Preterm infants' early growth and brain white matter maturation at term age.

BACKGROUND: Normal intrauterine conditions are essential to normal brain growth and development; premature birth and growth restriction can interrupt brain maturation. Maturation processes can be studied using diffusion tensor imaging. OBJECTIVE: The aim of this study was to use tract-based spatial statistics to assess the effect that early postnatal growth from birth to 40 gestational weeks has on brain white matter maturation. MATERIALS AND METHODS: A total of 36 preterm infants were accepted in the study. Postnatal growth was assessed by weight, length and head circumference. Birth weight z-score and gestational age were used as confounding covariates. RESULTS: Head circumference catch-up growth was associated with less mature diffusion parameters (P < 0.05). No significant associations were observed between weight or length growth and diffusion parameters. CONCLUSION: Growth-restricted infants seem to have delayed brain maturation that is not fully compensated at term, despite catch-up growth.

Measurement of brown adipose tissue mass using a novel dual-echo magnetic resonance imaging approach: a validation study.

OBJECTIVE: The aim of this study was to evaluate and validate magnetic resonance imaging (MRI) for the visualization and quantification of brown adipose tissue (BAT) in vivo in a rat model. We hypothesized that, based on differences in tissue water and lipid content, MRI could reliably differentiate between BAT and white adipose tissue (WAT) and could therefore be a possible alternative for (18)F-Fluorodeoxyglucose Positron Emission Tomography ((18)FDG-PET), the current gold standard for non-invasive BAT quantification. MATERIALS/METHODS: Eleven rats were studied using both (18)FDG-PET/CT and MRI (1.5 T). A dual echo (in-and-out-of-phase) sequence was used, both with and without spectral presaturation inversion recovery (SPIR) fat suppression (DUAL-SPIR) to visualize BAT, after which all BAT was surgically excised. The BAT volume measurements obtained via (18)FDG-PET/CT and DUAL-SPIR MR were quantitatively compared with the histological findings. All study protocols were reviewed and approved by the local ethics committee. RESULTS: The BAT mass measurements that were obtained using DUAL-SPIR MR subtraction images correlated better with the histological findings (P=0.017, R=0.89) than did the measurements obtained using (18)FDG-PET/CT (P=0.78, R=0.15), regardless of the BAT metabolic activation state. Additionally, the basic feasibility of the DUAL-SPIR method was demonstrated in three human pilot subjects. CONCLUSIONS: This study demonstrates the potential for MRI to reliably detect and quantify BAT in vivo. MRI can provide information beyond that provided by (18)FDG-PET imaging, and its ability to detect BAT is independent of its metabolic activation state. Additionally, MRI is a low-cost alternative that does not require radiation.

Obesity is associated with white matter atrophy: a combined diffusion tensor imaging and voxel-based morphometric study.

OBJECTIVE: Little is known about the mechanisms by which obesity influences brain structure. In this study, the obesity-related changes in brain white and gray matter integrity were examined. DESIGN AND METHODS: 23 morbidly obese subjects and 22 nonobese volunteers were studied using voxel-based analysis of diffusion tensor imaging and of T1-weighted MRI images. Full-volume statistical parametric mapping analysis was used to compare fractional anisotropy (FA) and mean diffusivity (MD) values as well as gray (GM) and white matter (WM) density between these groups. RESULTS: Obese subjects had lower FA and MD values and lower focal and global GM and WM volumes than control subjects did. The focal structural changes were observed in brain regions governing reward seeking, inhibitory control, and appetite. Regression analysis showed that FA and MD values as well as GM and WM density were negatively associated with body fat percentage. Moreover, the volume of abdominal subcutaneous fat was negatively associated with GM density in most regions. CONCLUSION: These findings imply that changes in GM and WM in obesity may be due to metabolic factors. Atrophy in regions involved in reward processing and appetite control may further promote abnormal reward seeking and eating behavior.

Diffusion tensor imaging and brain volumetry in Fabry disease patients.

