Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for ...the development and evaluation of preventive treatment therapies.
To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD.
Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status.
Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age.
Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.
While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.
Intelligence (IQ) scores are used in educational and vocational planning for individuals with autism spectrum disorder (ASD) yet little is known about the stability of IQ throughout development. We ...examined longitudinal age-related IQ stability in 119 individuals with ASD (3–36 years of age at first visit) and 128 typically developing controls. Intelligence measures were collected over a 20-year period. In ASD, Full Scale (FSIQ) and Verbal (VIQ) Intelligence started lower in childhood and increased at a greater rate with age relative to the control group. By early adulthood, VIQ and working memory stabilized, whereas nonverbal and perceptual scores continued to change. Our results suggest that in individuals with ASD, IQ estimates may be dynamic in childhood and young adulthood.
•Logarithmic growth of qR1 in the first year of non-human primate life.•Medial-to-lateral and posterior-to-anterior gradients of qR1 maturation.•Early individual differences in qR1 are not maintained ...across the first year.•qR1 and DTI metrics are correlated within-subjects, but not between-subjects.•Gestational age at birth predicts early postnatal qR1, unrelated to DTI at any age.
Alterations in white matter (WM) development are associated with many neuropsychiatric and neurodevelopmental disorders. Most MRI studies examining WM development employ diffusion tensor imaging (DTI), which relies on estimating diffusion patterns of water molecules as a reflection of WM microstructure. Quantitative relaxometry, an alternative method for characterizing WM microstructural changes, is based on molecular interactions associated with the magnetic relaxation of protons. In a longitudinal study of 34 infant non-human primates (NHP) (Macaca mulatta) across the first year of life, we implement a novel, high-resolution, T1-weighted MPnRAGE sequence to examine WM trajectories of the longitudinal relaxation rate (qR1) in relation to DTI metrics and gestational age at scan. To the best of our knowledge, this is the first study to assess developmental WM trajectories in NHPs using quantitative relaxometry and the first to directly compare DTI and relaxometry metrics during infancy. We demonstrate that qR1 exhibits robust logarithmic growth, unfolding in a posterior-anterior and medial-lateral fashion, similar to DTI metrics. On a within-subject level, DTI metrics and qR1 are highly correlated, but are largely unrelated on a between-subject level. Unlike DTI metrics, gestational age at birth (time in utero) is a strong predictor of early postnatal qR1 levels. Whereas individual differences in DTI metrics are maintained across the first year of life, this is not the case for qR1. These results point to the similarities and differences in using quantitative relaxometry and DTI in developmental studies, providing a basis for future studies to characterize the unique processes that these measures reflect at the cellular and molecular level.
The present study examined the effects of a visual-based biofeedback training on improving balance challenges in autism spectrum disorder (ASD). Twenty-nine youth with ASD (7–17 years) completed an ...intensive 6-week biofeedback-based videogame balance training. Participants exhibited training-related balance improvements that significantly accounted for postural-sway improvements outside of training. Participants perceived the training as beneficial and enjoyable. Significant moderators of training included milder stereotyped and ritualistic behaviors and better starting balance. Neither IQ nor BMI moderated training. These results suggest that biofeedback-based balance training is associated with balance improvements in youth with ASD, most robustly in those with less severe repetitive behaviors and better starting balance. The training was perceived as motivating, further suggesting its efficacy and likelihood of use.
The developing brain undergoes systematic changes that occur at successive stages of maturation. Deviations from the typical neurodevelopmental trajectory are hypothesized to underlie many early ...childhood disorders; thus, characterizing the earliest patterns of normative brain development is essential. Recent neuroimaging research provides insight into brain structure during late childhood and adolescence; however, few studies have examined the infant brain, particularly in infants under 3 months of age. Using high-resolution structural MRI, we measured subcortical gray and white matter brain volumes in a cohort (
N
= 143) of 1-month infants and examined characteristics of these volumetric measures throughout this early period of neurodevelopment. We show that brain volumes undergo age-related changes during the first month of life, with the corresponding patterns of regional asymmetry and sexual dimorphism. Specifically, males have larger total brain volume and volumes differ by sex in regionally specific brain regions, after correcting for total brain volume. Consistent with findings from studies of later childhood and adolescence, subcortical regions appear more rightward asymmetric. Neither sex differences nor regional asymmetries changed with gestation-corrected age. Our results complement a growing body of work investigating the earliest neurobiological changes associated with development and suggest that asymmetry and sexual dimorphism are present at birth.
Epithelial-mesenchymal transition (EMT) facilitates cancer invasion and is initiated by mesenchyme-driving transcription factors and actin cytoskeletal assembly. We show a cytoplasmic-to-nuclear ...transport gradient of the EMT transcription factor Zeb1 toward sites of invasion in lung adenocarcinoma (LUAD), driven by the EMT inducer Tgfb, which is expressed in M2 polarized macrophages. We show that Zeb1 binds free actin monomers and RhoA in the cytoplasm to inhibit actin polymerization, blocking cell migration and Yap1 nuclear transport. Tgfb causes turnover of the scaffold protein Rassf1a, which targets RhoA. Release of this RhoA inhibition in response to Tgfb overcomes Zeb1’s block of cytoskeleton assembly and frees it for nuclear transport. A ZEB1 nuclear transport signature highlights EMT progression, identifies dedifferentiated invasive/metastatic human LUADs, and predicts survival. Blocking Zeb1 nuclear transport with a small molecule identified in this study inhibits cytoskeleton assembly, cell migration, Yap1 nuclear transport, EMT, and precancerous-to-malignant transition.
