cho and Cr signals, ignoring all other compartments. Towards this end, 27 young healthy adults (18 men, 9 women), 29.9 ± 8.5 years old, were recruited and underwent T₁‐weighted MRI for tissue segmentation, non‐localizing, approximately 3 min WH ¹H–MRS (T_E/T_R/T_I = 5/10 1 /940 ms) and 30 min ¹H–MR spectroscopic imaging (MRSI) (T_E/T_R = 35/2100 ms) in a 360 cm³ volume of interest (VOI) at the brain's center. The VOI absolute NAA, Cr and Cho concentrations, 7.7 ± 0.5, 5.5 ± 0.4 and 1.3 ± 0.2 mM, were all within 10% of the WH: 8.6 ± 1.1, 6.0 ± 1.0 and 1.3 ± 0.2 mM. The mean NAA/Cr and NAA/Cho ratios in the WH were only slightly higher than the “brain‐only” VOI: 1.5 versus 1.4 (7%) and 6.6 versus 5.9 (11%); Cho/Cr were not different. The brain/WH volume ratio was 0.31 ± 0.03 (brain ≈ 30% of WH volume). Air‐tissue susceptibility‐driven local magnetic field changes going from the brain outwards showed sharp gradients of more than 100 Hz/cm (1 ppm/cm), explaining the skull's Cr and Cho signal losses through resonance shifts, line broadening and destructive interference. The similarity of non‐localized WH and localized VOI NAA, Cr and Cho concentrations and their ratios suggests that their signals originate predominantly from the brain. Therefore, the fast, comprehensive WH‐¹H‐MRS method may facilitate quantification of these metabolites, which are common surrogate markers in neurological disorders.     

In vivo measurement of apparent diffusion coefficients of hyperpolarized 13C‐labeled metabolites

The combination of hyperpolarized MRS with diffusion weighting (dw) allows for determination of the apparent diffusion coefficient (ADC), which is indicative of the intra‐ or extracellular localization of the metabolite. Here, a slice‐selective pulsed‐gradient spin echo sequence was implemented to acquire a series of dw spectra from rat muscle in vivo to determine the ADCs of multiple metabolites after a single injection of hyperpolarized [1‐¹³C]pyruvate. An optimal control optimized universal‐rotation pulse was used for refocusing to minimize signal loss caused by B₁ imperfections. Non‐dw spectra were acquired interleaved with the dw spectra and these were used to correct for signal decay during the acquisition as a result of T₁ decay, pulse imperfections, flow etc. The data showed that the ADC values for [1‐¹³C]lactate (0.4–0.7 µm²/ms) and [1‐¹³C]alanine (0.4–0.9 µm²/ms) were about a factor of two lower than the ADC of [1‐¹³C]pyruvate (1.1–1.5 µm²/ms). This indicates a more restricted diffusion space for the former two metabolites consistent with lactate and alanine being intracellular. The higher ADC for pyruvate (similar to the proton ADC) reflected that the injected substance was not confined inside the muscle cells but also present extracellular. Copyright © 2014 John Wiley & Sons, Ltd.     

Direct in vivo measurement of glycine and the neurochemical profile in the rat medulla oblongata

The medulla oblongata (MO) contains a high density of glycinergic synapses and a particularly high concentration of glycine. The aims of this study were to measure directly in vivo the neurochemical profile, including glycine, in MO using a spin‐echo‐based ¹H MRS sequence at TE = 2.8 ms and to compare it with three other brain regions (cortex, striatum and hippocampus) in the rat. Glycine was quantified in MO at TE = 2.8 ms with a Cramér–Rao lower bound (CRLB) of approximately 5%. As a result of the relatively low level of glycine in the other three regions, the measurement of glycine was performed at TE = 20 ms, which provides a favorable J‐modulation of overlapping myo‐inositol resonance. The other 14 metabolites composing the neurochemical profile were quantified in vivo in MO with CRLBs below 25%. Absolute concentrations of metabolites in MO, such as glutamate, glutamine, γ‐aminobutyrate, taurine and glycine, were in the range of previous in vitro quantifications in tissue extracts. Compared with the other regions, MO had a three‐fold higher glycine concentration, and was characterised by reduced (p < 0.001) concentrations of glutamate (?50 ± 4%), glutamine (–54 ± 3%) and taurine (?78 ± 3%). This study suggests that the functional specialisation of distinct brain regions is reflected in the neurochemical profile. Copyright © 2010 John Wiley & Sons, Ltd.     

