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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.
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.
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.
Age-related changes in cognition are partially mediated by the presence of neuropathology and neurodegeneration. This manuscript evaluates the degree to which biomarkers of Alzheimer's disease, (AD) neuropathology and longitudinal changes in brain structure, account for age-related differences in cognition. Data from the AD Neuroimaging Initiative (n = 1012) were analyzed, including individuals with normal cognition and mild cognitive impairment. Parallel process mixed effects regression models characterized longitudinal trajectories of cognitive variables and time-varying changes in brain volumes. Baseline age was associated with both memory and executive function at baseline (p's < 0.001) and change in memory and executive function performances over time (p's < 0.05). After adjusting for clinical diagnosis, baseline, and longitudinal changes in brain volume, and baseline levels of cerebrospinal fluid biomarkers, age effects on change in episodic memory and executive function were fully attenuated, age effects on baseline memory were substantially attenuated, but an association remained between age and baseline executive function. Results support previous studies that show that age effects on cognitive decline are fully mediated by disease and neurodegeneration variables but also show domain-specific age effects on baseline cognition, specifically an age pathway to executive function that is independent of brain and disease pathways.
Copyright © 2017 Elsevier Inc. All rights reserved.
Estrogen administration following menopause has been shown to support hippocampally mediated cognitive processes. A number of previous studies have examined the effect of estrogen on hippocampal structure to determine the mechanism underlying estrogen effects on hippocampal function. However, these studies have been largely observational and provided inconsistent results. We examined the effect of short-term estradiol administration on hippocampal gray-matter volume in a prospective study with multiple doses of estradiol (placebo, 1 mg, and 2 mg). Following 3 months of estradiol administration, bilateral posterior hippocampal voxel-based gray-matter volume was increased in women who received 2-mg estradiol. There were no significant differences in total hippocampal volume and no significant effects on gray-matter volume in women who received placebo or 1-mg estradiol. These findings accord with previous animal studies and provide evidence of estrogen effects on hippocampal morphology that may represent a neurobiological mechanism for estrogen effects on cognition in postmenopausal women.
Copyright © 2017 Elsevier Inc. All rights reserved.
Understanding brain volumetry is essential to understand neurodevelopment and disease. Historically, age-related changes have been studied in detail for specific age ranges (e.g., early childhood, teen, young adults, elderly, etc.) or more sparsely sampled for wider considerations of lifetime aging. Recent advancements in data sharing and robust processing have made available considerable quantities of brain images from normal, healthy volunteers. However, existing analysis approaches have had difficulty addressing (1) complex volumetric developments on the large cohort across the life time (e.g., beyond cubic age trends), (2) accounting for confound effects, and (3) maintaining an analysis framework consistent with the general linear model (GLM) approach pervasive in neuroscience. To address these challenges, we propose to use covariate-adjusted restricted cubic spline (C-RCS) regression within a multi-site cross-sectional framework. This model allows for flexible consideration of non-linear age-associated patterns while accounting for traditional covariates and interaction effects. As a demonstration of this approach on lifetime brain aging, we derive normative volumetric trajectories and 95% confidence intervals from 5111 healthy patients from 64 sites while accounting for confounding sex, intracranial volume and field strength effects. The volumetric results are shown to be consistent with traditional studies that have explored more limited age ranges using single-site analyses. This work represents the first integration of C-RCS with neuroimaging and the derivation of structural covariance networks (SCNs) from a large study of multi-site, cross-sectional data.
OBJECTIVE - To assess associations between nonalcoholic fatty liver disease (NAFLD) and measures of brain health in a population-based sample of adults.
METHODS - Participants from the CARDIA study (Y25 exam; age 43-55 years) with concurrent computed tomography quantification of liver fat, visceral adipose tissue (VAT), and brain magnetic resonance (MR) images were included (n = 505). NAFLD was identified after exclusion of other causes of liver fat. Total tissue volume (TTV) and gray matter cerebral blood flow (GM-CBF) were estimated using 3T brain MR images.