INTRODUCTION: Fabry disease is a rare lysosomal storage disorder leading to cellular accumulation of globotriaosylceramide, especially in blood vessels. It is associated with severe early onset cerebrovascular disease and kidney and heart failure. The purpose of this study was to reveal possible disturbances in white matter integrity in Fabry disease patients using voxelwise diffusion-tensor imaging (DTI) analysis. METHODS: Twelve Fabry disease patients, along with 13 healthy controls, underwent DTI and structural MRI. Voxel-based analysis of the DTI data was performed to assess possible differences in DTI parameters between Fabry disease patients and healthy controls. A selective region of interest analysis was performed for healthy volunteers and Fabry disease patients having a mild burden of T2-hyperintense lesions. We also measured normalised brain tissue volumes and performed a voxel-based volume analysis for grey matter. RESULTS: Voxel-based analysis of DTI data showed areas of significantly reduced fractional anisotropy and increased mean diffusivity in patients with Fabry disease. Eight patients had a mild burden of white matter lesions on their T2 scans. Region of interest analysis on areas showing reduced fractional anisotropy in voxelwise analysis also revealed reduced fractional anisotropy values in this patient group compared to eight healthy volunteers. The brain volume analyses did not reveal significant differences between the Fabry disease patients and the controls. CONCLUSION: These findings suggest a microstructural damage in brain white matter of Fabry disease patients, which can be revealed before excessive white matter lesions load is visible on conventional MR scans.

Effect of antenatal growth on brain white matter maturation in preterm infants at term using tract-based spatial statistics.

BACKGROUND: White matter maturation of infants can be studied using diffusion tensor imaging (DTI). DTI of the white matter of the infant brain provides the best available clinical measures of brain tissue organisation and integrity. OBJECTIVE: The purpose of this study was to compare white matter maturation between preterm infants born small for gestational age (SGA) and preterms with weight appropriate for gestational age (AGA) at birth. MATERIALS AND METHODS: A total of 36 preterm infants were enrolled in the study (SGA, n = 9). A rater-independent method called tract-based spatial statistics (TBSS) was used to assess white matter maturation. RESULTS: When measured by TBSS, the AGA infants showed higher fractional anisotrophy values in several white matter tracts than the SGA infants. Areas with significant differences included anterior thalamic radiation, corticospinal tract, forceps major and minor, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, superior longitudinal fasciculus, uncinate fasciculus, and superior longitudinal fasciculus (temporal part). No significant difference was found for mean diffusivity. CONCLUSION: As an objective and user-independent method, TBSS confirmed that preterm infants with impaired antenatal growth have impaired white matter maturation compared to preterm infants with normal antenatal growth. The differences were mainly detected in radiations that are myelinated first.

Effects of acute and one-week fatty acid lowering on cardiac function and insulin sensitivity in relation with myocardial and muscle fat and adiponectin levels.

BACKGROUND/AIM: We tested the hypothesis that a persistent reduction in free fatty acid (FFA) levels improves cardiac function and systemic insulin sensitivity via a reduction in the myocardial and skeletal muscle adiposities and a modulation in adipokine release. METHODS: Study subjects (body mass index 22-30 kg/m(2), 57 ± 3 yr old) underwent magnetic resonance imaging and spectroscopy to measure the cardiac function and the amounts of fat inside and around the myocardium and skeletal muscle, before (n = 10) and after acute (n = 8) and 1 wk (n = 7, one excluded from analysis) lowering of circulating FFA by acipimox. Circulating adipokines (leptin, adiponectin, resistin, TNFα, IL-6, IL-8, plasminogen activator inhibitor-I, macrophage chemoattractant protein-1) were measured. RESULTS: The ejection fraction (62 ± 2 vs. 56 ± 1%, P = 0.0035), cardiac output (6.6 ± 0.3 vs. 5.5 ± 0.2 liters/min, P = 0.0018), and forward work (708 ± 49 vs. 539 ± 44 mm Hg × liters/min, P = 0.018) were significantly lower after 1 wk of FFA lowering. In the six subjects undergoing all sessions, the stroke and end-diastolic volumes were also reduced, insulin sensitivity was increased by 33%, and adiponectinemia was decreased (-26%, P = 0.03). No change in intracellular cardiac and skeletal muscle triglyceride levels was observed. Metabolic changes correlated with the lowering of FFA. The reduction in cardiac function was related with changes in glycemia and insulin sensitivity, whereas the deflection in left ventricular work was correlated with the decline in FFA, lipid, and blood pressure levels. CONCLUSIONS: A 1-wk FFA depletion suppressed cardiac function and improved insulin sensitivity. Intracellular triglyceride deposits in the heart and skeletal muscle played no role in the observed changes. Our data show that FFA participate in the physiological regulation of adipokine levels.

