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.

Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome

“…In conclusion, we found significantly elevated Myo-Ins in the DS fetal brain, and elevated ratios of Myo:Cho, Myo:Cr, NAA:Cho and NAA:Cr in the developing neonatal brain with DS, compared to a typically developing population. DS is a multifactorial disorder with a wide spectrum of phenotypes attributable to a significant degree of individual variability in genotypes (Karmiloff-Smith et al, 2016;Baburamani et al, 2019). The differences in metabolite ratios may reflect ongoing metabolic deviations that may underlie some of the altered brain volumes previously reported (Patkee et al, 2020) in DS and may be correlated with subsequent cognitive delay and potentially with the development of dementia in later life.…”

Assessment of radial glia in the frontal lobe of fetuses with Down syndrome

“…We averaged anterior and medial ROIs to achieve total values for the oSVZ and IZ. Data was normalized to obtain immunopositive particles per mm 2 .…”

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

“…Trisomy 21, as an aneuploidy disorder, is characterized by an additional copy of human chromosome 21 (Hsa21) and causes Down syndrome (DS). DS is the most abundant human trisomy, affecting around 1 in 1100 neonates annually [1], making it the most common genetic cause for intellectual disability (ID) [2]. DS patients suffer from several cognitive impairments, accompanied by a low intelligence quotient (IQ) ranging from 30 to 70 [2], which can be attributed to brain abnormalities.…”

“…Therefore, much of the DS research aimed at identifying the underlying genetic interventions of altered neurogenesis. This information is essential for unraveling pharmacological approaches to ameliorate cognitive function (summarized in recent reviews [1,[4][5][6][7][8]). Nevertheless, over the last few years consideration has been given to the re-evaluation of the role of astroglial and oligodendroglial lineage cells in CNS pathologies characterized by neurodegeneration [3,9].…”