Faculty Bibliography

Context:Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective:The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design:Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants:In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures:Blood concentrations of 25(OH)D were measured for all participants. Results:Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions:Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.

OBJECTIVE:Three recent prospective longitudinal studies of population cohorts reported nontrivial rates of "adult-onset" ADHD. Given that this result is at odds with the neurodevelopmental conceptualization of ADHD, as well as with general clinical experience, we obtained report of onset of symptoms in a clinical sample of adults diagnosed with ADHD. METHOD/METHODS:One hundred four adults diagnosed with ADHD completed retrospective ratings of DSM-IV/DSM-5 ADHD symptoms between the ages of 5 and 12 years. RESULTS:Fifty percent of the sample met full retrospective child diagnostic symptom criteria of six ADHD symptoms in either the inattentive or hyperactive-impulsive domains. Seventy-five percent met a less stringent criterion of four symptoms in either domain. DISCUSSION/CONCLUSIONS:These results are interpreted in light of a dimensional model of ADHD that posits emergence of ADHD symptoms and corresponding impairment as a function of increasing performance demands and/or decreasing environmental supports during the course of development.

OBJECTIVE:Neuroimaging studies show structural differences in both cortical and subcortical brain regions in children and adults with autism spectrum disorder (ASD) compared with healthy subjects. Findings are inconsistent, however, and it is unclear how differences develop across the lifespan. The authors investigated brain morphometry differences between individuals with ASD and healthy subjects, cross-sectionally across the lifespan, in a large multinational sample from the Enhancing Neuroimaging Genetics Through Meta-Analysis (ENIGMA) ASD working group. METHOD/METHODS:The sample comprised 1,571 patients with ASD and 1,651 healthy control subjects (age range, 2-64 years) from 49 participating sites. MRI scans were preprocessed at individual sites with a harmonized protocol based on a validated automated-segmentation software program. Mega-analyses were used to test for case-control differences in subcortical volumes, cortical thickness, and surface area. Development of brain morphometry over the lifespan was modeled using a fractional polynomial approach. RESULTS:The case-control mega-analysis demonstrated that ASD was associated with smaller subcortical volumes of the pallidum, putamen, amygdala, and nucleus accumbens (effect sizes [Cohen's d], 0.13 to -0.13), as well as increased cortical thickness in the frontal cortex and decreased thickness in the temporal cortex (effect sizes, -0.21 to 0.20). Analyses of age effects indicate that the development of cortical thickness is altered in ASD, with the largest differences occurring around adolescence. No age-by-ASD interactions were observed in the subcortical partitions. CONCLUSIONS:The ENIGMA ASD working group provides the largest study of brain morphometry differences in ASD to date, using a well-established, validated, publicly available analysis pipeline. ASD patients showed altered morphometry in the cognitive and affective parts of the striatum, frontal cortex, and temporal cortex. Complex developmental trajectories were observed for the different regions, with a developmental peak around adolescence. These findings suggest an interplay in the abnormal development of the striatal, frontal, and temporal regions in ASD across the lifespan.

BACKGROUND:Teratogenicity of heavy prenatal alcohol exposure is established, but uncertainty remains regarding the impact of moderate alcohol exposure on cognitive deficits in infants. Separating in utero effects from environmental confounding is a challenge for observational studies; consideration of alcohol use by partners as well as mothers may help clarify this. This study examined associations between prenatal alcohol use by both mothers and their partners and infant cognitive developmental outcomes at 12-months. METHODS:Pregnant women (n = 1331) and their partners (n = 699) were recruited from antenatal clinics of three metropolitan public hospitals in Australia, and completed detailed interviews about alcohol consumptions throughout pregnancy. Infants were assessed with the Bayley Scales of Infant Development - Third edition (Bayley) at 12-months of age. RESULTS:Alcohol use during pregnancy was reported by 65.7% of mothers and 84.1% of partners. Using multiple methods to adjust for confounding factors, no evidence for impaired cognitive ability associated with alcohol use by mothers or their partners was observed. Children born to women who drank low-levels of alcohol had slightly higher Bayley cognitive scores than those born to abstaining women. There was some evidence for an interaction between sociodemographic factors and prenatal alcohol exposure on infant cognitive outcomes. CONCLUSION:This finding corroborates existing evidence to suggest there are no detrimental effects to infant cognitive development at 12-months of age following low-level prenatal alcohol exposure. Future prospective studies involving families of a broad range of backgrounds would be informative to clarify interaction between alcohol exposure and environmental factors on developmental outcomes.

Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a viable therapeutic, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons (BFCNs) in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aβ) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.

Massive galaxy clusters have been found that date to times as early as three billion years after the Big Bang, containing stars that formed at even earlier epochs^1-3. The high-redshift progenitors of these galaxy clusters-termed 'protoclusters'-can be identified in cosmological simulations that have the highest overdensities (greater-than-average densities) of dark matter^4-6. Protoclusters are expected to contain extremely massive galaxies that can be observed as luminous starbursts ⁷ . However, recent detections of possible protoclusters hosting such starbursts^8-11 do not support the kind of rapid cluster-core formation expected from simulations ¹² : the structures observed contain only a handful of starbursting galaxies spread throughout a broad region, with poor evidence for eventual collapse into a protocluster. Here we report observations of carbon monoxide and ionized carbon emission from the source SPT2349-56. We find that this source consists of at least 14 gas-rich galaxies, all lying at redshifts of 4.31. We demonstrate that each of these galaxies is forming stars between 50 and 1,000 times more quickly than our own Milky Way, and that all are located within a projected region that is only around 130 kiloparsecs in diameter. This galaxy surface density is more than ten times the average blank-field value (integrated over all redshifts), and more than 1,000 times the average field volume density. The velocity dispersion (approximately 410 kilometres per second) of these galaxies and the enormous gas and star-formation densities suggest that this system represents the core of a cluster of galaxies that was already at an advanced stage of formation when the Universe was only 1.4 billion years old. A comparison with other known protoclusters at high redshifts shows that SPT2349-56 could be building one of the most massive structures in the Universe today.

Executive function deficits are common in children and adolescents with epilepsy. Though the Wisconsin Card Sorting Task (WCST) is often considered the "gold standard" for executive function assessment, its sensitivity-particularly in the case of the 64-card version (WCST-64)-is insufficiently established in pediatric samples, including children and adolescents with epilepsy. The present investigation assesses the sensitivity of the WCST-64 in children and adolescents with epilepsy in comparison to another measure: the Tower of London - Drexel Version (TOL-DX). A total of 88 consecutively referred children and adolescents with epilepsy were administered both the WCST-64 and TOL-DX as part of a comprehensive neuropsychological evaluation. The sensitivity of WCST-64 and TOL-DX variables were established and relations with epilepsy severity measures and other executive function measures were assessed. Of the WCST-64 variables, Perseverative Responses is the most sensitive, but detected executive function impairment in only 19% of this clinically referred sample; in contrast, the TOL-DX Rule Violations detected executive function impairment in half of the sample. Further, TOL-DX performances are more strongly related to epilepsy severity variables and other executive function measures in comparison to the WCST-64. Despite its popularity amongst clinicians, the WCST-64 is not as sensitive to executive dysfunction in comparison to other measures of comparable administration time, such as the TOL-DX.

Statistical shape analysis captures the geometric properties of a given set of shapes, obtained from medical images, by means of statistical methods. Orthognathic surgery is a type of craniofacial surgery that is aimed at correcting severe skeletal deformities in the mandible and maxilla. Methods assuming spherical topology cannot represent the class of anatomical structures exhibiting complex geometries and topologies, including the mandible. In this paper we propose methodology based on non-rigid deformations of 3D geometries to be applied to objects with thin, complex structures. We are able to accurately and quantitatively characterize bone healing at the osteotomy site as well as condylar remodeling for three orthognathic surgery cases, demonstrating the effectiveness of the proposed methodology.