Robust tests for scatter separability beyond Gaussianity
Kim, Seungkyu; Park, Seongoh; Lim, Johan; Lee, Sang Han
Separability (a Kronecker product) of a scatter matrix is one of favorable structures when multivariate heavy-tailed data are collected in a matrix form, due to its parsimonious representation. However, little attempt has been made to test separability beyond Gaussianity. In this paper, we present nonparametric separability tests that can be applied to a larger class of multivariate distributions not only including elliptical distributions but also generalized elliptical distributions and transelliptical distributions. The proposed test statistic exploits robustness of Tyler's M (or Kendall's tau) estimator and a likelihood function of a scaled variable. Since its distribution is hard to specify, we approximate the p-value using a permutation procedure, whose unbiasedness is obtained from the permutation invariance of multivariate paired data. Our simulation study demonstrates the efficacy of our method against other alternatives, and we apply it to rhesus monkey data and corpus callosum data.
Correction to: Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer's Disease
Alldred, Melissa J; Penikalapati, Sai C; Lee, Sang Han; Heguy, Adriana; Roussos, Panos; Ginsberg, Stephen D
Profiling Basal Forebrain Cholinergic Neurons Reveals a Molecular Basis for Vulnerability Within the Ts65Dn Model of Down Syndrome and Alzheimer's Disease
Alldred, Melissa J; Penikalapati, Sai C; Lee, Sang Han; Heguy, Adriana; Roussos, Panos; Ginsberg, Stephen D
Basal forebrain cholinergic neuron (BFCN) degeneration is a hallmark of Down syndrome (DS) and Alzheimer's disease (AD). Current therapeutics have been unsuccessful in slowing disease progression, likely due to complex pathological interactions and dysregulated pathways that are poorly understood. The Ts65Dn trisomic mouse model recapitulates both cognitive and morphological deficits of DS and AD, including BFCN degeneration. We utilized Ts65Dn mice to understand mechanisms underlying BFCN degeneration to identify novel targets for therapeutic intervention. We performed high-throughput, single population RNA sequencing (RNA-seq) to interrogate transcriptomic changes within medial septal nucleus (MSN) BFCNs, using laser capture microdissection to individually isolate ~500 choline acetyltransferase-immunopositive neurons in Ts65Dn and normal disomic (2N) mice at 6 months of age (MO). Ts65Dn mice had unique MSN BFCN transcriptomic profiles at ~6 MO clearly differentiating them from 2N mice. Leveraging Ingenuity Pathway Analysis and KEGG analysis, we linked differentially expressed gene (DEG) changes within MSN BFCNs to several canonical pathways and aberrant physiological functions. The dysregulated transcriptomic profile of trisomic BFCNs provides key information underscoring selective vulnerability within the septohippocampal circuit. We propose both expected and novel therapeutic targets for DS and AD, including specific DEGs within cholinergic, glutamatergic, GABAergic, and neurotrophin pathways, as well as select targets for repairing oxidative phosphorylation status in neurons. We demonstrate and validate this interrogative quantitative bioinformatic analysis of a key dysregulated neuronal population linking single population transcript changes to an established pathological hallmark associated with cognitive decline for therapeutic development in human DS and AD.
Adiponectin Modulation by Genotype and Maternal Choline Supplementation in a Mouse Model of Down Syndrome and Alzheimer's Disease
Alldred, Melissa J; Lee, Sang Han; Ginsberg, Stephen D
Down syndrome (DS) is a genetic disorder caused by the triplication of human chromosome 21, which results in neurological and physiological pathologies. These deficits increase during aging and are exacerbated by cognitive decline and increase of Alzheimer's disease (AD) neuropathology. A nontoxic, noninvasive treatment, maternal choline supplementation (MCS) attenuates cognitive decline in mouse models of DS and AD. To evaluate potential underlying mechanisms, laser capture microdissection of individual neuronal populations of MCS offspring was performed, followed by RNA sequencing and bioinformatic inquiry. Results at ~6 months of age (MO) revealed DS mice (the well-established Ts65Dn model) have significant dysregulation of select genes within the Type 2 Diabetes Mellitus (T2DM) signaling pathway relative to normal disomic (2N) littermates. Accordingly, we interrogated key T2DM protein hormones by ELISA assay in addition to gene and encoded protein levels in the brain. We found dysregulation of adiponectin (APN) protein levels in the frontal cortex of ~6 MO trisomic mice, which was attenuated by MCS. APN receptors also displayed expression level changes in response to MCS. APN is a potential biomarker for AD pathology and may be relevant in DS. We posit that changes in APN signaling may be an early marker of cognitive decline and neurodegeneration.
