New approaches to studying early brain development in Down syndrome

Abstract

Down syndrome is the most common genetic developmental disorder in humans and is caused by partial or complete triplication of human chromosome 21 (trisomy 21). It is a complex condition which results in multiple lifelong health problems, including varying degrees of intellectual disability and delays in speech, memory, and learning. As both length and quality of life are improving for individuals with Down syndrome, attention is now being directed to understanding and potentially treating the associated cognitive difficulties and their underlying biological substrates. These have included imaging and postmortem studies which have identified decreased regional brain volumes and histological anomalies that accompany early onset dementia. In addition, advances in genome-wide analysis and Down syndrome mouse models are providing valuable insight into potential targets for intervention that could improve neurogenesis and long-term cognition. As little is known about early brain development in human Down syndrome, we review recent advances in magnetic resonance imaging that allow non-invasive visualization of brain macro- and microstructure, even in utero. It is hoped that together these advances may enable Down syndrome to become one of the first genetic disorders to be targeted by antenatal treatments designed to 'normalize' brain development. WHAT THIS PAPER ADDS: Magnetic resonance imaging can provide non-invasive characterization of early brain development in Down syndrome. Down syndrome mouse models enable study of underlying pathology and potential intervention strategies. Potential therapies could modify brain structure and improve early cognitive levels. Down syndrome may be the first genetic disorder to have targeted therapies which alter antenatal brain development.

Figure 1

T2 fetal image reconstruction. Top row: One loop of single shot T2 images acquired in the coronal plane (centre). Numerous black lines in the sagittal and axial images represent missing or motion corrupted data. Bottom row: The reconstructed images have been obtained by registering several loops of single shot T2 images to provide high signal to noise, high resolution volumetric data sets.87, 88, 89, 90

Figure 2

Segmentation of the brain from a fetus with Down syndrome at 33⁺² gestational weeks. Semi‐automated segmentation of T2‐weighted volumetric magnetic resonance images showing (a) whole brain; excluding cerebellum (red), (b) cortex (green), (c) lateral ventricles (dark blue), (d) extra cerebral cerebrospinal fluid (light blue), (e) cerebellar hemispheres (purple), cerebellar vermis (bright green), pons (yellow), and fourth ventricle (blue).97 [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 3

Automated segmentation of a brain from a neonate with Down syndrome at 42⁺⁵ weeks post menstrual age. T2‐weighted neonatal brain volumetric images in axial, sagittal, and coronal planes (left to right) segmented into multiple brain regions. (a) Raw T2 acquisition, (b) segmentation with nine regions of interest, and (c) segmentation with 87 regions of interest.98, 99, 100 [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 4

Fetal brain development. T2‐weighted axial images from fetal (23⁺⁶–38⁺² GA) and neonatal (40⁺⁰ GA) magnetic resonance imaging showing development of the brain across gestation. Note the marked increase in cortical complexity with increasing gestation. GA, gestational age expressed as weeks+days.

Figure 5

T2‐weighted fetal magnetic resonance imaging in a control fetus and a fetus with Down syndrome. T2‐weighted axial images showing the fourth (a,b) and lateral ventricle (c,d) in control (34⁺¹ GA; a,c) and fetus with Down syndrome (33⁺² GA; b,d). White arrows indicate enlarged fourth and lateral ventricles in a fetus with Down syndrome. T2‐weighted sagittal (e,g) and axial (f,h) images in a fetus with Down syndrome (30wks GA, g,h) compared to an age matched control (30wks GA, e,f). Red arrow indicates cerebellar vermis rotation (g) and fourth ventricle enlargement (h). GA, gestational age expressed as weeks+days. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 6

Fetal diffusion tensor imaging. Top row: Fibre orientations distributions per voxel. Bottom row: Tractography demonstrating major connections within the developing brain. [Colour figure can be viewed at wileyonlinelibrary.com]

Figure 7

Neuronal staining in the cortex of human fetal postmortem tissue. HuC/HuD, a marker for all neurons in brain from control fetus at 22⁺² GA (a) and fetus with Down syndrome at 21⁺¹ GA (c). In the fetal brain with Down syndrome (c,d), the black arrow indicates evidence of aberrant cortical folding, a ‘wavy’ pattern which is in contrast to the control brain (a,b) (Research Ethics Committee UK: 07/H0707/139). Scale bar=500μm. T2‐weighted fetal magnetic resonance imaging in the axial plane show decreased cortical folding in a fetus with Down syndrome (d), compared to an aged matched control (b). GA, gestational age expressed as weeks+days. [Colour figure can be viewed at wileyonlinelibrary.com]