Magnetic Resonance Biomarkers in Neonatal Encephalopathy
Condition: Neonatal Encephalopathy
MeSH terms: Brain Diseases
Study type: Observational

Summary: 
      N-acetylaspartate (NAA) is a surrogate neuronal marker and its proton magnetic resonance
      spectroscopy (1H MRS) signal decreases with increasing neuronal mortality associated with
      cerebral hypoxia-ischaemia. The MRS lactate (Lac)/NAA peak-area ratio increases during and
      after severe cerebral hypoxia-ischaemia reflecting mitochondrial injury and impaired
      oxidative phosphorylation.

      Aims: (1) To establish normative ranges for thalamic 1H MRS NAA concentration and Lac/NAA in
      healthy newborn infants (2) To examine the accuracies of thalamic 1H MRS NAA concentration
      and Lac/NAA for predicting adverse neurodevelopmental outcome in neonatal encephalopathy (NE)

      Design: Prospective observational study Methods: Year 1: Following 1H MRS methodology
      optimisation 40 healthy control infants will be recruited to collect normative data. Year 2
      to 3: 115 infants with NE, undergoing therapeutic hypothermia will be recruited. MRS will be
      performed aged less than 4 days and 7 to 14 days and thalamic NAA levels and Lac/NAA will be
      quantified; Qualitative interviews to evaluate parental understanding of this biomarker. Year
      4, 5: Outcome assessment by BSID III at 18 months.

      Outcomes: Mean thalamic NAA levels and Lac/NAA and appropriate confidence intervals in normal
      infants, and thalamic NAA levels and Lac/NAA in infants with NE according to
      neurodevelopmental outcome. Areas under curves for thalamic NAA and Lac/NAA will be examined
      separately for early & late MRS. Accuracy of early MRS will inform utility of this
      investigation in decisions about withdrawal of life support; late MRS will inform about
      efficacy as a surrogate end point in clinical trials. Qualitative interviews will be
      thematically analysed and reported.
    

Detailed description: 
      2. 1 PRIMARY OBJECTIVE To examine the accuracy of 1H MRS thalamic [NAA] for predicting
      adverse neurodevelopment in infants with NE undergoing therapeutic hypothermia

      2.2 SECONDARY OBJECTIVE 2.2.1 To examine inter and intra-center variability of thalamic [NAA]
      levels in healthy adult volunteers 2.2.2 To further develop normative ranges for 1H MRS
      thalamic [NAA] and other quantitative measures of potential utility in healthy term newborn
      infants 2.2.3 To compare the prognostic accuracy of 1H MRS thalamic [NAA] and other MRS
      quantities with that of the Lactate/NAA peak-area ratio acquired early (aged ≤ 4 days) and
      with that acquired late (aged 5 to 14 days) 2.2.4 To examine parental attitudes towards MR
      use in decisions about withdrawal of life support and counselling about long term outcomes

      3. METHODS Prospective observational study; the index test (1H MRS) and gold-standard test
      (neurological outcome at 18 months) will be performed independently and blinded to each
      other.

      3.3 Recruitment Control infants will be recruited from the postnatal wards at the
      participating hospitals. The MR scans will be performed before the infant is first discharged
      from hospital as far as possible (for example following a Caesarean delivery) i.e. within the
      first week of life. A lead research midwife will be identified in each of the participating
      hospitals who will approach the parents for recruitment and informed consent.

      NE infants will be recruited from neonatal intensive care units. MR scans will be performed
      twice after informed parental consent. The first scan at less than 4 days of age (if
      clinically feasible) and the second scan between 5 to 14 days of age. The first scan will be
      performed while the infant is still in the intensive care unit at the participating centre.
      At the time of the second MR scan, it is likely most babies would be off the ventilator.
      Sedation would be used if required in these babies.

      3.4 Neurodevelopmental evaluation Neurodevelopmental outcomes will be assessed at 18 months
      of age using Bayley Scale of Infant Development® (Version 3) blinded to the MRS information.
      Favourable outcome will be defined as survival without disability, no disability being
      defined as all of: developmental quotient (DQ) >84 (BSID III), no neuromotor impairment
      (neurological exam score ≥73 and Gross Motor Function Classification System (GMFCS) ≤I) [19],
      and normal vision and hearing on clinical examination. Unfavourable outcome will be defined
      as death or, in survivors, moderate or severe disability.

      3.5 Post-mortem evaluation If the infant dies (UCH cases only), parents will be given options
      of conventional autopsy or minimally invasive autopsy (MIA) at Great Ormond Street Hospital
      (GOSH) using the protocol established for the MaRIAS (Magnetic Resonance Imaging Autopsy
      Study)[20].

      3.6 Qualitative interviews About 6 months after death or discharge a parental sub group from
      20 NE cases recruited by stratified purposeful sampling from Royal Victoria Infirmary
      (Newcastle) will be invited to participate in an interview by a psychology Research Fellow.
      The parental understanding of, and attitudes towards use of, MR techniques for predicting
      long term outcomes and making decisions about withdrawal of life support (during hospital
      stay), will be collected thematically and analysed (aim 2.2.3). Tape recorded transcripts of
      parental interviews will be analysed and emerging themes grouped.

      4. ENDPOINTS AND DATA ANALYSIS

      1H MRS thalamic [NAA] (mean (SD); mmol/kg wet weight brain tissue) in NE infants will be
      compared with outcome. Sensitivity and specificity with 95% CI and area under the curve
      (Standard Error) will be reported for [NAA] and Lac/NAA peak-area ratio and the clinical
      significances of unit changes in these measures in terms of unit changes in motor and
      cognitive outcome scores examined. The prognostic accuracy of early acquisition 1H MRS will
      be compared with late acquisition using area under curve and diagnostic odds ratios. The
      accuracy of [NAA] for prediction of outcome will be compared with conventional MRI. 1H MRS
      thalamic [NAA] (mean (SD)) in healthy term infants will be reported.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Healthy control infants, Infants with Neonatal encephalopathy, Healthy adult volunteers
      
Biospecimen description: 
      Blood and urine
    
Keywords: MRI; Biomarkers; Neonatal encephalopathy; Therapeutic hypothermia