Measurement and modeling of diffusion time dependence of apparent diffusion coefficient and fractional anisotropy in prostate tissue ex vivo

The purpose of this study was to measure and model the diffusion time dependence of apparent diffusion coefficient (ADC) and fractional anisotropy (FA) derived from conventional prostate diffusion‐weighted imaging methods as used in recommended multiparametric MRI protocols. Diffusion tensor imaging (DTI) was performed at 9.4 T with three radical prostatectomy specimens, with diffusion times in the range 10–120 ms and b‐values 0–3000 s/mm². ADC and FA were calculated from DTI measurements at b‐values of 800 and 1600 s/mm². Independently, a two‐component model (restricted isotropic plus Gaussian anisotropic) was used to synthesize DTI data, from which ADC and FA were predicted and compared with the measured values. Measured ADC and FA exhibited a diffusion time dependence, which was closely predicted by the two‐component model. ADC decreased by about 0.10–0.15 μm²/ms as diffusion time increased from 10 to 120 ms. FA increased with diffusion time at b‐values of 800 and 1600 s/mm² but was predicted to be independent of diffusion time at b = 3000 s/mm². Both ADC and FA exhibited diffusion time dependence that could be modeled as two unmixed water pools — one having isotropic restricted dynamics, and the other unrestricted anisotropic dynamics. These results highlight the importance of considering and reporting diffusion times in conventional ADC and FA calculations and protocol recommendations, and inform the development of improved diffusion methods for prostate cancer imaging.     

Simultaneous spin‐echo and gradient‐echo BOLD measurements by dynamic MRS

This study aimed to dissociate the intravascular and extravascular contributions to spin‐echo (SE) and gradient‐echo (GE) blood oxygenation level‐dependent (BOLD) signals at 7 T, using dynamic diffusion‐weighted MRS. We simultaneously acquired SE and GE data using a point‐resolved spectroscopy sequence with diffusion weightings of 0, 600, and 1200 s/mm². The BOLD signals were quantified by fitting the free induction decays starting from the SE center to a mono‐exponential decay function. Without diffusion weighting, BOLD signals measured with SE and GE increased by 1.6 ± 0.5% (TE_SE = 40 ms) and 5.2 ± 1.4% (nominal TE_GE = 40 ms) during stimulation, respectively. With diffusion weighting, the BOLD increase during stimulation measured with SE decreased from 1.6 ± 0.5% to 1.3 ± 0.4% (P < 0.001), whereas that measured by GE was unaffected (P > 0.05); the post‐stimulation undershoots in the BOLD signal time courses were largely preserved in both SE and GE measurements. These results demonstrated the feasiblity of simultaneous SE and GE measurements of BOLD signals with and without interleaved diffusion weighting. The results also indicated a predominant extravascular contribution to the BOLD signal time courses, including post‐stimulation undershoots in both SE and GE measurements at 7 T.     

HR‐MAS MRS of the pancreas reveals reduced lipid and elevated lactate and taurine associated with early pancreatic cancer

The prognosis for patients with pancreatic cancer is extremely poor, as evidenced by the disease's five‐year survival rate of ~5%. New approaches are therefore urgently needed to improve detection, treatment, and monitoring of pancreatic cancer. MRS‐detectable metabolic changes provide useful biomarkers for tumor detection and response‐monitoring in other cancers. The goal of this study was to identify MRS‐detectable biomarkers of pancreatic cancer that could enhance currently available imaging approaches. We used ¹H high‐resolution magic angle spinning MRS to probe metabolite levels in pancreatic tissue samples from mouse models and patients. In mice, the levels of lipids dropped significantly in pancreata with lipopolysaccharide‐induced inflammation, in pancreata with pre‐cancerous metaplasia (4 week old p48‐Cre;LSL‐Kras^G12D mice), and in pancreata with pancreatic intraepithelial neoplasia, which precedes invasive pancreatic cancer (8 week old p48‐Cre LSL‐Kras^G12D mice), to 26 ± 19% (p = 0.03), 19 ± 16% (p = 0.04), and 26 ± 10% (p = 0.05) of controls, respectively. Lactate and taurine remained unchanged in inflammation and in pre‐cancerous metaplasia but increased significantly in pancreatic intraepithelial neoplasia to 266 ± 61% (p = 0.0001) and 999 ± 174% (p < 0.00001) of controls, respectively. Importantly, analysis of patient biopsies was consistent with the mouse findings. Lipids dropped in pancreatitis and in invasive cancer biopsies to 29 ± 15% (p = 0.01) and 26 ± 38% (p = 0.02) of normal tissue. In addition, lactate and taurine levels remained unchanged in inflammation but rose in tumor samples to 244 ± 155% (p = 0.02) and 188 ± 67% (p = 0.02), respectively, compared with normal tissue. Based on these findings, we propose that a drop in lipid levels could serve to inform on pancreatitis and cancer‐associated inflammation, whereas elevated lactate and taurine could serve to identify the presence of pancreatic intraepithelial neoplasia and invasive tumor. Our findings may help enhance current imaging methods to improve early pancreatic cancer detection and monitoring. Copyright © 2014 John Wiley & Sons, Ltd.     

