Comprehensive volumetric phenotyping of the neonatal brain in Down syndrome.

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.

Neurometabolite mapping highlights elevated myo-inositol profiles within the developing brain in down syndrome.

The neurodevelopmental phenotype in Down Syndrome (DS), or Trisomy 21, is variable including a wide spectrum of cognitive impairment and a high risk of early-onset Alzheimer's disease (AD). A key metabolite of interest within the brain in DS is Myo-inositol (mIns). The NA+/mIns co-transporter is located on human chromosome 21 and is overexpressed in DS. In adults with DS, elevated brain mIns was previously associated with cognitive impairment and proposed as a risk marker for progression to AD. However, it is unknown if brain mIns is increased earlier in development. The aim of this study was to estimate mIns concentration levels and key brain metabolites [N-acetylaspartate (NAA), Choline (Cho) and Creatine (Cr)] in the developing brain in DS and aged-matched controls. We used in vivo magnetic resonance spectroscopy (MRS) in neonates with DS (n = 12) and age-matched controls (n = 26) scanned just after birth (36-45 weeks postmenstrual age). Moreover, we used Mass Spectrometry in early (10-20 weeks post conception) ex vivo fetal brain tissue samples from DS (n = 14) and control (n = 30) cases. Relative to [Cho] and [Cr], we report elevated ratios of [mIns] in vivo in the basal ganglia/thalamus, in neonates with DS, when compared to age-matched typically developing controls. Glycine concentration ratios [Gly]/[Cr] and [Cho]/[Cr] also appear elevated. We observed elevated [mIns] in the ex vivo fetal cortical brain tissue in DS compared with controls. In conclusion, a higher level of brain mIns was evident as early as 10 weeks post conception and was measurable in vivo from 36 weeks post-menstrual age. Future work will determine if this early difference in metabolites is linked to cognitive outcomes in childhood or has utility as a potential treatment biomarker for early intervention.

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

Down syndrome (DS) occurs with triplication of human chromosome 21 and is associated with deviations in cortical development evidenced by simplified gyral appearance and reduced cortical surface area. Radial glia are neuronal and glial progenitors that also create a scaffolding structure essential for migrating neurons to reach cortical targets and therefore play a critical role in cortical development. The aim of this study was to characterise radial glial expression pattern and morphology in the frontal lobe of the developing human fetal brain with DS and age-matched controls. Secondly, we investigated whether microstructural information from in vivo magnetic resonance imaging (MRI) could reflect histological findings from human brain tissue samples. Immunohistochemistry was performed on paraffin-embedded human post-mortem brain tissue from nine fetuses and neonates with DS (15-39 gestational weeks (GW)) and nine euploid age-matched brains (18-39 GW). Radial glia markers CRYAB, HOPX, SOX2, GFAP and Vimentin were assessed in the Ventricular Zone, Subventricular Zone and Intermediate Zone. In vivo diffusion MRI was used to assess microstructure in these regions in one DS (21 GW) and one control (22 GW) fetal brain. We found a significant reduction in radial glial progenitor SOX2 and subtle deviations in radial glia expression (GFAP and Vimentin) prior to 24 GW in DS. In vivo, fetal MRI demonstrates underlying radial projections consistent with immunohistopathology. Radial glial alterations may contribute to the subsequent simplified gyral patterns and decreased cortical volumes observed in the DS brain. Recent advances in fetal MRI acquisition and analysis could provide non-invasive imaging-based biomarkers of early developmental deviations.

A multi-level developmental approach to exploring individual differences in Down syndrome: genes, brain, behaviour, and environment.

In this article, we focus on the causes of individual differences in Down syndrome (DS), exemplifying the multi-level, multi-method, lifespan developmental approach advocated by Karmiloff-Smith (1998, 2009, 2012, 2016). We evaluate the possibility of linking variations in infant and child development with variations in the (elevated) risk for Alzheimer's disease (AD) in adults with DS. We review the theoretical basis for this argument, considering genetics, epigenetics, brain, behaviour and environment. In studies 1 and 2, we focus on variation in language development. We utilise data from the MacArthur-Bates Communicative Development Inventories (CDI; Fenson et al., 2007), and Mullen Scales of Early Learning (MSEL) receptive and productive language subscales (Mullen, 1995) from 84 infants and children with DS (mean age 2;3, range 0;7 to 5;3). As expected, there was developmental delay in both receptive and expressive vocabulary and wide individual differences. Study 1 examined the influence of an environmental measure (socio-economic status as measured by parental occupation) on the observed variability. SES did not predict a reliable amount of the variation. Study 2 examined the predictive power of a specific genetic measure (apolipoprotein APOE genotype) which modulates risk for AD in adulthood. There was no reliable effect of APOE genotype, though weak evidence that development was faster for the genotype conferring greater AD risk (ε4 carriers), consistent with recent observations in infant attention (D'Souza, Mason et al., 2020). Study 3 considered the concerted effect of the DS genotype on early brain development. We describe new magnetic resonance imaging methods for measuring prenatal and neonatal brain structure in DS (e.g., volumes of supratentorial brain, cortex, cerebellar volume; Patkee et al., 2019). We establish the methodological viability of linking differences in early brain structure to measures of infant cognitive development, measured by the MSEL, as a potential early marker of clinical relevance. Five case studies are presented as proof of concept, but these are as yet too few to discern a pattern.

