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Background & Aims Liver ultrasound (US) is usually used in the clinical setting for the diagnosis and follow-up of patients with nonalcoholic fatty liver disease (NAFLD). However, no large study has carefully assessed its performance using a semiquantitative ultrasonographic scoring system in overweight/obese patients, in comparison to magnetic resonance spectroscopy (1H-MRS) and histology. Methods We recruited 146 patients and performed: a liver US using a 5-parameter scoring system, a liver 1H-MRS to quantify liver fat content, and a liver biopsy to assess histology. All measurements were repeated in a subgroup of patients (n = 62) after 18 months of follow-up. Results The performance of liver US (parenchymal echo alone) was rather modest, and significantly worse than 1H-MRS (AUROC: 0.82 [0.69–0.94] vs. 0.96 [0.90–1.00]; P = 0.04). However, the AUROC improved when different echographic parameters were taken into account (AUROC: 0.89 [0.83–0.96], P = 0.15 against 1H-MRS). Optimum sensitivity for liver US was achieved at a liver fat content ≥12.5%, suggesting that below this threshold, liver US is less sensitive. Liver 1H-MRS showed a high accuracy for the diagnosis of NAFLD, and correlated strongly with histological steatosis (r = 0.73, P

The role of adipose tissue insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains unclear. To evaluate this, we measured in 207 patients with NAFLD (age = 51 ± 1, body mass index = 34.1 ± 0.3 kg/m2) and 22 controls without NAFLD (no NAFLD) adipose tissue insulin resistance by means of a validated index (Adipo-IRi = plasma free fatty acids [FFA] x insulin [FPI] concentration) and as the suppression of plasma FFA during an oral glucose tolerance test and by a low-dose insulin infusion. We also explored the relationship between adipose tissue insulin resistance with metabolic and histological parameters by dividing them based on quartiles of adipose tissue insulin resistance (Adipo-IRi quartiles: Q1 = more sensitive; Q4 = more insulin resistant). Hepatic insulin resistance, measured as an index derived from endogenous glucose production x FPI (HIRi), and muscle insulin sensitivity, were assessed during a euglycemic insulin clamp with 3-[3H] glucose. Liver fat was measured by magnetic resonance imaging and spectroscopy, and a liver biopsy was performed to assess liver histology. Compared to patients without steatosis, patients with NAFLD were insulin resistant at the level of adipose tissue, liver, and skeletal muscle and had higher plasma aspartate aminotransferase and alanine aminotransferase, triglycerides, and lower high-density lipoprotein cholesterol and adiponectin levels (all P < 0.01). Metabolic parameters, hepatic insulin resistance, and liver fibrosis (but not necroinflammation) deteriorated as quartiles of adipose tissue insulin resistance worsened (all P < 0.01). Conclusion: Adipose tissue insulin resistance plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue insulin resistance (e.g., weight loss and thiazolidinediones) may be of value in this population. (HEPATOLOGY 2012)

Summary Background Plasma adiponectin is decreased in NASH patients and the mechanism(s) for histological improvement during thiazolidinedione treatment remain(s) poorly understood. Aim To evaluate the relationship between changes in plasma adiponectin following pioglitazone treatment and metabolic/histological improvement. Methods We measured in 47 NASH patients and 20 controls: (i) fasting glucose, insulin, FFA and adiponectin concentrations; (ii) hepatic fat content by magnetic resonance spectroscopy; and (iii) peripheral/hepatic insulin sensitivity (by double-tracer oral glucose tolerance test). Patients were then treated with pioglitazone (45 mg/day) or placebo and all measurements were repeated after 6 months. Results Patients with NASH had decreased plasma adiponectin levels independent of the presence of obesity. Pioglitazone increased 2.3-fold plasma adiponectin and improved insulin resistance, glucose tolerance and glucose clearance, steatosis and necroinflammation (all P

