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Reduced pancreas volume, as measured by non-contrast magnetic resonance imaging (MRI), is observed in individuals with newly-diagnosed type 1 diabetes (T1D) and declines over the first year after diagnosis. In this study, we determined the repeatability and inter-reader reproducibility of pancreas volume measurements by MRI. Test-retest scans in individuals with or without T1D (n = 16) had an intraclass correlation coefficient (ICC) of 0.985 (95% CI 0.961 to 0.995) for pancreas volume. Independent pancreas outlines by two board-certified radiologists (n = 30) yielded an ICC of 0.945 (95% CI 0.889 to 0.973). The mean Dice coefficient, a measurement of the degree of overlap between pancreas regions of interest between the two readers, was 0.77. Prandial state did not influence pancreatic measurements, as stomach volume did not correlate with pancreas volume. These data demonstrate that MRI measurements of pancreas volume between two readers are repeatable and reproducible with ICCs that correspond to excellent clinical significance (ICC > 0.9), are not related to changes in stomach volume, and could be a useful tool for clinical investigation of diabetes and other pancreas pathologies.
Because the white matter of the cerebral cortex contains axons that connect distant neurons in the cortical gray matter, the relationship between the volumes of the 2 cortical compartments is key for information transmission in the brain. It has been suggested that the volume of the white matter scales universally as a function of the volume of the gray matter across mammalian species, as would be expected if a global principle of wiring minimization applied. Using a systematic analysis across several mammalian clades, here we show that the volume of the white matter does not scale universally with the volume of the gray matter across mammals and is not optimized for wiring minimization. Instead, the ratio between volumes of gray and white matter is universally predicted by the same equation that predicts the degree of folding of the cerebral cortex, given the clade-specific scaling of cortical thickness, such that the volume of the gray matter (or the ratio of gray to total cortical volumes) divided by the square root of cortical thickness is a universal function of total cortical volume, regardless of the number of cortical neurons. Thus, the very mechanism that we propose to generate cortical folding also results in compactness of the white matter to a predictable degree across a wide variety of mammalian species.
OBJECTIVE - This study investigated the temporal dynamics of pancreas volume and microstructure in children and adolescents with recent-onset type 1 diabetes (T1D) and individuals without diabetes, including a subset expressing autoantibodies associated with the early stages of T1D.
RESEARCH DESIGN AND METHODS - MRI was performed in individuals with recent-onset stage 3 T1D ( = 51; median age 13 years) within 100 days after diagnosis (mean 67 days), 6 months, and 1 year postdiagnosis. Longitudinal MRI measurements were also made in similarly aged control participants ( = 57) and in autoantibody-positive individuals without diabetes ( = 20). The MRI protocol consisted of anatomical imaging to determine pancreas volume and quantitative MRI protocols interrogating tissue microstructure and composition.
RESULTS - Within 100 days of diabetes onset, individuals with T1D had a smaller pancreas (median volume 28.6 mL) than control participants (median volume 48.4 mL; < 0.001), including when normalized by individual weight ( < 0.001). Longitudinal measurements of pancreas volume increased in control participants over the year, consistent with adolescent growth, but pancreas volume declined over the first year after T1D diagnosis ( < 0.001). In multiple autoantibody-positive individuals, the pancreas volume was significantly larger than that of the T1D cohort ( = 0.017) but smaller than that of the control cohort ( = 0.04). Diffusion-weighted MRI showed that individuals with recent-onset T1D had a higher apparent diffusion coefficient ( = 0.012), suggesting a loss of cellular structural integrity, with heterogeneous pancreatic distribution.
CONCLUSIONS - These results indicate that pancreas volume is decreased in stages 1, 2, and 3 of T1D and decreases during the first year after diabetes onset and that this loss of pancreatic volume is accompanied by microstructural changes.
© 2018 by the American Diabetes Association.
