Down syndrome (DS) is a leading model for studying therapeutic implications of co-occurring conditions, including Alzheimer's disease (AD), intellectual disabilities (ID), and disturbances in cardiovascular (CV), pulmonary (P), and immune (Im) systems. These conditions cause significant suffering and remain unmet medical needs. Recent advances in iPSCs (induced pluripotent stem cells) derived from individuals with DS have helped accelerate research translation to clinical care. This study presents a unique panel of iPSCs designed to explore the contributions of distinct chromosomes, genomic genes, and gender to AD, ID, and CV, P, and Im systems. The Utah iPSC collection includes 17 cell lines from individuals with DS, most of which have paired fibroblast and lymphoblastoid cell lines. These individuals underwent deep phenotyping, including multimodal neural imaging, cognition assessments, and data from seven independent Pan-Omics databases. The panel includes samples from identical twins discordant for DS, partial trisomies (three without APP duplication), and individuals with genetic variants such as apolipoprotein e2/e2. We used proteomics, phosphoproteomics, RNA sequencing, microRNA analysis, metabolomics, and lipidomics to examine gene influences, including APP, IFNAR, ITSN1, DYRK1A, TTC3, DSCAM, MMU17, and their homologs. The iPSC panel provides valuable insights into AD, DS, and related systems by distinguishing gene influences. Integration of 14 multidimensional datasets—spanning behavioral, cognitive, and neural imaging data—offers a detailed view of brain function, behavior, and organ development. This comprehensive approach allows for the dissection of AD and DS pathogenesis and the modeling of multiple human organs and cell types This work creates a comprehensive resource to understand DS at the organismal, cellular, and systems levels. The Utah iPSC collection is an invaluable tool for accelerating research translation into therapeutic strategies to improve the quality of life for individuals with DS and related conditions.

Lateralized nervous system function is phylogenetically old but fundamentally important for human brain function. Although altered in developmental and psychiatric disorders, we know little about its genetics. To understand the genetic origins of hemispheric specialization, we investigated laterality in a genetic disorder, Williams Syndrome (WS), caused by ~ 27 deleted genes on 7q11.2. Using a multidisciplinary approach combining individuals' molecular genetic, electrophysiological, and behavioral data, we identify reversed lateralization, from right to left hemisphere for perceiving direction of motion in WS and show hemispheric strengths are inversely correlated. Moreover, we correlate decreased transcript levels of the deleted gene BUD23, with strength of the reversed lateralization and with decreased performance in mental rotation, another right hemisphere lateralized function. The results implicate dosed BUD23, an 18S ribosomal RNA methyltransferase, in human brain laterality, support an evolutionary origin and provide altered lateralization as a novel mechanism for impaired cognition in genetic and behavioral disorders.

Is the oxytocin-vasopressin (OT-AVP) system a part of the unseen force that subtly (in a clever and indirect way) directs our human fascination to ourselves? And is it possible that this fundamental drive is the inevitable handmaiden of the genetic selection for survival and reproduction that is played out at the level of the individual, the family and the society? Perhaps. But an equally intense biological drive to experience the unknown is intertwined and exists in the individual as “curiosity”. Both are essential for survival and success of the species. Curiously, the path to understanding ourselves, the joy of discovery and joining with others on this imperial journey to the OT-AVP system may itself be driven by the same system. I have been driven and inspired to understand “Us” for some unseen reason. This chapter relates how a driving curiosity and search for meaning led to the critical training and inspired mentorship essential for developing novel genetic, cellular and imaging technologies necessary for each advance toward this deeper understanding. Specifically, the chapter describes my recognition of human “Genetics” as the hub of medicine and the language of human neurobiology. We then set out the rationale for and sequential development of four technologies (dense whole genome arrays of genomic markers integrated with the recombination map; needed to genetically dissect and define the genetic contributions to the distinct features of brain and social behavior in Down syndrome and Williams syndrome. These include generation of 1) dense whole genome arrays of genomic markers integrated with the recombination and gene maps for defining rare cases of WS differing by one or more deleted genes, 2) analytic methods for parsing genetic contributions to standardized outcomes of cognitive and behavioral data, 3) technologies using multicolor and multi temporal fluorescence in situ hybridization to define the subcellular and neuroanatomic localization of candidate genes in the non-human primate (macaque) brain, and 4) an approach to integrating timed measures of blood neuropeptides and genomic DNA sequence variants with self-reported religious experience in devout members of the LDS church. Working across evolution and ontogeny at the cellular, neural systems and organismal levels, has led to a suspicion that a bit of the grand design may involve OT, AVP and their partners in the subtle and artful processes of the last one-half billion years that link survival of our species with our prized capacity for abstract thought and spirituality.