Oxidative Phosphorylation Is Dysregulated Within the Basocortical Circuit in a 6-month old Mouse Model of Down Syndrome and Alzheimer's Disease
Alldred, Melissa J; Lee, Sang Han; Stutzmann, Grace E; Ginsberg, Stephen D
Down syndrome (DS) is the primary genetic cause of intellectual disability (ID), which is due to the triplication of human chromosome 21 (HSA21). In addition to ID, HSA21 trisomy results in a number of neurological and physiological pathologies in individuals with DS, including progressive cognitive dysfunction and learning and memory deficits which worsen with age. Further exacerbating neurological dysfunction associated with DS is the concomitant basal forebrain cholinergic neuron (BFCN) degeneration and onset of Alzheimer's disease (AD) pathology in early mid-life. Recent single population RNA sequencing (RNA-seq) analysis in the Ts65Dn mouse model of DS, specifically the medial septal cholinergic neurons of the basal forebrain (BF), revealed the mitochondrial oxidative phosphorylation pathway was significantly impacted, with a large subset of genes within this pathway being downregulated. We further queried oxidative phosphorylation pathway dysregulation in Ts65Dn mice by examining genes and encoded proteins within brain regions comprising the basocortical system at the start of BFCN degeneration (6 months of age). In select Ts65Dn mice we demonstrate significant deficits in gene and/or encoded protein levels of Complex I-V of the mitochondrial oxidative phosphorylation pathway in the BF. In the frontal cortex (Fr Ctx) these complexes had concomitant alterations in select gene expression but not of the proteins queried from Complex I-V, suggesting that defects at this time point in the BF are more severe and occur prior to cortical dysfunction within the basocortical circuit. We propose dysregulation within mitochondrial oxidative phosphorylation complexes is an early marker of cognitive decline onset and specifically linked to BFCN degeneration that may propagate pathology throughout cortical memory and executive function circuits in DS and AD.
Expression profiling of precuneus layer III cathepsin D-immunopositive pyramidal neurons in mild cognitive impairment and Alzheimer's disease: Evidence for neuronal signaling vulnerability
He, Bin; Perez, Sylvia E; Lee, Sang Han; Ginsberg, Stephen D; Malek-Ahmadi, Michael; Mufson, Elliott J
The precuneus (PreC; Brodmann area 7), a key hub within the default mode network (DMN) displays amyloid and tau-containing neurofibrillary tangle (NFT) pathology during the onset of Alzheimer's disease (AD). PreC layer III projection neurons contain lysosomal hydrolase cathepsin D (CatD), 14)a marker of neurons vulnerable to NFT pathology. Here we applied single population laser capture microdissection coupled with custom-designed microarray profiling to determine the genetic signature of PreC CatD-positive-layer III neurons accrued from postmortem tissue obtained from the Rush Religious Orders Study (RROS) cases with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and AD. Expression profiling revealed significant differential expression of key transcripts in MCI and AD compared to NCI that underlie signaling defects, including dysregulation of genes within the endosomal-lysosomal and autophagy pathways, cytoskeletal elements, AD-related genes, ionotropic and metabotropic glutamate receptors, cholinergic enzyme and receptors, markers of monoamine neurotransmission as well as steroid-related transcripts. Pervasive defects in both MCI and AD were found in select transcripts within these key gene ontology categories, underscoring the vulnerability of these corticocortical neurons during the onset and progression of dementia. Select PreC dysregulated genes detected via custom-designed microarray analysis were validated using qPCR. In summary, expression profiling of CatD positive PreC layer III neurons revealed significant dysregulation of a mosaic of genes in MCI and AD that were not previously appreciated in terms of their indication of systems-wide signaling defects in a key hub of the DMN. This article is protected by copyright. All rights reserved.