Shortening of apparent transverse relaxation time of inorganic phosphate as a breast cancer biomarker

Phosphorus MRS offers a non‐invasive tool for monitoring cell energy and phospholipid metabolism and can be of additional value in diagnosing cancer and monitoring cancer therapy. In this study, we determined the transverse relaxation times of a number of phosphorous metabolites in a group of breast cancer patients by adiabatic multi‐echo spectroscopic imaging at 7 T. The transverse relaxation times of phosphoethanolamine, phosphocholine, inorganic phosphate (P_i), glycerophosphocholine and glycerophosphatidylcholine were 184 ± 8 ms, 203 ± 17 ms, 87 ± 8 ms, 240 ± 56 ms and 20 ± 10 ms, respectively. The transverse relaxation time of P_i in breast cancer tissue was less than half that of healthy fibroglandular tissue. This effect is most likely caused by an up‐regulation of glycolysis in breast cancer tissue that leads to interaction of P_i with the GAPDH enzyme, which forms part of the reversible pathway of exchange of P_i with gamma‐adenosine tri‐phosphate, thus shortening its apparent transverse relaxation time. As healthy breast tissue shows very little glycolytic activity, the apparent T₂ shortening of P_i due to malignant transformation could possibly be used as a biomarker for cancer.     

Alterations in creatine metabolism observed in experimental autoimmune myocarditis using ex vivo proton magic angle spinning MRS

Experimental autoimmune myocarditis (EAM) in rodents is an accepted model of myocarditis and dilated cardiomyopathy (DCM). Altered metabolism is thought to play an important role in the pathogenesis of DCM and heart failure (HF). Study of the metabolism may provide new diagnostic information and insights into the mechanisms of myocarditis and HF. Proton MRS (¹H‐MRS) has not yet been used to study the changes occurring in myocarditis and subsequent HF. We aimed to explore the changes in creatine metabolism using this model and compare them with the findings in healthy animals. Myocardial function of male young Lewis rats with EAM was quantified by performing left ventricular ejection fraction (LVEF) analysis in short‐axis cine images throughout the whole heart. Inflammatory cellular infiltrate was assessed by immunohistochemistry. Myocardial tissue was analyzed using ex vivo proton magic angle spinning MRS (¹H‐MAS‐MRS). Myocarditis was confirmed histologically by the presence of an inflammatory cellular infiltrate and CD68 positive staining. A significant increase in the metabolic ratio of Tau/tCr (taurine/total creatine) obtained by ¹H‐MAS‐MRS was observed in myocarditis compared with healthy controls (21 d acute EAM, 4.38 (±0.23); 21 d control, 2.84 (±0.08); 35 d chronic EAM, 4.47 (±0.83); 35 d control, 2.59 (±0.38); P < 0.001). LVEF was reduced in diseased animals (EAM, 55.2% (±11.3%); control, 72.6% (±3.8%); P < 0.01) and correlated with Tau/tCr ratio (R = 0.937, P < 0.001). Metabolic alterations occur acutely with the development of myocarditis. Myocardial Tau/tCr ratio as detected by ¹H‐MRS correlates with LVEF and is able to differentiate between healthy myocardium and myocardium from rats with EAM. Copyright © 2015 John Wiley & Sons, Ltd.     

