Ventriculomegaly in very‐low‐birthweight infants with Down syndrome

Movsas, Tammy Z.; Spitzer, Alan R.; Gewolb, Ira H

doi:10.1111/dmcn.13191

Cited by 13 publications

(7 citation statements)

References 24 publications

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“…In the brain, we detected increased ventricular volumes, which is consistent with the trend observed in our previous study at PD29 (Llambrich, González, et al, 2022) and the ventriculomegaly typically observed in humans and mouse models for DS (Ishihara et al, 2010;Movsas et al, 2016;Pearlson et al, 1998;Raveau et al, 2017). However, we also detected increased hippocampal, cerebellar, and whole brain volumes in TS untreated mice that do not match clinical reports indicating reduced brain, hippocampal and cerebellar volumes in humans with DS (Aylward et al, 1997;Hamner et al, 2018;Patkee et al, 2020;Pearlson et al, 1998;Pinter et al, 2001;Rodrigues et al, 2019;Smigielska-Kuzia et al, 2011), and other preclinical studies that did not find brain volume differences in Ts65Dn mice (Aldridge et al, 2007;Duchon et al, 2021;Holtzman et al, 1996;Insausti et al, 1998).…”

Section: Structural Domainsupporting

confidence: 92%

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model

Llambrich,

Tielemans,

Saliën

et al. 2023

Preprint

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Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, reduced bone mineral density, neurodevelopmental delay, hyperactivity, and impaired long-term memory with altered hippocampal metabolite concentration and gene expression. However, Ts65Dn mice showed milder phenotypes than previously described, suggesting a drift of the mouse model. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.

show abstract

Section: Structural Domainsupporting

confidence: 92%

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model

Llambrich,

Tielemans,

Saliën

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…In the brain, we detected increased ventricular volumes, which is consistent with the trend observed in our previous study at PD29 (Llambrich, González, et al, 2022 ) and the ventriculomegaly typically observed in humans and mouse models for DS (Ishihara et al, 2010 ;Movsas et al, 2016 ;Pearlson et al, 1998 ;Raveau et al, 2017 ). However, we also detected increased hippocampal, cerebellar, and whole brain volumes in TS untreated mice that do not match clinical reports indicating reduced brain, hippocampal and cerebellar volumes in humans with DS (Aylward et al, 1997 ;Hamner et al, 2018 ;Patkee et al, 2020 ;Pearlson et al, 1998 ;Pinter et al, 2001 ;Rodrigues et al, 2019 ;Smigielska-Kuzia et al, 2011 ), and other preclinical studies that did not find brain volume differences in Ts65Dn mice (Aldridge et al, 2007 ;Duchon et al, 2021 ;Holtzman et al, 1996 ;Insausti et al, 1998 ).…”

Section: Structural Domainsupporting

confidence: 92%

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model

Llambrich,

Tielemans,

Saliën

et al. 2024

Preprint

View full text Add to dashboard Cite

Down syndrome (DS) is characterized by skeletal and brain structural malformations, cognitive impairment, altered hippocampal metabolite concentration and gene expression imbalance. These alterations were usually investigated separately, and the potential rescuing effects of green tea extracts enriched in epigallocatechin-3-gallate (GTE-EGCG) provided disparate results due to different experimental conditions. We overcame these limitations by conducting the first longitudinal controlled experiment evaluating genotype and GTE-EGCG prenatal chronic treatment effects before and after treatment discontinuation. Our findings revealed that the Ts65Dn mouse model reflected the pleiotropic nature of DS, exhibiting brachycephalic skull, ventriculomegaly, neurodevelopmental delay, hyperactivity, and impaired memory robustness with altered hippocampal metabolite concentration and gene expression. GTE-EGCG treatment modulated most systems simultaneously but did not rescue DS phenotypes. On the contrary, the treatment exacerbated trisomic phenotypes including body weight, tibia microarchitecture, neurodevelopment, adult cognition, and metabolite concentration, not supporting the therapeutic use of GTE-EGCG as a prenatal chronic treatment. Our results highlight the importance of longitudinal experiments assessing the co-modulation of multiple systems throughout development when characterizing preclinical models in complex disorders and evaluating the pleiotropic effects and general safety of pharmacological treatments.

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“…Hydrocephalus, fetal ventriculomegaly (especially in very low birth weight infants < 1,500 g), and enlargement of the third ventricle, have been reported to occur in DS ( Farrell 1994 ; Schimmel et al. 2006 ; Movsas et al. 2016 ; Marano et al.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome

et al. 2023

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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.

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Ventriculomegaly in very‐low‐birthweight infants with Down syndrome

Abstract: Very preterm infants with Down syndrome are at increased risk for ventriculomegaly (but not for IVH) compared with other infants born very preterm.

Cited by 13 publications

References 24 publications

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model

Pleiotropic effects of trisomy and pharmacologic modulation on structural, functional, molecular, and genetic systems in a Down syndrome mouse model

Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome

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