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Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study.

ABSTRACT: INTRODUCTION:Despite cooling, adverse outcomes are seen in up to half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Rigorous evaluation of these therapies in phase II trials using surrogate MR biomarkers may speed up their bench to bedside translation. A recent systematic review of single-centre studies has suggested that MR spectroscopy biomarkers offer the best promise; however, the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makers is not known. METHODS AND ANALYSIS:The MR scanners (3?T; Philips, Siemens, GE) in all the participating sites will be harmonised using phantom experiments and healthy adult volunteers before the start of the study. We will then recruit 180 encephalopathic infants treated with whole body cooling from the participating centres. MRI and spectroscopy will be performed within 2?weeks of birth. Neurodevelopmental outcomes will be assessed at 18-24?months of age. Agreement between MR cerebral biomarkers and neurodevelopmental outcome will be reported. The sample size is calculated using the 'rule of 10', generally used to calculate the sample size requirements for developing prognostic models. Considering 9 parameters, we require 9×10 adverse events, which suggest that a total sample size of 180 is required. ETHICS AND DISSEMINATION:Human Research Ethics Committee approvals have been received from Brent Research Ethics Committee (London), and from Imperial College London (Sponsor). We will submit the results of the study to relevant journals and offer national and international presentations. TRIAL REGISTRATION NUMBER:Clinical Trials.gov Number: NCT01309711.

SUBMITTER: Lally PJ

PROVIDER: S-EPMC4593140 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study.

Lally Peter J PJ Pauliah Shreela S Montaldo Paolo P Chaban Badr B Oliveira Vania V Bainbridge Alan A Soe Aung A Pattnayak Santosh S Clarke Paul P Satodia Prakash P Harigopal Sundeep S Abernethy Laurence J LJ Turner Mark A MA Huertas-Ceballos Angela A Shankaran Seetha S Thayyil Sudhin S

BMJ open 20150930 9

<h4>Introduction</h4>Despite cooling, adverse outcomes are seen in up to half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Rigorous evaluation of these therapies in phase II trials using surrogate MR biomarkers may speed up their bench to bedside translation. A recent systematic review of single-centre studies has sugges ...[more]

PMID: 26423856

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Project description:BackgroundIn 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 be applied to increase the power of neuroprotection trials while reducing their duration.FundingNational Institute for Health Research UK.

Project description:Background: Hypoxic-ischemic encephalopathy (HIE) is a major contributor to child mortality and morbidity. Reliable prognostication for HIE is of key importance. Proton magnetic resonance spectroscopy (1H-MRS) is a quantitative, non-invasive method that has been demonstrated to be a suitable complementary tool for prediction. The aim of this study was to investigate the prognostic capability of 1H-MRS in the era of therapeutic hypothermia (TH). Methods: Databases, namely MEDLINE, Embase, Web of Science, and the Cochrane library (Cochrane Center Register of Controlled Trials), were searched for studies published before July 17, 2017. Study selection and data extraction were performed by two independent reviewers. The mean difference (MD) or standardized MD (SMD) and 95% confidence interval (CI) were calculated using random-effects models. Subgroup analyses were conducted based on the use of TH. Results: Among the 1,150 relevant studies, seven were included for meta-analysis, but only two small studies were conducted under TH. For 1H-MRS measurement, three peak area ratios revealed predictive values for adverse outcomes in TH subgroup and the combined results (with and without TH): N-acetylaspartate (NAA)/creatine in basal ganglia/thalamus (BG/T) in TH (MD -0.31, 95%CI -0.55 to -0.07) and combined results (MD -0.37, 95% CI -0.49 to -0.25); NAA/choline in BG/T in TH (MD -0.89, 95%CI -1.43 to -0.35) and combined results (MD -0.25, 95%CI -0.42 to -0.07); and myo-inositol/choline in cerebral cortex in TH (MD -1.94, 95%CI -3.69 to -0.19) and combined results (MD -1.64, 95%CI -2.64 to -0.64). Moreover, NAA relative concentration is associated with adverse outcomes: in TH (MD -0.04, 95%CI -0.06 to -0.02) and combined results (MD -0.06, 95%CI -0.11 to -0.01) in white matter; in TH (MD -0.04, 95%CI -0.07 to -0.01) and combined results (MD -0.05, 95%CI -0.07 to -0.02) in gray matter. Conclusions: NAA may be a potential marker in outcome prediction for all HIE subjects. It seems that MDs for the ratios including NAA are larger than for its relative concentration, and therefore are more likely to be measurable in a clinical context. Larger prospective multicenter studies with a standardized protocol for both measurement protocols and analysis methods are required in future studies.

Project description:BackgroundCardinal features of Parkinson disease (PD) are motor symptoms, but nonmotor features such as mild cognitive impairment (MCI) are common early in the disease process. MCI can progress and convert to dementia in advanced stages, creating significant disability and reduced quality of life. The primary pathological substrate for cognitive decline in PD is unclear, and there are no reliable biomarkers predicting the risk of conversion to dementia. A subgroup of PD patients with visual hallucinations may display more rapid conversion to dementia, suggesting that regional markers of visuoperceptual dysfunction may be sensitive to pathologic density in posterior cortical regions.ObjectiveThe purpose of this project is to characterize PD-MCI and evaluate the utility of genetic and neuroimaging biomarkers in predicting cognitive outcomes with a prospective longitudinal study. We will evaluate whether accelerated cognitive progression may be reflected in biomarkers of early posterior cortical changes reflective of α-synuclein deposition.MethodsWe will evaluate a cohort of early-stage PD patients with the following methods to predict cognitive progression: (1) serial neuropsychological evaluations including detailed visuoperceptual functioning across 4 years; (2) genetic analysis of SNCA (α-synuclein), MAPT (microtubule-associated tau), and APOE (apolipoprotein E); (3) an event-related functional magnetic resonance imaging paradigm of object recognition memory; and (4) anatomical and regional brain activation changes (resting-state functional magnetic resonance imaging) across 4 years.ResultsThe project received funding from the National Institutes of Health in August 2017, and data collection began in February 2018. Enrollment is ongoing, and subjects will be evaluated annually for 4 years extended across a 5-year project including data analysis and image processing.ConclusionsCognitive, genetic, and structural and functional magnetic resonance imaging will characterize neural network changes predictive of cognitive progression in PD across 4 years. Identification of biomarkers with sensitivity for early prediction and estimation of risk for conversion to dementia in PD will pave the way for effective intervention with neuroprotective therapies during the critical stage when treatment can have the greatest impact.International registered report identifier (irrid)DERR1-10.2196/12870.

Dataset Information

Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study.

Publications

Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study.

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