Neurochemical profile of the mouse hypothalamus using in vivo 1H MRS at 14.1T

The hypothalamus plays an essential role in the central nervous system of mammals by among others regulating glucose homeostasis, food intake, temperature, and to some extent blood pressure. Assessments of hypothalamic metabolism using, e.g. ¹H MRS in mouse models can provide important insights into its function. To date, direct in vivo ¹H MRS measurements of hypothalamus have not been reported. Here, we report that in vivo single voxel measurements of mouse hypothalamus are feasible using ¹H MRS at 14.1T. Localized ¹H MR spectra from hypothalamus were obtained unilaterally (2–2.2 µL, VOI) and bilaterally (4–4.4 µL) with a quality comparable to that of hippocampus (3–3.5 µL). Using LCModel, a neurochemical profile consisting of 21 metabolites was quantified for both hypothalamus and hippocampus with most of the Cramér‐Rao lower bounds within 20%. Relative to the hippocampus, the hypothalamus was characterized by high γ‐aminobutryric acid and myo‐inositol, and low taurine concentrations. When studying transgenic mice with no glucose transporter isoform 8 expressed, small metabolic changes were observed, yet glucose homeostasis was well maintained. We conclude that a specific neurochemical profile of mouse hypothalamus can be measured by ¹H MRS which will allow identifying and following metabolic alterations longitudinally in the hypothalamus of genetic modified models. Copyright © 2010 John Wiley & Sons, Ltd.     

Bi‐exponential 23Na T2* component analysis in the human brain

The purpose of this study was to measure the sodium transverse relaxation time T₂* in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms. T₂* values were fitted on a voxel‐by‐voxel basis using a bi‐exponential model. Data were also analysed using a continuous distribution fit with a region of interest‐based inverse Laplace transform. Average T₂* values were 3.4 ± 0.2 ms and 23.5 ± 1.8 ms in white matter (WM) for the short and long components, respectively, and 3.9 ± 0.5 ms and 26.3 ± 2.6 ms in grey matter (GM) for the short and long components, respectively, using the bi‐exponential model. Continuous distribution fits yielded results of 3.1 ± 0.3 ms and 18.8 ± 3.2 ms in WM for the short and long components, respectively, and 2.9 ± 0.4 ms and 17.2 ± 2 ms in GM for the short and long components, respectively. ²³Na T₂* values of the brain for the short and long components for various anatomical locations using ultra‐short TEs are presented for the first time.     

In vivo mouse myocardial 31P MRS using three‐dimensional image‐selected in vivo spectroscopy (3D ISIS): technical considerations and biochemical validations

³¹P MRS provides a unique non‐invasive window into myocardial energy homeostasis. Mouse models of cardiac disease are widely used in preclinical studies, but the application of ³¹P MRS in the in vivo mouse heart has been limited. The small‐sized, fast‐beating mouse heart imposes challenges regarding localized signal acquisition devoid of contamination with signal originating from surrounding tissues. Here, we report the implementation and validation of three‐dimensional image‐selected in vivo spectroscopy (3D ISIS) for localized ³¹P MRS of the in vivo mouse heart at 9.4 T. Cardiac ³¹P MR spectra were acquired in vivo in healthy mice (n = 9) and in transverse aortic constricted (TAC) mice (n = 8) using respiratory‐gated, cardiac‐triggered 3D ISIS. Localization and potential signal contamination were assessed with ³¹P MRS experiments in the anterior myocardial wall, liver, skeletal muscle and blood. For healthy hearts, results were validated against ex vivo biochemical assays. Effects of isoflurane anesthesia were assessed by measuring in vivo hemodynamics and blood gases. The myocardial energy status, assessed via the phosphocreatine (PCr) to adenosine 5′‐triphosphate (ATP) ratio, was approximately 25% lower in TAC mice compared with controls (0.76 ± 0.13 versus 1.00 ± 0.15; P < 0.01). Localization with one‐dimensional (1D) ISIS resulted in two‐fold higher PCr/ATP ratios than measured with 3D ISIS, because of the high PCr levels of chest skeletal muscle that contaminate the 1D ISIS measurements. Ex vivo determinations of the myocardial PCr/ATP ratio (0.94 ± 0.24; n = 8) confirmed the in vivo observations in control mice. Heart rate (497 ± 76 beats/min), mean arterial pressure (90 ± 3.3 mmHg) and blood oxygen saturation (96.2 ± 0.6%) during the experimental conditions of in vivo ³¹P MRS were within the normal physiological range. Our results show that respiratory‐gated, cardiac‐triggered 3D ISIS allows for non‐invasive assessments of in vivo mouse myocardial energy homeostasis with ³¹P MRS under physiological conditions. Copyright © 2015 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.     