Early alterations in cortical and cerebellar regional brain growth in Down Syndrome: An in vivo fetal and neonatal MRI assessment.

Down Syndrome (DS) is the most frequent genetic cause of intellectual disability with a wide spectrum of neurodevelopmental outcomes. At present, the relationship between structural brain morphology and the spectrum of cognitive phenotypes in DS, is not well understood. This study aimed to quantify the development of the fetal and neonatal brain in DS participants, with and without a congenital cardiac defect compared with a control population using dedicated, optimised and motion-corrected in vivo magnetic resonance imaging (MRI). We detected deviations in development and altered regional brain growth in the fetus with DS from 21 weeks' gestation, when compared to age-matched controls. Reduced cerebellar volume was apparent in the second trimester with significant alteration in cortical growth becoming evident during the third trimester. Developmental abnormalities in the cortex and cerebellum are likely substrates for later neurocognitive impairment, and ongoing studies will allow us to confirm the role of antenatal MRI as an early biomarker for subsequent cognitive ability in DS. In the era of rapidly developing technologies, we believe that the results of this study will assist counselling for prospective parents.

New approaches to studying early brain development in Down syndrome.

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.

NUEVOS ENFOQUES PARA ESTUDIAR EL DESARROLLO CEREBRAL TEMPRANO EN EL SÍNDROME DE DOWN: El síndrome de Down es el trastorno del desarrollo genético más común en los seres humanos y es causado por la triplicación parcial o completa del cromosoma 21 (trisomía 21). Es una condición compleja que se traduce en múltiples problemas de salud a lo largo de toda la vida, incluidos diversos grados de discapacidad intelectual y retrasos en el habla, la memoria y el aprendizaje. Debido a que la duración y la calidad de vida están mejorando para las personas con síndrome de Down, ahora se está prestando atención a la comprensión y al tratamiento de las dificultades cognitivas asociadas y sus sustratos biológicos subyacentes. Estos estudios han incluido estudios de imagen y postmortem que han identificado volúmenes cerebrales regionales disminuidos y anomalías histológicas que acompañan a la demencia de inicio temprano. Además, los avances en el análisis del genoma completo y los modelos de ratones con síndrome de Down brindan información valiosa sobre los posibles objetivos de la intervención que podrían mejorar la neurogénesis y la cognición a largo plazo. Como se sabe poco sobre el desarrollo temprano del cerebro en el síndrome de Down humano, revisamos los avances recientes en imágenes de resonancia magnética que permiten la visualización no invasiva de la macro y microestructura cerebral, incluso en el útero. Se espera que, en conjunto, estos avances puedan permitir que el síndrome de Down se convierta en uno de los primeros trastornos genéticos a los que se aplican tratamientos prenatales diseñados para "encauzar" el desarrollo cerebral.

NOVAS ABORDAGENS PARA O ESTUDO DE DESENVOLVIMENTO CEREBRAL PRECOCE NA SÍNDROME DE DOWN: A síndrome de Down é a desordem desenvolvimental de origem genética mais comum em humanos. É causada por triplicação parcial ou completa do cromossomo 21 (trissomia do 21). Trata-se de uma condição complexa que resulta em múltiplos problemas de saúde ao longo da vida, incluindo graus variados de deficiência intelectual, e atrasos na fala, memória e aprendizagem. Como tanto a duração quanto a qualidade de vida têm melhorado para indivíduos com síndrome de Down, agora a atenção se volta para compreender e potencialmente tratar dificuldades cognitivas associadas e seus substratos biológicos de base. Incluem-se estudos de imagem e pós-morte que identificaram menores volumes cerebrais e anomalias histológicas que acompanham a demência de início precoe. Além disso, avanços na análise do genoma em modelos de ratos com síndrome de Down fornecem informações valiosas sobre potenciais alvos para intervenção que podem melhorar a neurogênese e a cognição em longo prazo. Como pouco se sabe sobre o desenvolvimento cerebral precoce na síndrome de Down, nós revisamos avanços recentes em imagens por ressonância magnética que permitem visualização não-invasiva da macro- e micro-estrutura do cérebro, mesmo no útero. Espera-se que, juntos, estes avanços possibilitem que a síndrome de Down se torne a primeira desorgem genética a ser alvo de tratamentos antenatais voltados para "normalizar" o desenvolvimento cerebral.