Gene networks for disorders of social behavior provide the mechanisms critical for identifying therapeutic targets and biomarkers. Large behavioral phenotypic effects of small human deletions make the positive sociality of Williams syndrome (WS) ideal for determining transcriptional networks for social dysfunction currently based on DNA variations for disorders such as Autistic spectrum disorder (ASD). Consensus on WS networks has been elusive due to the need for larger cohort size, sensitive genome wide detection, and analytic tools. We report a core set of WS network perturbations in a cohort of 58 individuals (34 with typical, six atypical deletions and 18 controls). Genome-wide exon-level expression arrays robustly detected changes in differentially expressed gene (DEG) transcripts from WS deleted genes that ranked in the top 11 of 12 122 transcripts, validated by qRT-PCR, RNASeq and Western blots. WS DEG's were strictly dosed in the full but not the atypical deletions that revealed a breakpoint position effect on non-deleted CLIP2, a caveat for current phenotypic mapping based on CNV. Network analyses tested the role of the top WS DEG's in the dendritic spine, employing GeneMANIA to harmonize WS DEGs with comparable query gene-sets. The results indicate perturbed actin cytoskeletal signaling analogous to the excitatory dendritic spine. Independent Protein-Protein Interaction analyses of top WS DEGs generated a 100-node graph annotated topologically revealing three interacting pathways, MAPK, IGF1-PI3K-AKT-mTOR/insulin, and actin signaling at the synapse. The results indicate striking similarity of WS transcriptional networks to GWAS-based ASD risk suggesting common network dysfunction for these disorders of divergent sociality.

April 24, 2018April 10, 2018Free AccessComparison of Functional Connectivity Abnormalities in Autism and Williams Syndrome (P3.303)Jeffrey Anderson, Molly Prigge, Mikle South, Jace King, and Julie R. KorenbergAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement) Letters to the Editor

April 26, 2018April 10, 2018Free AccessMassive Ballooning of redundant myelin sheaths in DS (P5.336)Alfred Van Hoek, Anna Ramirez, Michael Sauer, Jacob Tippetts, Dolan Pritchett, and Julie R. KorenbergAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.P5.336 Letters to the Editor

Williams syndrome (WS) is a genetic condition characterized by a hypersocial personality and desire to form close relationships, juxtaposed with significant anxieties of nonsocial events. The neural underpinnings of anxiety in individuals with WS are currently unknown. Aberrations in the anatomical and microstructural integrity of the uncinate fasciculus (UF) have been recently implicated in social and generalized anxiety disorders. Based on these findings, we tested the hypothesis that the reported anxieties in individuals with WS share similar neuropathological correlates. Toward this end, diffusion tensor imaging (DTI) methods were employed to examine the microstructural integrity (fractional anisotropy, mean diffusivity, longitudinal diffusivity) of the UF in 18 WS and 15 typically developing adults (TD). Anxiety and sociability questionnaires were administered to determine associations with DTI indices of UF across groups. Results revealed comparable white matter integrity of the UF across groups, yet elevated subjective experience of anxiety in those with WS. Additionally, sociability and UF microstructural properties were dissociated across both groups. Whereas no relationships were found between DTI indices and anxiety in TD participants, strong negative associations were observed between these constructs in individuals with WS. Findings indicated that increased anxiety manifested by individuals with WS was associated with DTI measures of the UF and may signal structural or possibly physiological aberration involving this tract within the prefrontal-temporal network.

