WashU weekly Neuroscience publications

Altered functional network connectivity relates to motor development in children born very preterm
(2018) NeuroImage, 183, pp. 574-583. 

Wheelock, M.D.^a , Austin, N.C.^b , Bora, S.^c , Eggebrecht, A.T.^d , Melzer, T.R.^e , Woodward, L.J.^f , Smyser, C.D.^{d g h}

^a Department of Psychiatry, Washington University in St. Louis, St. Louis, United States
^b Department of Pediatrics, University of Otago Christchurch, New Zealand
^c Mothers, Babies and Women’s Health Program, Mater Research Institute, The University of Queensland, South Brisbane, Australia
^d Department of Radiology, Washington University in St. Louis, St. Louis, United States
^e Department of Medicine, University of Otago, New Zealand Brain Research Institute, Christchurch, New Zealand
^f Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, United States
^g Department of Neurology, Washington University in St. Louis, St. Louis, United States
^h Department of Pediatrics, Washington University in St. Louis, St. Louis, United States

Abstract
Individuals born very preterm (<32 weeks gestation) are at increased risk for neuromotor impairments. The ability to characterize the structural and functional mechanisms underlying these impairments remains limited using existing neuroimaging techniques. Resting state-functional magnetic resonance imaging (rs-fMRI) holds promise for defining the functional network architecture of the developing brain in relation to typical and aberrant neurodevelopment. In 58 very preterm and 65 term-born children studied from birth to age 12 years, we examined relations between functional connectivity measures from low-motion rs-fMRI data and motor skills assessed using the Movement Assessment Battery for Children, 2nd edition. Across all subscales, motor performance was better in term than very preterm children. Examination of relations between functional connectivity and motor measures using enrichment analysis revealed between-group differences within cerebellar, frontoparietal, and default mode networks, and between basal ganglia-motor, thalamus-motor, basal ganglia-auditory, and dorsal attention-default mode networks. Specifically, very preterm children exhibited weaker associations between motor scores and thalamus-motor and basal ganglia-motor network connectivity. These findings highlight key functional brain systems underlying motor development. They also demonstrate persisting developmental effects of preterm birth on functional connectivity and motor performance in childhood, providing evidence for an alternative network architecture supporting motor function in preterm children. © 2018 Elsevier Inc.

Author Keywords
Functional connectivity;  Motor development;  Neurodevelopmental outcome;  Prematurity;  Resting state functional MRI

Document Type: Article
Source: Scopus

Hydrophobic gating in BK channels
(2018) Nature Communications, 9 (1), art. no. 3408, . 

Jia, Z.^a , Yazdani, M.^a , Zhang, G.^b , Cui, J.^b , Chen, J.^{a c}

^a Department of Chemistry, University of Massachusetts, Amherst, MA 01003, United States
^b Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St Louis, MO 63130, United States
^c Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, United States

Abstract
The gating mechanism of transmembrane ion channels is crucial for understanding how these proteins control ion flow across membranes in various physiological processes. Big potassium (BK) channels are particularly interesting with large single-channel conductance and dual regulation by membrane voltage and intracellular Ca2+. Recent atomistic structures of BK channels failed to identify structural features that could physically block the ion flow in the closed state. Here, we show that gating of BK channels does not seem to require a physical gate. Instead, changes in the pore shape and surface hydrophobicity in the Ca2+-free state allow the channel to readily undergo hydrophobic dewetting transitions, giving rise to a large free energy barrier for K+ permeation. Importantly, the dry pore remains physically open and is readily accessible to quaternary ammonium channel blockers. The hydrophobic gating mechanism is also consistent with scanning mutagenesis studies showing that modulation of pore hydrophobicity is correlated with activation properties. © 2018, The Author(s).

Document Type: Article
Source: Scopus
Access Type: Open Access

Additive neuroprotective effects of 24(S)-hydroxycholesterol and allopregnanolone in an ex vivo rat glaucoma model
(2018) Scientific Reports, 8 (1), art. no. 12851, . 

Ishikawa, M.^a , Yoshitomi, T.^a , Covey, D.F.^{b c} , Zorumski, C.F.^{c d e} , Izumi, Y.^{c d e}

^a Department of Ophthalmology, Akita University Graduate School of Medicine, Akita, Japan
^b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^c The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
^d Center for Brain Research in Mood Disorders, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
In a rat ex vivo acute glaucoma model, high pressure (75 mmHg) causes swelling of ganglion cell axons and elevates levels of the endogenous steroids 24(S)-hydroxycholesterol (24SH) and allopregnanolone (AlloP). Furthermore, 24SH (0.1 µM) alone elevates AlloP levels via NMDA receptors. With this model, we now investigate possible interactions between 24SH and AlloP. We found that inhibition of AlloP synthesis with dutasteride under high pressure results in severe excitotoxicity in addition to axonal swelling. The excitotoxicity is prevented by exogenous AlloP but not 24SH, indicating that endogenous AlloP is crucial for protection. However, inhibition of 24SH synthesis with voriconazole induces severe excitotoxicity under normal pressure. Paradoxically, the excitotoxicity by voriconazole is better prevented by AlloP than 24SH. These findings suggest that inhibition of 24SH synthesis becomes excitotoxic in the absence of AlloP. We also observed that co-administration of sub-micromolar 24SH (0.1 µM) and AlloP (0.1 µM), concentrations that are only partially effective when administered alone, prevents axonal swelling under high pressure. This apparent enhanced protection indicates strong interaction between the two neurosteroids to preserve neuronal integrity, with 24SH contributing to AlloP synthesis via NMDA receptors and with AlloP playing an essential role in neuroprotection via GABAA receptors. © 2018, The Author(s).