Automated pixel‐wise brain tissue segmentation of diffusion‐weighted images via machine learning

The diffusion‐weighted (DW) MR signal sampled over a wide range of b‐values potentially allows for tissue differentiation in terms of cellularity, microstructure, perfusion, and T₂ relaxivity. This study aimed to implement a machine learning algorithm for automatic brain tissue segmentation from DW‐MRI datasets, and to determine the optimal sub‐set of features for accurate segmentation. DWI was performed at 3 T in eight healthy volunteers using 15 b‐values and 20 diffusion‐encoding directions. The pixel‐wise signal attenuation, as well as the trace and fractional anisotropy (FA) of the diffusion tensor, were used as features to train a support vector machine classifier for gray matter, white matter, and cerebrospinal fluid classes. The datasets of two volunteers were used for validation. For each subject, tissue classification was also performed on 3D T₁‐weighted data sets with a probabilistic framework. Confusion matrices were generated for quantitative assessment of image classification accuracy in comparison with the reference method. DWI‐based tissue segmentation resulted in an accuracy of 82.1% on the validation dataset and of 82.2% on the training dataset, excluding relevant model over‐fitting. A mean Dice coefficient (DSC) of 0.79 ± 0.08 was found. About 50% of the classification performance was attributable to five features (i.e. signal measured at b‐values of 5/10/500/1200 s/mm² and the FA). This reduced set of features led to almost identical performances for the validation (82.2%) and the training (81.4%) datasets (DSC = 0.79 ± 0.08). Machine learning techniques applied to DWI data allow for accurate brain tissue segmentation based on both morphological and functional information.     

Neurometabolic profiles of the substantia nigra and striatum of MPTP‐intoxicated common marmosets: An in vivo proton MRS study at 9.4 T

Given the strong coupling between the substantia nigra (SN) and striatum (STR) in the early stage of Parkinson's disease (PD), yet only a few studies reported to date that have simultaneously investigated the neurochemistry of these two brain regions in vivo, we performed longitudinal metabolic profiling in the SN and STR of 1‐methyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐intoxicated common marmoset monkey models of PD (n = 10) by using proton MRS (¹H–MRS) at 9.4 T. T₂ relaxometry was also performed in the SN by using MRI. Data were classified into control, MPTP_2weeks, and MPTP_6‐10 weeks groups according to the treatment duration. In the SN, T₂ of the MPTP_6‐10 weeks group was lower than that of the control group (44.33 ± 1.75 versus 47.21 ± 2.47 ms, p < 0.05). The N‐acetylaspartate to total creatine ratio (NAA/tCr) and γ‐aminobutyric acid to tCr ratio (GABA/tCr) of the MPTP_6‐10 weeks group were lower than those of the control group (0.41 ± 0.04 versus 0.54 ± 0.08 (p < 0.01) and 0.19 ± 0.03 versus 0.30 ± 0.09 (p < 0.05), respectively). The glutathione to tCr ratio (GSH/tCr) was correlated with T₂ for the MPTP_6‐10 weeks group (r = 0.83, p = 0.04). In the STR, however, GABA/tCr of the MPTP_6‐10 weeks group was higher than that of the control group (0.25 ± 0.10 versus 0.16 ± 0.05, p < 0.05). These findings may be an in vivo depiction of the altered basal ganglion circuit in PD brain resulting from the degeneration of nigral dopaminergic neurons and disruption of nigrostriatal dopaminergic projections. Given the important role of non‐human primates in translational studies, our findings provide better understanding of the complicated evolution of PD.     

Precision and accuracy of diffusion kurtosis estimation and the influence of b‐value selection