Purpose The purpose of this work was to develop methods for defining, constructing, and evaluating a "minimal deformation target" (MDT) brain for multisubject studies based on analysis of the entire group. The goal is to provide a procedure that will create a standard, reproducible target brain image based on common features of a group of three-dimensional MR brain images. Method The average deformation and dispersion distance, derived from discrete three-dimensional deformation fields (DFs), are used to identify the best individual target (BIT) brain. This brain is assumed to be the one with the minimal deformation bias within a group of MR brain images. The BIT brain is determined as the one with the minimal target quality score, our cost function based on the deformation displacement and dispersion distance. The BIT brain is then transformed to the MDT brain using an average DF to create an optimized target brain. This analysis requires the calculation of a large number of DFs. To overcome this limitation, we developed an analysis method (the fast method) that reduces the task from order N2 complexity to one of order N, a tremendous advantage for large-N studies. Results Multiscale correlation analysis in a group of 20 subjects demonstrated the superiority of warping using the MDT target brain, made from the BIT brain, over several individual and MDT-transformed target brains also from the group. Conclusion Analysis of three-dimensional DF provides a means to quickly create a reproducible MDT target brain for any set of subjects. Warping to the MDT target was shown by an independent multiscale correlation method to produce superior results.

BACKGROUND The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited. OBJECTIVE To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM. DESIGN Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682). SETTING University hospital. PARTICIPANTS Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics. INTERVENTION All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment. MEASUREMENTS The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters. RESULTS Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of therapy. The overall rate of adverse events did not differ between groups, although weight gain was greater with pioglitazone (2.5 kg vs. placebo). LIMITATION Single-center study. CONCLUSION Long-term pioglitazone treatment is safe and effective in patients with prediabetes or T2DM and NASH. PRIMARY FUNDING SOURCE Burroughs Wellcome Fund and American Diabetes Association.

OBJECTIVE Prediabetes and type 2 diabetes mellitus (T2DM) are believed to be common and associated with a worse metabolic profile in patients with nonalcoholic fatty liver disease (NAFLD). However, no previous study has systematically screened this population. RESEARCH DESIGN AND METHODS We studied the prevalence and the metabolic impact of prediabetes and T2DM in 118 patients with NAFLD. The control group comprised 20 subjects without NAFLD matched for age, sex, and adiposity. We measured 1) plasma glucose, insulin, and free fatty acid (FFA) concentration during an oral glucose tolerance test; 2) liver fat by magnetic resonance spectroscopy (MRS); 3) liver and muscle insulin sensitivity (euglycemic insulin clamp with 3-[3H]glucose); and 4) indexes of insulin resistance (IR) at the level of the liver (HIRi= endogenous glucose production × fasting plasma insulin [FPI]) and adipose tissue (Adipo-IRi= fasting FFA × FPI). RESULTS Prediabetes and T2DM was present in 85% versus 30% in controls (P < 0.0001), all unaware of having abnormal glucose metabolism. NAFLD patients were IR at the level of the adipose tissue, liver, and muscle (all P < 0.01–0.001). Muscle and liver insulin sensitivity were impaired in patients with NAFLD to a similar degree, whether they had prediabetes or T2DM. Only adipose tissue IR worsened in T2DM and correlated with the severity of muscle (r = 0.34; P < 0.001) and hepatic (r = 0.57; P < 0.0001) IR and steatosis by MRS (r = 0.35; P < 0.0001). CONCLUSIONS Patients with NAFLD may benefit from early screening for T2DM, because the prevalence of abnormal glucose metabolism is much higher than previously appreciated. Regardless of glucose tolerance status, severe IR is common. In patients with T2DM, adipose tissue IR appears to play a major role in the severity of NAFLD.