Orientation distribution functions (ODFs) are widely used to resolve fiber crossing problems in high angular resolution diffusion imaging (HARDI). The characteristics of the ODFs are often assessed using a visual criterion, although the use of objective criteria is also reported, which are directly borrowed from classic signal and image processing theory because they are intuitive and simple to compute. However, they are not always pertinent for the characterization of ODFs. We propose a more general paradigm for assessing the characteristics of ODFs. The idea consists in regarding an ODF as a three-dimensional (3D) point cloud, projecting the 3D point cloud onto an angle-distance map, constructing an angle-distance matrix, and calculating metrics such as length ratio, separability, and uncertainty. The results from both simulated and real data show that the proposed metrics allow for the assessment of the characteristics of ODFs in a quantitative and relatively complete manner.

High-level cognitive and emotional experience arises from brain activity, but the specific brain substrates for religious and spiritual euphoria remain unclear. We demonstrate using functional magnetic resonance imaging scans in 19 devout Mormons that a recognizable feeling central to their devotional practice was reproducibly associated with activation in nucleus accumbens, ventromedial prefrontal cortex, and frontal attentional regions. Nucleus accumbens activation preceded peak spiritual feelings by 1-3 s and was replicated in four separate tasks. Attentional activation in the anterior cingulate and frontal eye fields was greater in the right hemisphere. The association of abstract ideas and brain reward circuitry may interact with frontal attentional and emotive salience processing, suggesting a mechanism whereby doctrinal concepts may come to be intrinsically rewarding and motivate behavior in religious individuals.

A human neurodevelopmental model fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain. Individuals with the neurodevelopmental disorder Williams syndrome (WS) lack a region of about 25 genes on chromosome 7. The condition is characterized by hypersociability and a range of cognitive and behavioural impairments, but how specific genes contribute to the neuroanatomical and functional alterations is not known. Alysson Muotri and colleagues have used cellular reprogramming technologies to generate induced pluripotent stem cells (iPSCs) from individuals with WS and controls. iPSC-derived neural progenitor cells from individuals with WS had increased apoptosis owing to haploinsufficiency of the gene FZD9. In addition, iPSC-derived WS cortical neurons displayed altered activity and morphological changes, some of which matched those seen in postmortem brains of individuals with WS. This human iPSC model may provide insights into the molecular and cellular mechanisms underlying the various features of the disorder. Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1, 2, 3, 4, 5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome6,7, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells8 fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

Williams syndrome (WS) is a genetic condition characterized by an overly gregarious personality, including high empathetic concern for others. Although seemingly disparate from the profile of autism spectrum disorder (ASD), both are associated with deficits in social communication/cognition. Notably, the mirror neuron system (MNS) has been implicated in social dysfunction for ASD; yet, the integrity of this network and its association with social functioning in WS remains unknown. Magnetic resonance imaging (MRI) methods were used to examine the structural integrity of the MNS of adults with WS versus typically developing (TD) individuals. The Social Responsiveness Scale (SRS), a tool typically used to screen for social features of ASD, was also employed to assess the relationships between social functioning with the MNS morphology in WS participants. WS individuals showed reduced cortical surface area of MNS substrates yet relatively preserved cortical thickness as compared to TD adults. Increased cortical thickness of the inferior parietal lobule (IPL) was associated with increased deficits in social communication, social awareness, social cognition, and autistic mannerisms. However, social motivation was not related to anatomical features of the MNS. Our findings indicate that social deficits typical to both ASD and WS may be attributed to an aberrant MNS, whereas the unusual social drive marked in WS is subserved by substrates distinct from this network.

Diffusion tensor imaging and high angular resolution diffusion imaging are often used to analyze the fiber complexity of tissues. In these imaging techniques, the most commonly calculated metric is anisotropy, such as fractional anisotropy (FA), generalized anisotropy (GA), and generalized fractional anisotropy (GFA). The basic idea underlying these metrics is to compute the deviation from free or spherical diffusion. However, in many cases, the question is not really to know whether it concerns spherical diffusion. Instead, the main concern is to describe and quantify fiber complexity such as fiber crossing in a voxel. In this context, it would be more direct and effective to compute the deviation from a single fiber bundle instead of a sphere. We propose a new metric, called PEAM (PEAnut Metric), which is based on computing the deviation of orientation diffusion functions (ODFs) from a single fiber bundle ODF represented by a peanut. As an example, the proposed PEAM metric is used to classify intravoxel fiber configurations. The results on simulated data, physical phantom data and real brain data consistently showed that the proposed PEAM provides greater accuracy than FA, GA and GFA and enables parallel and complex fibers to be better distinguished.