Urgent engagement in 9/11 pregnant widows and their infants: Transmission of trauma
Beebe, Beatrice; Hoven, Christina W; Kaitz, Marsha; Steele, Miriam; Musa, George; Margolis, Amy; Ewing, Julie; Sossin, K Mark; Lee, Sang Han
The potential effects of maternal trauma on mother-infant interaction remain insufficiently studied empirically. This study examined the effects of the September 11, 2001, trauma on mother-infant interaction in mothers who were pregnant and widowed on 9/11, and their infants aged 4-6Â months. Split-screen videotaped interaction was coded on a one-second basis for infant gaze, facial affect, and vocal affect; and mother gaze, facial affect, and touch. We examined the temporal dynamics of communication: self-contingency and interactive contingency of behavior by time-series methods. We documented heightened maternal and infant efforts at engagement in the 9/11 (vs. control) dyads. Both partners had difficulty tolerating moments of looking away as well as moments of negative behavior patterns. Heightened efforts to maintain a positive visual engagement may be adaptive and a potential source of resilience, but these patterns may also carry risk: working too hard to make it work. A vigilant, hyper-contingent, high-arousal engagement was the central mode of the interpersonal transmission of the trauma to these infants, with implications for intervention.
Grant Report on Social Reward Learning in Schizophrenia â€
Butler, Pamela D; Hoptman, Matthew J; Smith, David V; Ermel, Julia A; Calderone, Daniel J; Lee, Sang Han; Barch, Deanna M
We report on the ongoing R21 project "Social Reward Learning in Schizophrenia". Impairments in social cognition are a hallmark of schizophrenia. However, little work has been done on social reward learning deficits in schizophrenia. The overall goal of the project is to assess social reward learning in schizophrenia. A probabilistic reward learning (PRL) task is being used in the MRI scanner to evaluate reward learning to negative and positive social feedback. Monetary reward learning is used as a comparison to assess specificity. Behavioral outcomes and brain areas, included those involved in reward, are assessed in patients with schizophrenia or schizoaffective disorder and controls. It is also critical to determine whether decreased expected value (EV) of social stimuli and/or reward prediction error (RPE) learning underlie social reward learning deficits to inform potential treatment pathways. Our central hypothesis is that the pattern of social learning deficits is an extension of a more general reward learning impairment in schizophrenia and that social reward learning deficits critically contribute to deficits in social motivation and pleasure. We hypothesize that people with schizophrenia will show impaired behavioral social reward learning compared to controls, as well as decreased ventromedial prefrontal cortex (vmPFC) EV signaling at time of choice and decreased striatal RPE signaling at time of outcome, with potentially greater impairment to positive than negative feedback. The grant is in its second year. It is hoped that this innovative approach may lead to novel and more targeted treatment approaches for social cognitive impairments, using cognitive remediation and/or brain stimulation.
Functional linear regression model with randomly censored data: Predicting conversion time to Alzheimer's disease
Yang, Seong J.; Shin, Hyejin; Lee, Sang Han; Lee, Seokho
Profiles of infant communicative behavior
Margolis, Amy E; Lee, Sang Han; Peterson, Bradley S; Beebe, Beatrice
Prior studies of mother-infant interaction have generally used a variable-centered approach to associate face-to-face communication with psychosocial outcomes. Herein, we use a person-centered approach to identify clusters of infants who exhibit similar behavioral profiles during face-to-face communication with their mothers. Four infant communication channels were examined-gaze, facial affect, vocal affect, and head orientation-coded from videotape at a 1-s temporal resolution. We used k-means clustering to classify community infants (N = 132) into 10 groups, based on variation in the intercept and the autocorrelation function at the first time lag, representing respectively the overall level of behavior and the predictability of the infant's moment-by-moment behavioral stream, in each of the 4 communication channels. In this exploratory study, 10 clusters were identified, some with unusual levels or predictability of behavior in varying channels, and clusters associated differentially with risk outcomes (infant 4-month temperament and 12-month attachment). Distinct forms of affective dysregulation were identified: sustained negative vocal affect associated with degree of disorganization; random vocal affect associated with attachment resistance; random facial affect and vocal affect, irrespective of positive/negative valence, associated with infant difficult temperament. Clustering multiple channels of infant communication generated unique behavioral profiles and predicted 4- and 12-month outcomes, suggesting that these clusters may indeed represent natural types of infant communicative behavior, not easily observed with the naked eye, that may be useful behavioral markers of clinical risk. (PsycINFO Database Record (c) 2019 APA, all rights reserved).