Aim: To assess the effect of muraglitazar, a dual peroxisome proliferator-activated receptor (PPAR)γ-α agonist, versus placebo on metabolic parameters and body composition in subjects with type 2 diabetes mellitus (T2DM). Methods: Twenty-seven T2DM subjects received oral glucose tolerance test (OGTT), euglycaemic insulin clamp with deuterated glucose, measurement of total body fat (DEXA), quantitation of muscle/liver (MRS) and abdominal subcutaneous and visceral (MRI) fat, and then were randomized to receive, in addition to diet, muraglitazar (MURA), 5 mg/day, or placebo (PLAC) for 4 months. Results: HbA1cc decreased similarly (2.1%) during both MURA and PLAC treatments despite significant weight gain with MURA (+2.5 kg) and weight loss with PLAC (−0.7 kg). Plasma triglyceride, LDL cholesterol, free fatty acid (FFA), hsCRP levels all decreased with MURA while plasma adiponectin and HDL cholesterol increased (p < 0.05–0.001). Total body (muscle), hepatic and adipose tissue sensitivity to insulin and β cell function all improved with MURA (p < 0.05–0.01). Intramyocellular, hepatic and abdominal visceral fat content decreased, while total body and subcutaneous abdominal fat increased with MURA (p < 0.05–0.01). Conclusions: Muraglitazar (i) improves glycaemic control by enhancing insulin sensitivity and β cell function in T2DM subjects, (ii) improves multiple cardiovascular risk factors, (iii) reduces muscle, visceral and hepatic fat content in T2DM subjects. Despite similar reduction in A1c with PLAC/diet, insulin sensitivity and β cell function did not improve significantly.

We explored relationships between decline in cognitive processing speed (CPS) and change in frontal lobe MRI/MRS-based indices of cerebral integrity in 38 healthy adults (age 57-90 years). CPS was assessed using a battery of four timed neuropsychological tests: Grooved Pegboard, Coding, Symbol Digit Modalities Test and Category Fluency (Fruits and Furniture). The neuropsychological tests were factor analyzed to extract two components of CPS: psychomotor (PM) and psychophysical (PP). MRI-based indices of cerebral integrity included three cortical measurements per hemisphere (GM thickness, intergyral and sulcal spans) and two subcortical indices (fractional anisotropy (FA), measured using track-based spatial statistics (TBSS), and the volume of hyperintense WM (HWM)). MRS indices included levels of choline-containing compounds (GPC+PC), phosphocreatine plus creatine (PCr+Cr), and N-acetylaspartate (NAA), measured bilaterally in the frontal WM bundles. A substantial fraction of the variance in the PM-CPS (58%) was attributed to atrophic changes in frontal WM, observed as increases in sulcal span, declines in FA values and reductions in concentrations of NAA and choline-containing compounds. A smaller proportion (20%) of variance in the PP-CPS could be explained by bilateral increases in frontal sulcal span and increases in HWM volumes.

BACKGROUND No pharmacologic therapy has conclusively proved to be effective for the treatment of nonalcoholic steatohepatitis, which is characterized by insulin resistance, steatosis, and necroinflammation with or without centrilobular fibrosis. Pioglitazone is a thiazolidinedione that ameliorates insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus. METHODS We randomly assigned 55 patients with impaired glucose tolerance or type 2 diabetes and liver biopsy–confirmed nonalcoholic steatohepatitis to 6 months of treatment with a hypocaloric diet (a reduction of 500 kcal per day in relation to the calculated daily intake required to maintain body weight) plus pioglitazone (45 mg daily) or a hypocaloric diet plus placebo. Before and after treatment, we assessed hepatic histologic features, hepatic fat content by means of magnetic resonance spectroscopy, and glucose turnover during an oral glucose tolerance test ([ 14 C]glucose given with the oral glucose load and [ 3 H]glucose given by intravenous infusion). RESULTS Diet plus pioglitazone, as compared with diet plus placebo, improved glycemic control and glucose tolerance (P

