Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome
Authors: Fukami - Gartner Abi , Baburamani Ana A. , Dimitrova Ralica , Patkee Prachi A. , Alfageme Olatz Ojinaga , Bonthrone Alexandra F. , Cromb Daniel , Uus Alena , Counsell Serena J. , Hajnal Joseph V. , O’Muircheartaigh Jonathan , Rutherford Mary A. 
Published: October 2022

Down syndrome (DS) is the most common genetic cause of intellectual disability with a wide spectrum of neurodevelopmental outcomes. Magnetic resonance imaging (MRI) has been used to investigate differences in whole and/or regional brain volumes in DS from infancy to adulthood. However, to date, there have been relatively few in vivo neonatal brain imaging studies in DS, despite the presence of clearly identifiable characteristics at birth. Improved understanding of early brain development in DS is needed to assess phenotypic severity and identify appropriate time windows for early intervention. In this study, we used in vivo brain MRI to conduct a comprehensive volumetric phenotyping of the neonatal brain in DS. Using a robust cross-sectional reference sample of close to 500 preterm- to term-born control neonates, we have performed normative modelling and quantified volumetric deviation from the normative mean in 25 individual infants with DS [postmenstrual age at scan, median (range) = 40.57 (32.43 – 45.57) weeks], corrected for sex, age at scan and age from birth. We found that absolute whole brain volume was significantly reduced in neonates with DS (pFDR <0.0001), as were most underlying absolute tissue volumes, except for the lentiform nuclei and the extracerebral cerebrospinal fluid (eCSF), which were not significantly different, and the lateral ventricles, which were significantly enlarged (pFDR <0.0001). Relative volumes, adjusting for underlying differences in whole brain volume, revealed a dynamic shift in brain proportions in neonates with DS. In particular, the cerebellum, as well as the cingulate, frontal, insular and occipital white matter (WM) segments were significantly reduced in proportion (pFDR <0.0001). Conversely, deep grey matter (GM) structures, such as the thalami and lentiform nuclei, as well as CSF-filled compartments, such as the eCSF and the lateral ventricles were significantly enlarged in proportion (pFDR <0.0001). We also observed proportionally reduced frontal and occipital lobar volumes, in contrast with proportionally enlarged temporal and parietal lobar volumes. Lastly, we noted age-related volumetric differences between neonates with and without a congenital heart defect (CHD), indicating that there may be a baseline brain phenotype in neonates with DS, which is further altered in the presence of CHD. In summary, we provide a comprehensive volumetric phenotyping of the neonatal brain in DS and observe many features that appear to follow a developmental continuum, as noted in older age cohorts. There are currently no paediatric longitudinal neuroimaging investigations in DS, starting from the earliest time points, which greatly impedes our understanding of the developmental continuum of neuroanatomical parameters in DS. Whilst life expectancy of individuals with DS has greatly improved over the last few decades, early interventions may be essential to help improve outcomes and quality of life.

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