Exposure to stress has been causally linked to changes in hippocampal volume (HV). Given that the hippocampus undergoes rapid changes in the first years of life, stressful experiences during this period may be particularly important in understanding individual differences in the development of the hippocampus. One hundred seventy-eight early adolescents (ages 9-13 years; 43% male) were interviewed regarding exposure to and age of onset of experiences of stress; the severity of each stressful event was rated by an objective panel. All participants underwent structural magnetic resonance imaging, from which HVs were automatically segmented. Without considering the age of onset for stressful experiences, there was a small but statistically significant negative association of stress severity with bilateral HV. When considering the age of onset, there was a moderate and significant negative association between stress severity during early childhood (through 5 years of age) and HV; there was no association between stress severity during later childhood (age 6 years and older) and HV. We provide evidence of a sensitive period through 5 years of age for the effects of life stress on HV in adolescence. It will be important in future research to elucidate how reduced HV stemming from early life stress may contribute to stress-related health outcomes.
© 2018 John Wiley & Sons Ltd.
Substance use may confound the study of brain structure in schizophrenia. We used voxel-based morphometry (VBM) to examine whether differences in regional gray matter volumes exist between schizophrenia patients with (n = 92) and without (n = 66) clinically significant cannabis and/or alcohol use histories compared to 88 healthy control subjects. Relative to controls, patients with schizophrenia had reduced gray matter volume in the bilateral precentral gyrus, right medial frontal cortex, right visual cortex, right occipital pole, right thalamus, bilateral amygdala, and bilateral cerebellum regardless of substance use history. Within these regions, we found no volume differences between patients with schizophrenia and a history of cannabis and/or alcohol compared to patients with schizophrenia without a clinically significant substance use history. Our data support the idea that a clinically meaningful history of alcohol or cannabis use does not significantly compound the gray matter deficits associated with schizophrenia.
Copyright © 2018. Published by Elsevier B.V.
BACKGROUND AND PURPOSE - Intracerebral hemorrhage is a considerable source of morbidity and mortality. This 3-center study describes outcomes of pediatric intracerebral hemorrhage and identifies 2-year neurological outcome predictors.
METHODS - Children 29 days to 18 years of age presenting with intracerebral hemorrhage from March 2007 to May 2015 were enrolled prospectively. Exclusion criteria included trauma; intracranial tumor; hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis; isolated subdural, epidural, or subarachnoid hemorrhage; and abnormal baseline neurological function. Intracerebral hemorrhage and total brain volumes were measured on neuroimaging. The Pediatric Stroke Outcome Measure assessed outcomes.
RESULTS - Sixty-nine children were included (median age: 9.7 years; interquartile range: 2.2-14). Six children (9%) died during hospitalization. Outcomes in survivors were assessed at early follow-up in 98% (median 3.1 months; interquartile range: 3.1-3.8) and at later follow-up in 94% (median: 2.1 years; interquartile range: 1.3-2.8). Over a third had a significant disability at 2 years (Pediatric Stroke Outcome Measure >2). Total Pediatric Stroke Outcome Measure score improved over time (=0.0003), paralleling improvements in the sensorimotor subscore (=0.0004). Altered mental status (odds ratio, 13; 95% confidence interval, 3.9-46; <0.001), hemorrhage volume ≥4% of total brain volume (odds ratio, 17; 95% confidence interval, 1.9-156; =0.01), and intensive care unit length of stay (odds ratio, 1.1; 95% confidence interval, 1.0-1.2; =0.002) were significantly associated with poor 2-year outcome.
CONCLUSIONS - Over one third of children experienced significant disability at 2 years. Improvements in outcomes were driven by recovery of sensorimotor function. Altered mental status, hemorrhage volume ≥4% of total brain volume, and intensive care unit length of stay were independent predictors of significant disability at 2 years.
© 2018 American Heart Association, Inc.
Researchers are becoming increasingly interested in linking specific forms of early life stress (ELS) to specific neurobiological markers, including alterations in the morphology of stress-sensitive brain regions. We used a person-centered, multi-informant approach to investigate the associations of specific constellations of ELS with hippocampal and amygdala volume in a community sample of 211 9- to 13-year-old early adolescents. Further, we compared this approach to a cumulative risk model of ELS, in which ELS was quantified by the total number of stressors reported. Using latent class analysis, we identified three classes of ELS (labeled typical/low, family instability, and direct victimization) that were distinguished by experiences of family instability and victimization. Adolescents in the direct victimization class had significantly smaller hippocampal volume than did adolescents in the typical/low class; ELS classes were not significantly associated with amygdala volume. The cumulative risk model of ELS had a poorer fit than did the person-centered model; moreover, cumulative ELS was not significantly associated with hippocampal or amygdala volume. Our results underscore the utility of taking a person-centered approach to identify alterations in stress-sensitive brain regions based on constellations of ELS, and suggest victimization is specifically associated with hippocampal hypotrophy observed in early adolescence.