Abdominal fat accumulation (visceral/hepatic) has been associated with hepatic insulin resistance (IR) in obesity and type 2 diabetes (T2DM). We examined the relationship between visceral/hepatic fat accumulation and hepatic IR/accelerated gluconeogenesis (GNG).In 14 normal glucose tolerant (NGT) (body mass index [BMI] = 25 +/- 1 kg/m(2)) and 43 T2DM (24 nonobese, BMI = 26 +/- 1; 19 obese, BMI = 32 +/- 1 kg/m(2)) subjects, we measured endogenous (hepatic) glucose production (3-(3)H-glucose) and GNG ((2)H(2)O) in the basal state and during 240 pmol/m(2)/min euglycemic-hyperinsulinemic clamp, and liver (LF) subcutaneous (SAT)/visceral (VAT) fat content by magnetic resonance spectroscopy/magnetic resonance imaging.LF was increased in lean T2DM compared with lean NGT (18% +/- 3% vs 9% +/- 2%, P.03), but was similar in lean T2DM and obese T2DM (18% +/- 3% vs 22% +/- 3%; P = NS). Both VAT and SAT increased progressively from lean NGT to lean T2DM to obese T2DM. T2DM had increased basal endogenous glucose production (EGP) (NGT, 15.1 +/- 0.5; lean T2DM, 16.3 +/- 0.4; obese T2DM, 17.2 +/- 0.6 micromol/min/kg(ffm); P = .02) and basal GNG flux (NGT, 8.6 +/- 0.4; lean T2DM, 9.6 +/- 0.4; obese T2DM, 11.1 +/- 0.6 micromol/min/kg(ffm); P = .02). Basal hepatic IR index (EGP x fasting plasma insulin) was increased in T2DM (NGT, 816 +/- 54; lean T2DM, 1252 +/- 164; obese T2DM, 1810 +/- 210; P = .007). In T2DM, after accounting for age, sex, and BMI, both LF and VAT, but not SAT, were correlated significantly (P.05) with basal hepatic IR and residual EGP during insulin clamp. Basal percentage of GNG and GNG flux were correlated positively with VAT (P.05), but not with LF. LF, but not VAT, was correlated with fasting insulin, insulin-stimulated glucose disposal, and impaired FFA suppression by insulin (all P.05).Abdominal adiposity significantly affects both lipid (FFA) and glucose metabolism. Excess VAT primarily increases GNG flux. Both VAT and LF are associated with hepatic IR.

Most individuals with constitutional deletions of chromosome 18q have developmental delays, dysmyelination of the brain, and growth failure due to growth hormone deficiency. We monitored the effects of growth hormone treatment by evaluating 23 individuals for changes in growth, nonverbal intelligence quotient (nIQ), and quantitative brain MRI changes. Over an average of 37 months, the treated group of 13 children had an average nIQ increase of 17 points, an increase in height standard deviation score of 1.7, and significant change in T1 relaxation times in the caudate and frontal white matter. Cognitive changes of this magnitude are clinically significant and are anticipated to have an effect on the long-term outcomes for the treated individuals.