RESULTS - NAFLD prevalence was 18%. NAFLD was associated with lower TTV and GM-CBF after adjusting for intracranial volume, demographics, and health behaviors (P < 0.04 for all). In models with additional adjustment for cardiovascular risk factors, the association of NAFLD with GM-CBF remained significant (P = 0.04) but was attenuated after adjustment for VAT (P = 0.06) and eliminated with BMI (P = 0.20). NAFLD was not associated with TTV after adjustment for cardiovascular risk factors (P = 0.10) or additional adjustment for VAT (P = 0.14) or BMI (P = 0.05).
CONCLUSIONS - NAFLD is negatively associated with early brain health as assessed by MR measures of structure (TTV) and perfusion (GM-CBF). BMI and VAT attenuated this relationship, providing insight into the potential metabolic role of liver fat in brain health and disease.
© 2017 The Obesity Society.
Using a transgenic mouse model to express MafA, Pdx1, and Neurog3 (3TF) in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to β-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis, resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new β-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new β-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Plasma levels of insulin-like growth factor binding protein-2 (IGFBP-2) have been associated with Alzheimer's disease (AD) and brain atrophy. Some evidence suggests a potential synergistic effect of IGFBP-2 and AD neuropathology on neurodegeneration, while other evidence suggests the effect of IGFBP-2 on neurodegeneration is independent of AD neuropathology. Therefore, the current study investigated the interaction between plasma IGFBP-2 and cerebrospinal fluid (CSF) biomarkers of AD neuropathology on hippocampal volume and cognitive function. AD Neuroimaging Initiative data were accessed (n = 354, 75 ± 7 years, 38 % female), including plasma IGFBP-2, CSF total tau, CSF Aβ-42, MRI-quantified hippocampal volume, and neuropsychological performances. Mixed effects regression models evaluated the interaction between IGFBP-2 and AD biomarkers on hippocampal volume and neuropsychological performance, adjusting for age, sex, education, APOE ε4 status, and cognitive diagnosis. A baseline interaction between IGFBP-2 and CSF Aβ-42 was observed in relation to left (t(305) = -6.37, p = 0.002) and right hippocampal volume (t(305) = -7.74, p = 0.001). In both cases, higher IGFBP-2 levels were associated with smaller hippocampal volumes but only among amyloid negative individuals. The observed interaction suggests IGFBP-2 drives neurodegeneration through a separate pathway independent of AD neuropathology.
OBJECTIVE - To define robust resilience metrics by leveraging CSF biomarkers of Alzheimer disease (AD) pathology within a latent variable framework and to demonstrate the ability of such metrics to predict slower rates of cognitive decline and protection against diagnostic conversion.
METHODS - Participants with normal cognition (n = 297) and mild cognitive impairment (n = 432) were drawn from the Alzheimer's Disease Neuroimaging Initiative. Resilience metrics were defined at baseline by examining the residuals when regressing brain aging outcomes (hippocampal volume and cognition) on CSF biomarkers. A positive residual reflected better outcomes than expected for a given level of pathology (high resilience). Residuals were integrated into a latent variable model of resilience and validated by testing their ability to independently predict diagnostic conversion, cognitive decline, and the rate of ventricular dilation.
RESULTS - Latent variables of resilience predicted a decreased risk of conversion (hazard ratio < 0.54, p < 0.0001), slower cognitive decline (β > 0.02, p < 0.001), and slower rates of ventricular dilation (β < -4.7, p < 2 × 10). These results were significant even when analyses were restricted to clinically normal individuals. Furthermore, resilience metrics interacted with biomarker status such that biomarker-positive individuals with low resilience showed the greatest risk of subsequent decline.
CONCLUSIONS - Robust phenotypes of resilience calculated by leveraging AD biomarkers and baseline brain aging outcomes provide insight into which individuals are at greatest risk of short-term decline. Such comprehensive definitions of resilience are needed to further our understanding of the mechanisms that protect individuals from the clinical manifestation of AD dementia, especially among biomarker-positive individuals.
© 2016 American Academy of Neurology.