Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome

Abstract

Down syndrome (DS) is the most common genetic cause of intellectual disability with a wide range of neurodevelopmental outcomes. To date, there have been very few in vivo neuroimaging studies of the neonatal brain in DS. In this study we used a cross-sectional sample of 493 preterm- to term-born control neonates from the developing Human Connectome Project to perform normative modeling of regional brain tissue volumes from 32 to 46 weeks postmenstrual age, accounting for sex and age variables. Deviation from the normative mean was quantified in 25 neonates with DS with postnatally confirmed karyotypes from the Early Brain Imaging in DS study. Here, we provide the first comprehensive volumetric phenotyping of the neonatal brain in DS, which is characterized by significantly reduced whole brain, cerebral white matter, and cerebellar volumes; reduced relative frontal and occipital lobar volumes, in contrast with enlarged relative temporal and parietal lobar volumes; enlarged relative deep gray matter volume (particularly the lentiform nuclei); and enlargement of the lateral ventricles, amongst other features. In future, the ability to assess phenotypic severity at the neonatal stage may help guide early interventions and, ultimately, help improve neurodevelopmental outcomes in children with DS.

Investigating brain alterations in the Dp1Tyb mouse model of Down syndrome

“…The biological interpretation of these enlargements, whether they are developmental or compensatory, is not clear due to the diverse range of functions associated with these regions. Overall, our mouse findings further underscore the relevance and validity of the Dp1Tyb model as it recapitulates some neuroanatomical alterations observed in humans with DS ( Fukami-Gartner et al, 2023 ).…”

“…These observed changes in the Dp1Tyb model resemble the heterogeneous findings from humans with DS. For instance, studies in humans have also highlighted the significance of decreased prefrontal cortex and hippocampal volume as key neuroanatomical correlates of cognitive deficits in this population ( Fukami-Gartner et al, 2023 ; McCann et al, 2021 ; Pinter et al, 2001 ; Teipel et al, 2004 ). On the other hand, reports of slight enlargements of deep grey matter structures are reminiscent of our findings of increased subcortical volumes ( Raz et al, 1995 ; White et al, 2003 ; Wilson et al, 2019 ).…”

“…To this end, magnetic resonance imaging (MRI) studies have shown decreases in the overall brain volume in people with DS compared to neurotypical people, with several brain regions particularly affected, such as the frontal lobes, the hippocampus, and the cerebellum ( Koenig et al, 2021 ; McCann et al, 2021 ). On the other hand, the complexity of this syndrome is also reflected in some posterior cortical and subcortical regions that are relatively preserved or even increased in volume ( Fukami-Gartner et al, 2023 ; Pinter et al, 2001 ). Regarding cellular and molecular changes, increases in glial markers (such as inositol and glutamine) and decreases in neuronal markers (such as glutamate) have been reported using magnetic resonance spectroscopy (MRS), in both humans and animal models of DS ( Lin et al, 2016 ; Patkee et al, 2021 ; Shonk and Ross, 1995 ; Vacca et al, 2019 ).…”

Dissecting the contribution of human chromosome 21 syntenic regions to recognition memory processes in adult and aged mouse models of Down syndrome

“…In DS, temporal lobe volume is greatly reduced compared to neurotypical individuals ( Takashima et al, 1994 ; Pinter et al, 2001 ; Guidi et al, 2008 ), with MRI studies reporting a ~30% volume reduction in the hippocampus (HPC), the primary structure supporting declarative recognition and spatial memory functions ( Barker and Warburton, 2011 ). Morphological alterations of the HPC are already present in DS fetuses, persist through adulthood and are exacerbated with age ( Takashima et al, 1994 ; Guidi et al, 2008 ; Fukami-Gartner et al, 2023 ).…”

Investigating Brain Alterations in the Dp1Tyb Mouse Model of Down Syndrome

“…To this end, magnetic resonance imaging (MRI) studies have shown decreases in the overall brain volume in people with DS compared to neurotypical people, with several brain regions particularly affected, such as the frontal lobes, the hippocampus, and the cerebellum (Koenig et al, 2021;McCann et al, 2021). On the other hand, the complexity of this syndrome is also reflected in some posterior cortical and subcortical regions that are relatively preserved or even increased in volume (Fukami-Gartner et al, 2023;Pinter et al, 2001). Regarding cellular and molecular changes, increases in glial markers (such as inositol and glutamine) and decreases in neuronal markers (such as glutamate) have been reported using magnetic resonance spectroscopy (MRS), in both humans and animal models of DS (Lin et al, 2016;Patkee et al, 2021;Shonk and Ross, 1995;Vacca et al, 2019).…”