Improved detection of localized prostate cancer using co-registered MRI and 11C-acetate PET/CT.

OBJECTIVES: We aimed to study the ability of contrast enhanced MRI at 1.5 T and 11C-acetate PET/CT, both individually and using fused data, to detect localized prostate cancer. METHODS: Thirty-six men with untreated prostate cancer and negative for metastatic disease on pelvic CT and bone scan were prospectively enrolled. A pelvic 11C-acetate PET/CT scan was performed in all patients, and a contrast enhanced MRI scan in 33 patients (6 examinations using both endorectal coil and surface coils, and 27 examinations using surface coils only). After the imaging studies 10 patients underwent prostatectomy and 26 were treated by image guided external beam radiation treatment. Image fusion of co-registered PET and MRI data was performed based on anatomical landmarks visible on CT and MRI using an advanced in-house developed software package. PET/CT, MRI and fused PET/MRI data were evaluated visually and compared with biopsy findings on a lobar level, while a sextant approach was used for patients undergoing prostatectomy. RESULTS: When using biopsy samples as method of reference, the sensitivity, specificity and accuracy for visual detection of prostate cancer on a lobar level by contrast enhanced MRI was 85%, 37%, 73% and that of 11C-acetate PET/CT 88%, 41%, 74%, respectively. Fusion of PET with MRI data increased sensitivity, specificity and accuracy to 90%, 72% and 85%, respectively. CONCLUSIONS: Fusion of sequentially obtained PET/CT and MRI data for the localization of prostate cancer is feasible and superior to the performance of each individual modality alone.

Fractional anisotropy and mean diffusivity parameters of the brain white matter tracts in preterm infants: reproducibility of region-of-interest measurements.

BACKGROUND: Diffusion tensor parameters can be analysed by fitting regions of interest (ROIs) to selected brain structures. The clinical usefulness of these measurements is influenced by their reproducibility and validity. OBJECTIVE: To investigate the reproducibility of fractional anisotropy (FA) and mean diffusivity (MD) measurements. MATERIAL AND METHODS: Seventy-six infants were imaged once at term-equivalent age. We measured several brain regions. Reproducibility was assessed using intraclass correlation coefficient and Bland-Altman method. RESULTS: Intra-observer reproducibility was excellent for FA in the calcarine cortex (right) and frontal white matter (left), and for MD in the corpus callosum (anterior), internal capsule, corona radiata, putamen, frontal white matter, optic radiation (left), thalamus (right) and calcarine cortex (right). Inter-observer reproducibility was excellent for FA in the corpus callosum (posterior) and for MD in the internal capsule and corona radiata (right). Inter-observer reproducibility was poor for FA in frontal and posterior white matter (right) and for MD in the inferior colliculus (right). Reproducibility was fair to good in other areas. The Bland-Altman plots showed no considerable bias, and variance was independent of the mean value. CONCLUSION: Reproducibility of ROI measurement was fair to good for both FA and MD.

Mitochondrial diabetes is associated with insulin resistance in subcutaneous adipose tissue but not with increased liver fat content.

We recently showed that patients with mitochondrial diabetes are insulin resistant in skeletal muscle before the decline in insulin secretion is observed. In this study, we further evaluate whether insulin resistance is associated with increased ectopic fat accumulation and altered adipose and hepatic tissue insulin sensitivity. We studied 15 nonobese patients with the m.3243A > G mutation. Five were without diabetes (group 1), three had newly diagnosed diabetes (group 2), and seven had previously diagnosed diabetes (group 3). Thirteen healthy volunteers of similar age and body mass index (BMI) served as controls. Insulin-stimulated glucose uptake was measured with positron emission tomography using 2- [(18)F]-fluoro-2-deoxyglucose during euglycemic hyperinsulinemia. Fat masses and liver fat content were measured with magnetic resonance imaging and spectroscopy. Compared with controls, insulin-stimulated glucose uptake in adipose tissue was decreased by ∼50% in all groups with the m.3243A > G mutation. In addition, fat masses were not different, but insulin-mediated suppression of lipolysis and adiponectin metabolism were blunted in patients with the m.3243A > G mutation. Hepatic fat content was normal (<5.6%) in 80% of patients and significantly elevated in one case only. Hepatic glucose metabolism in patients with m.3243A > G did not differ from that of controls. In conclusion, m.3243A > G mutation affects subcutaneous adipose tissue metabolism. This seems to occur before aberrant liver metabolism, if any, can be observed or before beta-cell failure results in mitochondrial diabetes.

