Quantitative MRI Analyses of Regional Brain Growth in Living Fetuses with Down Syndrome

Abstract

Down syndrome (DS) is the most common liveborn autosomal chromosomal anomaly and is a major cause of developmental disability. Atypical brain development and the resulting intellectual disability originate during the fetal period. Perinatal interventions to correct such aberrant development are on the horizon in preclinical studies. However, we lack tools to sensitively measure aberrant structural brain development in living human fetuses with DS. In this study, we aimed to develop safe and precise neuroimaging measures to monitor fetal brain development in DS. We measured growth patterns of regional brain structures in 10 fetal brains with DS (29.1 ± 4.2, weeks of gestation, mean ± SD, range 21.7~35.1) and 12 control fetuses (25.2 ± 5.0, range 18.6~33.3) using regional volumetric analysis of fetal brain MRI. All cases with DS had confirmed karyotypes. We performed non-linear regression models to compare fitted regional growth curves between DS and controls. We found decreased growth trajectories of the cortical plate (P = 0.033), the subcortical parenchyma (P = 0.010), and the cerebellar hemispheres (P < 0.0001) in DS compared to controls. This study provides proof of principle that regional volumetric analysis of fetal brain MRI facilitates successful evaluation of brain development in living fetuses with DS.

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

“…Guidi et al, (2018) have reported a comparable number of GFAP-labelled astrocytes and reduced number of neurons, suggestive of increased percentage of astrocytic cells (< 21GW), in the fusiform and inferior temporal gyrus [ 18 ]. We did not assess neuronal number in this study, but the decreased number of SOX2 cells in the oSVZ of DS and observed decreases in cortical volumes from fetal MRI studies could reflect decreased neuronal numbers observed in the cortex of the DS brain after birth [ 14 , 45 , 50 , 55 , 63 ].…”

“…The neurodevelopmental phenotype is variable and associated with cognitive deficits and impairments in speech, motor and language functions. Whilst the neurological phenotype of DS changes over a lifetime, smaller whole brain volumes, predominantly in the cortex and cerebellum, have been observed in early fetal life [19,45,55]. Structural magnetic resonance imaging (MRI) studies show that the cortex develops with a simplified gyral appearance (less folded), reduced overall cortical surface area and volume, and abnormal cortical thickness in children and young adults with DS [33,34].…”

“…We have previously shown that in other forms of genetic mutations (ACTG1 variant), disturbances in radial glia and migratory signals dramatically affect brain development [62]. We and others recently found that quantifiable deviations in cortical growth arise from 28 to 30 GW in fetuses with DS, measured from T2-weighted fetal magnetic resonance imaging (MRI) [45,55]. Altered radial glial function, impacting neuronal migration may underlie these cortical disturbances.…”

Longitudinal neuroanatomical and behavioral analyses show phenotypic drift and variability in the Ts65Dn mouse model of Down syndrome

“…The original differences in gross measurements in the trisomic embryos from the 1924 2007 analysis were thought to be derived from changes in the expansion of the developing pallial wall, similar to how changes in the developing cortical wall may underlie the later microencephaly in humans with DS (Tarui et al, 2020). In particular, the 1924 2007 cohort displayed a significantly smaller thickness of the total pallium from E13.5 to E16.5 in the trisomic embryos compared to the euploid controls (Chakrabarti et al, 2007).…”

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

“…Identification of neural differences much earlier in the life course in DS, could potentially offer opportunities for more effective intervention. We and others have recently demonstrated that fetuses and neonates with DS have reduced whole brain, cortical and cerebellar volumes from as early as 20 weeks gestational age (GA), using in vivo volumetric MRI (Tarui et al, 2019;Patkee et al, 2020). Whether such anatomical differences are accompanied by early differences in the metabolite levels, that reflect neuronal and glial function, and alter neurodevelopmental outcome, remains unknown.…”