We examined the effect of pioglitazone on abdominal fat distribution to elucidate the mechanisms via which pioglitazone improves insulin resistance in patients with type 2 diabetes mellitus. Thirteen type 2 diabetic patients (nine men and four women; age, 52 ± 3 yr; body mass index, 29.0 ± 1.1 kg/m2), who were being treated with a stable dose of sulfonylurea (n = 7) or with diet alone (n = 6), received pioglitazone (45 mg/d) for 16 wk. Before and after pioglitazone treatment, subjects underwent a 75-g oral glucose tolerance test (OGTT) and two-step euglycemic insulin clamp (insulin infusion rates, 40 and 160 mU/m2·min) with [3H]glucose. Abdominal fat distribution was evaluated using magnetic resonance imaging at L4–5. After 16 wk of pioglitazone treatment, fasting plasma glucose (179 ± 10 to 140 ± 10 mg/dl; P < 0.01), mean plasma glucose during OGTT (295 ± 13 to 233 ± 14 mg/dl; P < 0.01), and hemoglobin A1c (8.6 ± 0.4% to 7.2 ± 0.5%; P < 0.01) decreased without a change in fasting or post-OGTT insulin levels. Fasting plasma FFA (674 ± 38 to 569 ± 31 μEq/liter; P < 0.05) and mean plasma FFA (539 ± 20 to 396 ± 29 μEq/liter; P < 0.01) during OGTT decreased after pioglitazone. In the postabsorptive state, hepatic insulin resistance [basal endogenous glucose production (EGP) × basal plasma insulin concentration] decreased from 41 ± 7 to 25 ± 3 mg/kg fat-free mass (FFM)·min × μU/ml; P < 0.05) and suppression of EGP during the first insulin clamp step (1.1 ± 0.1 to 0.6 ± 0.2 mg/kg FFM·min; P < 0.05) improved after pioglitazone treatment. The total body glucose MCR during the first and second insulin clamp steps increased after pioglitazone treatment [first MCR, 3.5 ± 0.5 to 4.4 ± 0.4 ml/kg FFM·min (P < 0.05); second MCR, 8.7 ± 1.0 to 11.3 ± 1.1 ml/kg FFM·min (P < 0.01)]. The improvement in hepatic and peripheral tissue insulin sensitivity occurred despite increases in body weight (82 ± 4 to 85 ± 4 kg; P < 0.05) and fat mass (27 ± 2 to 30 ± 3 kg; P < 0.05). After pioglitazone treatment, sc fat area at L4–5 (301 ± 44 to 342 ± 44 cm2; P < 0.01) increased, whereas visceral fat area at L4–5 (144 ± 13 to 131 ± 16 cm2; P < 0.05) and the ratio of visceral to sc fat (0.59 ± 0.08 to 0.44 ± 0.06; P < 0.01) decreased. In the postabsorptive state hepatic insulin resistance (basal EGP × basal immunoreactive insulin) correlated positively with visceral fat area (r = 0.55; P < 0.01). The glucose MCRs during the first (r = −0.45; P < 0.05) and second (r = −0.44; P < 0.05) insulin clamp steps were negatively correlated with the visceral fat area. These results demonstrate that a shift of fat distribution from visceral to sc adipose depots after pioglitazone treatment is associated with improvements in hepatic and peripheral tissue sensitivity to insulin.

The goal of regional spatial normalization is to remove anatomical differences between individual three‐dimensional (3D) brain images by warping them to match features of a standard brain atlas. Processing to fit features at the limiting resolution of a 3D MR image volume is computationally intensive, limiting the broad use of full‐resolution regional spatial normalization. In Kochunov et al. (1999: NeuroImage 10:724–737), we proposed a regional spatial normalization algorithm called octree spatial normalization (OSN) that reduces processing time to minutes while targeting the accuracy of previous methods. In the current study, modifications of the OSN algorithm for use in human brain images are described and tested. An automated brain tissue segmentation procedure was adopted to create anatomical templates to drive feature matching in white matter, gray matter, and cerebral‐spinal fluid. Three similarity measurement functions (fast‐cross correlation (CC), sum‐square error, and centroid) were evaluated in a group of six subjects. A combination of fast‐CC and centroid was found to provide the best feature matching and speed. Multiple iterations and multiple applications of the OSN algorithm were evaluated to improve fit quality. Two applications of the OSN algorithm with two iterations per application were found to significantly reduce volumetric mismatch (up to six times for lateral ventricle) while keeping processing time under 30 min. The refined version of OSN was tested with anatomical landmarks from several major sulci in a group of nine subjects. Anatomical variability was appreciably reduced for every sulcus investigated, and mean sulcal tracings accurately followed sulcal tracings in the target brain. Hum. Brain Mapping 11:193–206, 2000. © 2000 Wiley‐Liss, Inc.