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•Cytoplasmic Zeb1 inhibits actin cytoskeleton assembly•TGFb regulates Zeb1 nuclear transport•A Zeb1 nuclear transport signature predicts LUAD outcome•Zeb1 controls Yap1 nuclear transport
Guo et al. show that Zeb1 cycles between the cytoplasm and nucleus in lung cancer, where it controls cytoskeleton assembly and Yap1 nuclear transport in the cytoplasm and initiates epithelial-mesenchymal transition gene expression as TGFB drives its transition to the nucleus.
Cortical development and white matter myelination are hallmark processes of infant and child neurodevelopment, and play a central role in the evolution of cognitive and behavioral functioning. ...Non-invasive magnetic resonance imaging (MRI) has been used to independently track these microstructural and morphological changes in vivo, however few studies have investigated the relationship between them despite their concurrency in the developing brain. Further, because measures of cortical morphology rely on underlying gray–white matter tissue contrast, which itself is a function of white matter myelination, it is unclear if contrast-based measures of cortical development accurately reflect cortical architecture, or if they merely represent adjacent white matter maturation. This may be particularly true in young children, in whom brain structure is rapidly maturing. Here for the first time, we investigate the dynamic relationship between cortical and white matter development across early childhood, from 1 to 6years. We present measurements of cortical thickness with respect to cortical and adjacent myelin water fraction (MWF) in 33 bilateral cortical regions. Significant results in only 14 of 66 (21%) cortical regions suggest that cortical thickness measures are not heavily driven by changes in adjacent white matter, and that brain imaging studies of cortical and white matter maturation reflect distinct, but complimentary, neurodevelopmental processes.
•Cortical thickness follows a decreasing logarithmic trajectory in most brain regions.•Cortical thickness is not heavily driven by changes in adjacent white matter.•These distinct, but complimentary, processes may be temporally linked.
•Robust logarithmic growth in FA, MD, and RD during the first year of primate life.•Rapid WM development in first 10 weeks of life in rhesus monkeys.•Individual differences in DTI metrics are ...maintained through first year of life.•Early emergence of regional heterogeneity in WM development.
White matter (WM) development early in life is a critical component of brain development that facilitates the coordinated function of neuronal pathways. Additionally, alterations in WM have been implicated in various neurodevelopmental disorders, including psychiatric disorders. Because of the need to understand WM development in the weeks immediately following birth, we characterized changes in WM microstructure throughout the postnatal macaque brain during the first year of life. This is a period in primates during which genetic, developmental, and environmental factors may have long-lasting impacts on WM microstructure. Studies in nonhuman primates (NHPs) are particularly valuable as a model for understanding human brain development because of their evolutionary relatedness to humans. Here, 34 rhesus monkeys (23 females, 11 males) were imaged longitudinally at 3, 7, 13, 25, and 53 weeks of age with T1-weighted (MPnRAGE) and diffusion tensor imaging (DTI). With linear mixed-effects (LME) modeling, we demonstrated robust logarithmic growth in FA, MD, and RD trajectories extracted from 18 WM tracts across the brain. Estimated rate of change curves for FA, MD, and RD exhibited an initial 10-week period of exceedingly rapid WM development, followed by a precipitous decline in growth rates. K-means clustering of raw DTI trajectories and rank ordering of LME model parameters revealed distinct posterior-to-anterior and medial-to-lateral gradients in WM maturation. Finally, we found that individual differences in WM microstructure assessed at 3 weeks of age were significantly related to those at 1 year of age. This study provides a quantitative characterization of very early WM growth in NHPs and lays the foundation for future work focused on the impact of alterations in early WM developmental trajectories in relation to human psychopathology.
Most mutations in retinitis pigmentosa (RP) arise in rod photoreceptors, but cone photoreceptors, responsible for high-resolution daylight and color vision, are subsequently affected, causing the ...most debilitating features of the disease. We used mass spectroscopy to follow 13C metabolites delivered to the outer retina and single-cell RNA sequencing to assess photoreceptor transcriptomes. The S cone metabolic transcriptome suggests engagement of the TCA cycle and ongoing response to ROS characteristic of oxidative phosphorylation, which we link to their histone modification transcriptome. Tumor necrosis factor (TNF) and its downstream effector RIP3, which drive ROS generation via mitochondrial dysfunction, are induced and activated as S cones undergo early apoptosis in RP. The long/medium-wavelength (L/M) cone transcriptome shows enhanced glycolytic capacity, which maintains their function as RP progresses. Then, as extracellular glucose eventually diminishes, L/M cones are sustained in long-term dormancy by lactate metabolism.
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•A Metabolic switch protects cone photoreceptors in retinitis pigmentosa progression•Distinct metabolomes highlight the different photoreceptor types•S cones show early vulnerability in retinitis pigmentosa
Lee et al. utilize in vivo transport of 13C metabolites to the choroid and single-cell RNA sequencing of photoreceptors to characterize unique photoreceptor metabolomes that drive S cone vulnerability and L/M cone survival during progression of retinitis pigmentosa.
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