Background: The ability to recognize and respond appropriately to threat is critical to survival, and the neural substrates subserving attention to threat may be probed using depictions of media violence. Whether neural responses to potential threat differ in Down syndrome is not known.Methods: We performed functional MRI scans of 15 adolescent and adult Down syndrome and 14 typically developing individuals, group matched by age and gender, during 50 min of passive cartoon viewing. Brain activation to auditory and visual features, violence, and presence of the protagonist and antagonist were compared across cartoon segments. fMRI signal from the brain's dorsal attention network was compared to thematic and violent events within the cartoons between Down syndrome and control samples.Results: We found that in typical development, the brain's dorsal attention network was most active during violent scenes in the cartoons and that this was significantly and specifically reduced in Down syndrome. When the antagonist was on screen, there was significantly less activation in the left medial temporal lobe of individuals with Down syndrome. As scenes represented greater relative threat, the disparity between attentional brain activation in Down syndrome and control individuals increased. There was a reduction in the temporal autocorrelation of the dorsal attention network, consistent with a shortened attention span in Down syndrome. Individuals with Down syndrome exhibited significantly reduced activation in primary sensory cortices, and such perceptual impairments may constrain their ability to respond to more complex social cues such as violence.Conclusions: These findings may indicate a relative deficit in emotive perception of violence in Down syndrome, possibly mediated by impaired sensory perception and hypoactivation of medial temporal structures in response to threats, with relative preservation of activity in pro-social brain regions. These findings indicate that specific genetic differences associated with Down syndrome can modulate the brain's response to violence and other complex emotive ideas.

We propose a generic method for the statistical analysis of collections of anatomical shape complexes, namely sets of surfaces that were previously segmented and labeled in a group of subjects. The method estimates an anatomical model, the template complex, that is representative of the population under study. Its shape reflects anatomical invariants within the dataset. In addition, the method automatically places control points near the most variable parts of the template complex. Vectors attached to these points are parameters of deformations of the ambient 3D space. These deformations warp the template to each subject's complex in a way that preserves the organization of the anatomical structures. Multivariate statistical analysis is applied to these deformation parameters to test for group differences. Results of the statistical analysis are then expressed in terms of deformation patterns of the template complex, and can be visualized and interpreted. The user needs only to specify the topology of the template complex and the number of control points. The method then automatically estimates the shape of the template complex, the optimal position of control points and deformation parameters. The proposed approach is completely generic with respect to any type of application and well adapted to efficient use in clinical studies, in that it does not require point correspondence across surfaces and is robust to mesh imperfections such as holes, spikes, inconsistent orientation or irregular meshing. The approach is illustrated with a neuroimaging study of Down syndrome (DS). The results demonstrate that the complex of deep brain structures shows a statistically significant shape difference between control and DS subjects. The deformation-based modelingis able to classify subjects with very high specificity and sensitivity, thus showing important generalization capability even given a low sample size. We show that the results remain significant even if the number of control points, and hence the dimension of variables in the statistical model, are drastically reduced. The analysis may even suggest that parsimonious models have an increased statistical performance. The method has been implemented in the software Deformetrica, which is publicly available at www.deformetrica.org.

In this study of eight rare atypical deletion cases with Williams-Beuren syndrome (WS; also known as 7q11.23 deletion syndrome) consisting of three different patterns of deletions, compared to typical WS and typically developing (TD) individuals, we show preliminary evidence of dissociable genetic contributions to brain structure and human cognition. Univariate and multivariate pattern classification results of morphometric brain patterns complemented by behavior implicate a possible role for the chromosomal region that includes: 1) GTF2I/GTF2IRD1 in visuo-spatial/motor integration, intraparietal as well as overall gray matter structures, 2) the region spanning ABHD11 through RFC2 including LIMK1, in social cognition, in particular approachability, as well as orbitofrontal, amygdala and fusiform anatomy, and 3) the regions including STX1A, and/or CYLN2 in overall white matter structure. This knowledge contributes to our understanding of the role of genetics on human brain structure, cognition and pathophysiology of altered cognition in WS. The current study builds on ongoing research designed to characterize the impact of multiple genes, gene-gene interactions and changes in gene expression on the human brain.