Diffusion kurtosis imaging (DKI) is an extension of diffusion tensor imaging that accounts for leading non‐Gaussian diffusion effects. In DKI studies, a wide range of different gradient strengths (b‐values) is used, which is known to affect the estimated diffusivity and kurtosis parameters. Hence there is a need to assess the accuracy and precision of the estimated parameters as a function of b‐value. This work examines the error in the estimation of mean of the kurtosis tensor (MKT) with respect to the ground truth, using simulations based on a biophysical model for both gray (GM) and white (WM) matter. Model parameters are derived from densely sampled experimental data acquired in ex vivo rat brain and in vivo human brain. Additionally, the variability of MKT is studied using the experimental data. Prevalent fitting protocols are implemented and investigated. The results show strong dependence on the maximum b‐value of both net relative error and standard deviation of error for all of the employed fitting protocols. The choice of b‐values with minimum MKT estimation error and standard deviation of error was found to depend on the protocol type and the tissue. Protocols that utilize two terms of the cumulant expansion (DKI) were found to achieve minimum error in GM at b‐values less than 1 ms/μm², whereas maximal b‐values of about 2.5 ms/μm² were found to be optimal in WM. Protocols including additional higher order terms of the cumulant expansion were found to provide higher accuracy for the more commonly used b‐value regime in GM, but were associated with higher error in WM. Averaged over multiple voxels, a net average error of around 15% for both WM and GM was observed for the optimal b‐value choice. These results suggest caution when using DKI generated metrics for microstructural modeling and when comparing results obtained using different fitting techniques and b‐values.     

Global gray and white matter metabolic changes after simian immunodeficiency virus infection in CD8‐depleted rhesus macaques: proton MRS imaging at 3 T

To test the hypotheses that global decreased neuro‐axonal integrity reflected by decreased N‐acetylaspartate (NAA) and increased glial activation reflected by an elevation in its marker, the myo‐inositol (mI), present in a CD8‐depleted rhesus macaque model of HIV‐associated neurocognitive disorders. To this end, we performed quantitative MRI and 16 × 16 × 4 multivoxel proton MRS imaging (TE/TR = 33/1400 ms) in five macaques pre‐ and 4–6 weeks post‐simian immunodeficiency virus infection. Absolute NAA, creatine, choline (Cho), and mI concentrations, gray and white matter (GM and WM) and cerebrospinal fluid fractions were obtained. Global GM and WM concentrations were estimated from 224 voxels (at 0.125 cm³ spatial resolution over ~35% of the brain) using linear regression. Pre‐ to post‐infection global WM NAA declined 8%: 6.6 ± 0.4 to 6.0 ± 0.5 mM (p = 0.05); GM Cho declined 20%: 1.3 ± 0.2 to 1.0 ± 0.1 mM (p < 0.003); global mI increased 11%: 5.7 ± 0.4 to 6.5 ± 0.5 mM (p < 0.03). Global GM and WM brain volume fraction changes were statistically insignificant. These metabolic changes are consistent with global WM (axonal) injury and glial activation, and suggest a possible GM host immune response. Copyright © 2013 John Wiley & Sons, Ltd.     

Characterization of the response of taurine protons to PRESS at 9.4 T for Resolving choline and Determining taurine T2

Point‐resolved spectroscopy (PRESS), characterized by two TEs (TE₁ and TE₂), can be employed to perform animal magnetic resonance spectroscopy (MRS) studies at 9.4 T. Taurine (Tau) and choline (Cho) are relevant metabolites that can be measured by MRS. In this work, the response of the J‐coupled protons of Tau as a function of PRESS TE₁ and TE₂ was characterized at 9.4 T to achieve two objectives. The first was to determine two TE₁ and TE₂ combinations that could be used to obtain T₂‐corrected measures of Tau (3.42 ppm) that were minimally influenced by J coupling. The second was to exploit the Tau J coupling to find a timing combination that minimized the 3.25‐ppm Tau signal to enable the Cho (3.22 ppm) resonance to be resolved from the overlapping Tau signal. The response of Tau protons was investigated both numerically and experimentally. It was numerically determined that the timings {TE₁, TE₂} = {17 ms, 10 ms} and {TE₁, TE₂} = {80 ms, 70 ms} yielded similar 3.42‐ppm Tau resonance areas (5% difference), rendering them suitable for Tau T₂ determination. {TE₁, TE₂} = {25 ms, 50 ms} was found to yield minimal 3.25‐ppm Tau signal, reducing its interference with Cho. The efficacy of the timings was demonstrated on phantom solutions and in vivo in four Sprague Dawley rats. LCModel was employed to analyse the in vivo spectra and Tau T₂ values were estimated by fitting the Tau peak areas obtained with {TE₁, TE₂} = {17 ms, 10 ms} and {TE₁, TE₂} = {80 ms, 70 ms} to a monoexponentially decaying function. An average Tau T₂ of 106 ms (standard deviation, 12 ms) was obtained. LCModel analysis of rat spectra obtained with {TE₁, TE₂} = {25 ms, 50 ms} demonstrated negligible levels of Tau signal, compared with that obtained with short TE.