Children from lower-SES families exhibit smaller hippocampal volume than do their higher-SES peers. Few studies, however, have compared hippocampal developmental trajectories as a function of SES. Thus, it is unclear whether initial rank-order stability is preserved, or whether volumes diverge/converge over the course of adolescence. In a sample of 101 girls ages 10-24 years, we examined the longitudinal association between family income and parental education, proxies for SES, and changes in hippocampal volume. Hippocampal volume was obtained using MRI; using mixed modeling, we examined the effects of income and education on hippocampal volume across age. As expected, changes in volume were non-linear across development. Further, trajectories diverged in mid-adolescence, with lower-income girls exhibiting reductions in hippocampal volume. Maximal income-related differences were observed at 18 years, and trajectories converged thereafter. This interaction remained significant when accounting for maternal hippocampal volume, suggesting a unique contribution of environment over potential heritable differences. In contrast, the association between parental education and offspring hippocampal volume appeared to be stable across adolescence, with higher levels of parental education predicting consistently larger hippocampal volume. These findings constitute preliminary evidence that girls from lower-income homes exhibit unique trajectories of hippocampal growth, with differences most evident in late adolescence.
Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.
Deficiencies in pancreatic β-cell mass contribute to both type 1 and type 2 diabetes. We investigated the role of the glucose-regulated protein (GRP) 94, an endoplasmic reticulum protein abundantly expressed in the pancreatic acini and islets, in β-cell development, survival, and function. We used a conditional knockout (KO) mouse in which the GRP94 gene, Hsp90b1, was specifically deleted in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. These Hsp90b1 flox/flox;Pdx1Cre KO mice exhibited pancreatic hypoplasia at embryonic day (E) 16.5 to E18.5 and had significantly reduced β-cell mass at 4 weeks after birth. Further mechanistic studies showed that deletion of GRP94 reduced β-cell proliferation with increased cell apoptosis in both Pdx1+ endocrine progenitor cells and differentiated β cells. Although Hsp90b1 flox/flox;Pdx1Cre KO mice remained euglycemic at 8 weeks of age, they exhibited impaired glucose tolerance. In aggregate, these findings indicate that GRP94 is an essential regulator of pancreatic β-cell development, mass, and function.
Copyright © 2018 Endocrine Society.
Hypoxia in the embryo is a frequent cause of intra-uterine growth retardation, low birth weight, and multiple organ defects. In the kidney, this can lead to low nephron endowment, predisposing to chronic kidney disease and arterial hypertension. A key component in cellular adaptation to hypoxia is the hypoxia-inducible factor pathway, which is regulated by prolyl-4-hydroxylase domain (PHD) dioxygenases PHD1, PHD2, and PHD3. In the adult kidney, PHD oxygen sensors are differentially expressed in a cell type-dependent manner and control the production of erythropoietin in interstitial cells. However, the role of interstitial cell PHDs in renal development has not been examined. Here we used a genetic approach in mice to interrogate PHD function in FOXD1-expressing stroma during nephrogenesis. We demonstrate that PHD2 and PHD3 are essential for normal kidney development as the combined inactivation of stromal PHD2 and PHD3 resulted in renal failure that was associated with reduced kidney size, decreased numbers of glomeruli, and abnormal postnatal nephron formation. In contrast, nephrogenesis was normal in animals with individual PHD inactivation. We furthermore demonstrate that the defect in nephron formation in PHD2/PHD3 double mutants required intact hypoxia-inducible factor-2 signaling and was dependent on the extent of stromal hypoxia-inducible factor activation. Thus, hypoxia-inducible factor prolyl-4-hydroxylation in renal interstitial cells is critical for normal nephron formation.
Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.