Liver and pancreatic fat content and metabolism in healthy monozygotic twins with discordant physical activity.

BACKGROUND & AIMS: Ectopic fat in muscle and liver is linked to obesity and type 2 diabetes. Recently, pancreatic lipid accumulation has also been associated with ß-cell dysfunction and reduced insulin production, leading to the development of type 2 diabetes. Physical exercise training has been shown to attenuate ß-cell dysfunction in patients, but little is known about its effects on pancreatic and hepatic fat accumulation. In this study, we validated in-vivo proton magnetic resonance spectroscopy ((1)H MRS) in pancreatic fat measurement with biochemical measurements in a pig model. Thereafter, the effects of increased physical activity on the amounts of pancreatic and liver fat were studied in eight monozygotic twin pairs who have discordant physical activity and fitness. METHODS: Pancreatic fat content was studied in 15 pigs using (1)H MRS and/or biochemical analyses. In addition, liver and pancreatic fat were assessed using (1)H MRS in eight monozygotic male twin pairs with 18% mean difference in VO(2max) between the twin brothers. RESULTS: Twins with higher physical fitness had 23% less liver fat (1.3±1.3% vs. 2.1±2.6%, p=0.022) but no such difference was observed in the pancreatic fat (8.2±9.3% vs. 9.8±8.5%, respectively, p=0.3). Hepatic fat content was inversely associated with VO(2max). A positive association was found between pancreatic and liver fat contents (ß=5.18, p=0.012). Pancreatic fat content was also associated with insulin sensitivity indexes and plasma adiponectin and glutamyltransferase concentrations. CONCLUSIONS: Pancreatic fat content is associated with insulin resistance and hepatic fat content. An active lifestyle seems to beneficially influence hepatic fat metabolism.

Functional imaging of localized prostate cancer aggressiveness using 11C-acetate PET/CT and 1H-MR spectroscopy.

UNLABELLED: We assessed the ability of (11)C-acetate PET/CT, MRI, and proton MR spectroscopy ((1)H-MRS) to image localized prostate cancer and detect its aggressiveness, using qualitative and quantitative approaches. METHODS: Twenty-one patients with untreated localized prostate cancer, diagnosed using transrectal ultrasound-guided biopsy, were prospectively enrolled. Cancer laterality was based on the percentage of cancer and the highest Gleason score determined from biopsies. In addition to PET/CT, 3-dimensional (1)H-MRS of the entire prostate volume using a quantitative approach was performed. The imaging and histologic findings of 8 patients undergoing subsequent prostatectomy were compared on a sextant level. For each lobe and sextant, standardized uptake values (SUVs) and (choline + creatine + polyamines)-to-citrate (CCP/C) ratios were obtained from (11)C-acetate PET/CT and (1)H-MRS, respectively. The visual and quantitative findings on PET/CT and MRI data were compared with cancer laterality and aggressiveness based on the Gleason score and with prostate-specific antigen (PSA) velocity and international risk group classification. RESULTS: The sensitivity, specificity, and accuracy, on a lobar level using visual analysis, of (11)C-acetate PET/CT were 80%, 29%, 71%, respectively, and 89%, 29%, 79%, respectively, using contrast-enhanced MRI. The sensitivity and accuracy of (11)C-acetate PET/CT decreased to 64% and 63% and specificity increased to 62% when sextant analysis was performed. The agreement between prostate cancer laterality based on biopsy findings and visual interpretation of (11)C-acetate PET/CT and contrast-enhanced MRI was similar at 71%. The mean SUV maximum and CCP/C maximum for the dominant tumor lesion were 5.5 and 1.48, respectively, and did not differ significantly from values in the nondominant lobe. The dominant-lesion SUVs or CCP/C values were not associated with histologically determined prostate cancer aggressiveness, nor did PSA velocity correlate with the SUV or CCP/C values from the entire gland. CONCLUSION: (11)C-acetate PET/CT, MRI, and (1)H-MRS enable detection of localized prostate cancer with comparable and limited accuracy but fail to provide information on cancer aggressiveness.

Contribution of glucose tolerance and gender to cardiac adiposity.

