SummaryBackgroundIn neonatal encephalopathy, the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy.MethodsWe did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy. We excluded infants with life-threatening congenital malformations, syndromic disorders, neurometabolic diseases, or any alternative diagnoses for encephalopathy that were apparent within 6 h of birth. We obtained T1-weighted, T2-weighted, and diffusion-weighted MRI and thalamic proton MRS 4–14 days after birth. Clinical neurodevelopmental tests were done 18–24 months later. The primary outcome was the association between MR biomarkers and an adverse neurodevelopmental outcome, defined as death or moderate or severe disability, measured using a multivariable prognostic model. We used receiver operating characteristic (ROC) curves to examine the prognostic accuracy of the individual biomarkers. This trial is registered with ClinicalTrials.gov, number NCT01309711.FindingsBetween Jan 29, 2013, and June 25, 2016, we recruited 223 infants who all underwent MRI and MRS at a median age of 7 days (IQR 5–10), with 190 (85%) followed up for neurological examination at a median age of 23 months (20–25). Of those followed up, 31 (16%) had moderate or severe disability, including one death. Multiple logistic regression analysis could not be done because thalamic N-acetylaspartate (NAA) concentration alone accurately predicted an adverse neurodevelopmental outcome (area under the curve [AUC] of 0·99 [95% CI 0·94–1·00]; sensitivity 100% [74–100]; specificity 97% [90–100]; n=82); the models would not converge when any additional variable was examined. The AUC (95% CI) of clinical examination at 6 h (n=190) and at discharge (n=167) were 0·72 (0·65–0·78) and 0·60 (0·53–0·68), respectively, and the AUC of abnormal amplitude integrated EEG at 6 h (n=169) was 0·73 (0·65–0·79). On conventional MRI (n=190), cortical injury had an AUC of 0·67 (0·60–0·73), basal ganglia or thalamic injury had an AUC of 0·81 (0·75–0·87), and abnormal signal in the posterior limb of internal capsule (PLIC) had an AUC of 0·82 (0·76–0·87). Fractional anisotropy of PLIC (n=65) had an AUC of 0·82 (0·76–0·87). MRS metabolite peak-area ratios (n=160) of NAA–creatine (<1·29) had an AUC of 0·79 (0·72–0·85), of NAA–choline had an AUC of 0·74 (0·66–0·80), and of lactate–NAA (>0·22) had an AUC of 0·94 (0·89–0·97).InterpretationThalamic proton MRS measures acquired soon after birth in neonatal encephalopathy had the highest accuracy to predict neurdevelopment 2 years later. These methods could...

White matter lesions (WML) on magnetic resonance imaging (MRI) brain scans are associated with ageing. They are unrelated to specific disorders, and their impact on cognitive and other brain functions is poorly characterized. Pathological studies often omit systematic survey of WML because of the need to study multiple full coronal tissue blocks, and uncertainty over the significance of lesions identified in periventricular and deep subcortical regions. Post-mortem MRI provides a means of mapping WML but the sensitivity and specificity of the method are unresolved. In this study post-mortem MRI of WML in fixed brain slices was compared with pathology in 33 brains donated to the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). This study shows that MRI detection of WML was less sensitive than pathology: periventricaular lesions (PVL) sensitivity = 95% (87-99%), specificity = 71% (44-90%); deep subcortical lesions (DSCL) sensitivity = 86% (79-93%), specificity = 80% (72-88%). False negative MRI was associated with milder pathology, but lesions detected by myelin attenuation alone showed both microglial and endothelial activation. Therefore post-mortem MRI of formalin-fixed brain slices is a reliable method to obtain systematic data on the severity and distribution of cerebral white matter disease, and appears to detect those WML most likely to have clinical impact.

. Real-time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes.

Complaints of cognitive decline are significantly associated with the severity of WML, independently of level of cognition and depression.

OBJECTIVE-Hepatic triglyceride is closely associated with hepatic insulin resistance and is known to be decreased by thiazolididinediones. We studied the effect of pioglitazone on hepatic triglyceride content and the consequent effect on postprandial endogenous glucose production (EGP) in type 2 diabetes.RESEARCH DESIGN AND METHODS-Ten subjects with type 2 diabetes on sulfonylurea therapy were treated with pioglitazone (30 mg daily) for 16 weeks. EGP was measured using a dynamic isotopic methodology after a standard liquid test meal both before and after pioglitazone treatment. Liver and muscle triglyceride levels were measured by 1 H magnetic resonance spectroscopy, and intra-abdominal fat content was measured by magnetic resonance imaging.RESULTS-Pioglitazone treatment reduced mean plasma fasting glucose and mean peak postprandial glucose levels. Fasting EGP decreased after pioglitazone treatment (16.6 Ϯ 1.0 vs. 12.2 Ϯ 0.7 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.005). Between 80 and 260 min postprandially, EGP was twofold lower on pioglitazone (2.58 Ϯ 0.25 vs. 1.26 Ϯ 0.30 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.001). Hepatic triglyceride content decreased by ϳ50% (P ϭ 0.03), and muscle (anterior tibialis) triglyceride content decreased by ϳ55% (P ϭ 0.02). Hepatic triglyceride content was directly correlated with fasting EGP (r ϭ 0.64, P ϭ 0.01) and inversely correlated to percentage suppression of EGP (time 150 min, r ϭ Ϫ0.63, P ϭ 0.02). Muscle triglyceride, subcutaneous fat, and visceral fat content were not related to EGP. H epatic triglyceride has been shown to be strongly associated with hepatic insulin resistance in type 2 diabetes (1-3). The exact mechanism by which hepatic triglyceride induces hepatic insulin resistance is unknown but is thought to relate to accumulation of intracellular fatty acid metabolites and consequent activation of a serine kinase cascade and induction of cellular insulin resistance (4). Reduction in hepatic triglyceride content by moderate weight reduction normalizes rates of basal endogenous glucose production (EGP) in patients with type 2 diabetes (2). Hepatic insulin resistance is also associated with impaired postprandial suppression of EGP in type 2 diabetes, but the effect of reduction of hepatic triglyceride content on postprandial suppression of EGP in type 2 diabetes is unknown. CONCLUSIONS-ReductionThiazolidinediones, such as pioglitazone, possess insulin-sensitizing properties and have been shown to decrease hepatic triglyceride content in type 2 diabetes (5). Because thiazolidinediones have been shown to reduce both fasting and postprandial glucose levels (6,7), we hypothesized that pioglitazone treatment in type 2 diabetes would reduce hepatic triglyceride content and consequently reduce basal and postprandial EGP. In addition, visceral fat has also been implicated in hepatic insulin resistance, and pioglitazone has been reported to decrease visceral fat content (8). The effect of this on EGP requires definition.To test our hypothesis, we used noninvasive 1 H magnetic resonance spectrosc...