The cerebellar transcriptome during postnatal development of the Ts1Cje mouse, a segmental trisomy model for Down syndrome

The central nervous system of persons with Down syndrome presents cytoarchitectural abnormalities that likely result from gene-dosage effects affecting the expression of key developmental genes. To test this hypothesis, we have investigated the transcriptome of the cerebellum of the Ts1Cje mouse model of Down syndrome during postnatal development using microarrays and quantitative PCR (qPCR). Genes present in three copies were consistently overexpressed, with a mean ratio relative to euploid of 1.52 as determined by qPCR. Out of 63 three-copy genes tested, only five, nine and seven genes had ratios >2 or <1.2 at postnatal days 0 (P0), P15 and P30, respectively. This gene-dosage effect was associated with a dysregulation of the expression of some two-copy genes. Out of 8258 genes examined, the Ts1Cje/euploid ratios differed significantly from 1.0 for 406 (80 and 154 with ratios above 1.5 and below 0.7, respectively), 333 (11 above 1.5 and 55 below 0.7) and 246 genes (59 above 1.5 and 69 below 0.7) at P0, P15 and P30, respectively. Among the two-copy genes differentially expressed in the trisomic cerebellum, six homeobox genes, two belonging to the Notch pathway, were severely repressed. Overall, at P0, transcripts involved in cell differentiation and development were over-represented among the dysregulated genes, suggesting that cell differentiation and migration might be more altered than cell proliferation. Finally, global gene profiling revealed that transcription in Ts1Cje mice is more affected by the developmental changes than by the trisomic state, and that there is no apparent detectable delay in the postnatal development of the cerebellum of Ts1Cje mic

Validation of an MRI brain injury and growth scoring system in very preterm infants scanned at 29-to 35-week postmenstrual age

Background and Purpose: The diagnostic and prognostic potential of brain MR imaging before term-equivalent age is limited until valid MR imaging scoring systems are available. This study aimed to validate an MR imaging scoring system of brain injury and impaired growth for use at 29 to 35 weeks postmenstrual age in infants born at &lt; 31 weeks gestational age. Materials and Methods: Eighty-three infants in a prospective cohort study underwent early 3T MR imaging between 29 and 35 weeks' postmenstrual age (mean, 32 +2 ± 1 +3 weeks; 49 males, born at median gestation of 28 +4 weeks; range, 23 +6 -30 +6 weeks; mean birthweight, 1068±312 g). Seventy-seven infants had a secondMRscan at term-equivalent age (mean, 40 +6 ±1 +3 weeks). Structural images were scored using a modified scoring system which generated WM, cortical gray matter, deep gray matter, cerebellar, and global scores. Outcome at 12-months corrected age (mean, 12 months 4 days ± 1 +2 weeks) consisted of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley III), and the Neuro-Sensory Motor Developmental Assessment. Results: Early MR imaging global, WM, and deep gray matter scores were negatively associated with Bayley III motor (regression coefficient for global score ß =-1.31; 95% CI,-2.39 to-0.23; P = .02), cognitive (ß =-1.52; 95% CI,-2.39 to-0.65; P &lt; .01) and the Neuro-Sensory Motor Developmental Assessment outcomes (ß =-1.73; 95% CI,-3.19 to-0.28; P = .02). Early MR imaging cerebellar scores were negatively associated with the Neuro-Sensory Motor Developmental Assessment (ß =-5.99; 95% CI,-11.82 to-0.16; P = .04). Results were reconfirmed at term-equivalent-age MR imaging. Conclusions: This clinically accessible MR imaging scoring system is valid for use at 29 to 35 weeks postmenstrual age in infants born very preterm. It enables identification of infants at risk of adverse outcomes before the current standard of term-equivalent age