CONTEXT AND OBJECTIVE: To examine whether pericardial and myocardial fat depots may contribute to the association between diabetes and cardiovascular risk, including sex-related differences, and the role of adiponectin, we evaluated data in patients with obesity and without diabetes [nondiabetic (ND)] or with impaired glucose tolerance or type 2 diabetes and in lean ND controls. METHODS: Magnetic resonance imaging and spectroscopy were used to measure left ventricular (LV) function and abdominal sc and visceral fat areas to estimate respective masses, pericardial fat depots, and myocardial triglyceride content in 53 subjects (10 lean ND, 25 obese ND, six impaired-glucose-tolerance, and 12 type 2 diabetic patients with macrovascular disease); gender effects and adiponectin levels were evaluated in the available subset of subjects. RESULTS: Myocardial and pericardial fat increased progressively across study groups. They were lower in obese women than men (P = 0.002), but cardiac steatosis caught up in hyperglycemic women (+81% vs. ND, P = 0.01). Adiponectin was inversely related with both fat depots (P < 0.01) and LV mass (P = 0.003) and positively with LV function (P = 0.03). In multiple regression analysis, myocardial and pericardial fat were independently related with plasma glucose levels, only pericardial fat mass was associated with visceral adiposity and myocardial fat with cardiac output and work. CONCLUSIONS: We conclude that glycemia, gender, adiponectin, and cardiac workload are associated with, and hyperglycemia and male gender are independent positive predictors of, heart adiposity. Once glucose tolerance becomes impaired, the evolution of cardiac steatosis is more pronounced in women.

Cerebral oxygen and glucose metabolism in patients with mitochondrial m.3243A>G mutation.

The m.3243A>G mutation is the most common pathogenic mutation in mitochondrial DNA. It leads to defective oxidative phosphorylation, decreased oxygen consumption and increased glucose utilization and lactate production in vitro. However, oxygen and glucose metabolism has not been studied in the brain of patients harbouring the m.3243A>G mutation. Therefore, 14 patients with the m.3243A>G mutation, not experiencing acute stroke-like episodes and 14 age-matched controls underwent positron emission tomography using 2-[(18)F]fluoro-2-deoxyglucose, [(15)O]H(2)O and [(15)O]O(2) as the tracers during normoglycaemia. The metabolic rate of oxygen and glucose were determined using a quantitative region of interest analysis. Metabolites in unaffected periventricular tissue were measured using magnetic resonance spectroscopy. We found that the cerebral metabolic rate of oxygen was decreased by 26% (range 18%-29%) in the grey as well as the white matter of patients with the m.3243A>G mutation. A decrease in the metabolic rate of glucose was found with predilection to the posterior part of the brain. No major changes were detected in cerebral blood flow or the number of white matter lesions. Our results show that the m.3243A>G mutation leads to a global decrease in oxygen consumption in the grey matter including areas where no other signs of disease were present.

Effect of caloric restriction on myocardial fatty acid uptake, left ventricular mass, and cardiac work in obese adults.

Obesity is associated with increased fatty acid uptake in the myocardium, and this may have deleterious effects on cardiac function. The aim of this study was to evaluate how weight loss influences myocardial metabolism and cardiac work in obese adults. Thirty-four obese (mean body mass index 33.7 +/- 0.7 kg/m(2)) but otherwise healthy subjects consumed a very low calorie diet for 6 weeks. Cardiac substrate metabolism and work were measured before and after the diet. Myocardial fatty acid uptake was measured in 18 subjects using fluorine-18-fluoro-6-thia-heptadecanoic acid and positron emission tomography, and myocardial glucose uptake was measured in 16 subjects using fluorine-18-2-fluoro-2-deoxyglucose. Myocardial structure and cardiac function were measured using magnetic resonance imaging. Consumption of the very low calorie diet decreased weight (-11.2 +/- 0.6 kg, p <0.0001). Myocardial fatty acid uptake decreased from 4.2 +/- 0.4 to 2.9 +/- 0.2 micromol/100 g/min (p <0.0001). Myocardial mass decreased by 7% (p <0.005), and cardiac work decreased by 26% (p <0.0001). Whole-body insulin sensitivity increased by 33% (p <0.01), but insulin-stimulated myocardial glucose uptake remained unchanged (p = 0.90). Myocardial triglyceride content decreased by 31% (n = 8, p = 0.076). In conclusion, weight reduction decreases myocardial fatty acid uptake in parallel with myocardial mass and cardiac work. These results show that the increased fatty acid uptake found in the hearts of obese patients can be reversed by weight loss.