The Relationship Between Developing Prenatal And Postnatal Brain Structure And Connectivity, And Later Neurocognitive Profiles In Infants With Trisomy 21 (Down Syndrome)

Trisomy 21 (Down’s syndrome [DS]) represents the most common genetic cause of cognitive impairment. Children display a wide spectrum of cognitive and behavioural impairments, with many adults with DS then showing early cognitive declines. Although a genetic disorder with a single cause, individuals can show wide variation in the severity of cognitive deficits. In mothers who choose to continue with a pregnancy following a diagnosis that a foetus has DS, no early indication is available of the potential developmental trajectory of their child, other than during the gradual emergence of problems in early childhood. Early predictors of individual developmental predictors would be invaluable to manage expectations and plan supporting interventions in early life.

This project will employ magnetic resonance imaging of prenatal brain structure to predict cognitive profiles in infancy, for typically developing babies and babies with Trisomy 21 (Down syndrome). The project represents a unique opportunity for a student to gain training in multi-disciplinary research in developmental cognitive neuroscience, and to be involved at the ground level of an innovative study. Thus far, no study has demonstrated the relationship between prenatal brain growth and infant cognitive abilities.

The project will involve recruitment of mothers pregnant with babies with DS, and a control sample of mothers pregnant with typically developing babies (band 1 participants). The first phase of the project will involve the student gaining training with Rutherford in foetal and neonatal structural brain imaging using MRI. Each infant will have two structural scans, one prenatally, the second a few weeks after birth. The student will gain training in methods to objectively quantify structure and connectivity of the early developing brain using state of the art techniques to derive quantified parameters of brain growth and development. For the foetus, this involves partitioning the brain into a small number of regions to quantify volume, and then measures of white matter connectivity. More detailed scans are available postnatally. Given the rate of recruitment to date at Rutherford’s specialist imaging centre, we anticipate N=15 DS families is achievable, with a similar number of controls. Rutherford has a large existing control cohort for foetal imaging against which new data can be referenced. The project will take advantage of the ERC-funded dHCP project (developingconnectome.com) in which Rutherford’s team have optimised advanced imaging techniques to obtain high resolution datasets from mobile foetuses and unsedated neonates. As evidence of the imaging protocol is firmly established, to date Rutherford has good foetal imaging data on a cohort of 25 foetuses with DS across gestation (21 to 36 weeks), 11 with cardiac lesions, and 52 controls all analysed, and 18 neonates with MR Spectroscopy and MRI, and 20 controls (36-46 weeks postmenstrual age).

The second phase of the project will involve training the student in the labs of Farran and Thomas to carry out the neurocognitive test battery on the band 1 infants from six months of age. Part of the work will involve follow-up measures (behavioural measures, high-density electroencephalography, eye tracking, and sleep actigraphy) on the cohort of 100 infants already tested (band 2 participants), who are now entering early childhood. The aim will be to project forward the implications of the variable cognitive profiles already measured (Thomas et al., 2009).

The final phase of the project will involve statistical modelling of the relationship between early brain measures and cognitive profiles from six months using band 1 data, and linking previous data in infancy with early childhood outcomes using band 2 data. The student will be given training in the relevant statistical techniques.

The project provides the simultaneous goals of practically offering parents of infants with DS information about their children’s likely development, and theoretically, tracing back the causes of atypical development to prenatal brain development, where unfolding genetic events may cause structural and functional atypicalities. In both cases, the proposed project will be unique and innovative.

Timetable (3 years)

Year 1, 1-6 months: Training in MRI data acquisition and analysis; recruitment of band 1 mothers; MRI data collection; training in neurocognitive battery
Year 1, 7-12 months: band 1 MRI data collection; band 2 testing older children for longitudinal follow-up
Year 2, 1-6 months: band 1 MRI data collection; band 2 testing older children for longitudinal follow-up
Year 2, 7-12 months: band 1 testing infants on neurocognitive battery; data analysis and write-up of band 2 data
Year 3, 1-6 months: band 1 testing infants on neurocognitive battery; band 1 data analysis
Year 3, 7-12 months: Final data analysis and write-up.