Document Type: Article
Source: Scopus
Access Type: Open Access

The Lifespan Human Connectome Project in Development: A large-scale study of brain connectivity development in 5–21 year olds
(2018) NeuroImage, 183, pp. 456-468. 

Somerville, L.H.^{a b} , Bookheimer, S.Y.^c , Buckner, R.L.^{a b d e} , Burgess, G.C.^f , Curtiss, S.W.^g , Dapretto, M.^c , Elam, J.S.^g , Gaffrey, M.S.^f , Harms, M.P.^f , Hodge, C.^f , Kandala, S.^f , Kastman, E.K.^{a b} , Nichols, T.E.^{h i j} , Schlaggar, B.L.^{f g k l m} , Smith, S.M.^j , Thomas, K.M.ⁿ , Yacoub, E.^o , Van Essen, D.C.^g , Barch, D.M.^{f m p}

^a Department of Psychology, Harvard University, Cambridge, MA, United States
^b Center for Brain Science, Harvard University, Cambridge, MA, United States
^c Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA, United States
^d Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^e Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^f Department of Psychiatry, Washington University Medical School, St. Louis, MO, United States
^g Department of Neuroscience, Washington University Medical School, St. Louis, MO, United States
^h Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
ⁱ Department of Statistics, University of Warwick, Coventry, United Kingdom
^j Wellcome Centre for Integrative Neuroimaging, Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
^k Department of Neurology, Washington University Medical School, St. Louis, MO, United States
^l Department of Pediatrics, Washington University Medical School, St. Louis, MO, United States
^m Department of Radiology, Washington University Medical School, St. Louis, MO, United States
ⁿ Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
^o Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States
^p Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Recent technological and analytical progress in brain imaging has enabled the examination of brain organization and connectivity at unprecedented levels of detail. The Human Connectome Project in Development (HCP-D) is exploiting these tools to chart developmental changes in brain connectivity. When complete, the HCP-D will comprise approximately ∼1750 open access datasets from 1300 + healthy human participants, ages 5–21 years, acquired at four sites across the USA. The participants are from diverse geographical, ethnic, and socioeconomic backgrounds. While most participants are tested once, others take part in a three-wave longitudinal component focused on the pubertal period (ages 9–17 years). Brain imaging sessions are acquired on a 3 T Siemens Prisma platform and include structural, functional (resting state and task-based), diffusion, and perfusion imaging, physiological monitoring, and a battery of cognitive tasks and self-reports. For minors, parents additionally complete a battery of instruments to characterize cognitive and emotional development, and environmental variables relevant to development. Participants provide biological samples of blood, saliva, and hair, enabling assays of pubertal hormones, health markers, and banked DNA samples. This paper outlines the overarching aims of the project, the approach taken to acquire maximally informative data while minimizing participant burden, preliminary analyses, and discussion of the intended uses and limitations of the dataset. © 2018 Elsevier Inc.

Author Keywords
Adolescent;  Brain;  Child;  Connectivity;  Connectome;  Development;  MRI;  Network;  Neurodevelopment

Document Type: Article
Source: Scopus

Myelin Oligodendrocyte Glycoprotein Antibody–Positive Optic Neuritis: Clinical Characteristics, Radiologic Clues, and Outcome
(2018) American Journal of Ophthalmology, 195, pp. 8-15. 

Chen, J.J.^{a b} , Flanagan, E.P.^{b c e} , Jitprapaikulsan, J.^{b c} , López-Chiriboga, A.S.S.^b , Fryer, J.P.^c , Leavitt, J.A.^a , Weinshenker, B.G.^{b e} , McKeon, A.^{b c e} , Tillema, J.-M.^b , Lennon, V.A.^{b c d e} , Tobin, W.O.^{b e} , Keegan, B.M.^{b e} , Lucchinetti, C.F.^{b e} , Kantarci, O.H.^{b e} , McClelland, C.M.^f , Lee, M.S.^f , Bennett, J.L.^g , Pelak, V.S.^g , Chen, Y.^h , VanStavern, G.ⁱ , Adesina, O.-O.O.^j , Eggenberger, E.R.^k , Acierno, M.D.^l , Wingerchuk, D.M.^m , Brazis, P.W.^k , Sagen, J.^e , Pittock, S.J.^{b c e}

^a Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
^b Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States
^c Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States
^d Department of Immunology, Mayo Clinic, Rochester, Minnesota, United States
^e Center for MS and Autoimmune Neurology, Mayo Clinic, Rochester, Minnesota, United States
^f Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States
^g Departments of Neurology and Ophthalmology, University of Colorado Denver School of Medicine, Aurora, Colorado, United States
^h Department of Ophthalmology, Neurology and Neurosurgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States
ⁱ Departments of Ophthalmology and Visual Sciences and Neurology, Washington University, St. Louis School of Medicine, St. Louis, Missouri, United States
^j Departments of Ophthalmology and Visual Science and Neurology, McGovern Medical School, Houston, Texas, United States
^k Departments of Neurology and Neuro-Ophthalmology Mayo Clinic, Jacksonville, Florida, United States
^l Department of Ophthalmology, Mayo Clinic, Scottsdale, Arizona, United States
^m Department of Neurology, Mayo Clinic, Scottsdale, Arizona, United States

Abstract
Purpose: To characterize the clinical phenotype of myelin oligodendrocyte glycoprotein antibody (MOG-IgG) optic neuritis. Design: Observational case series. Methods: SETTING: Multicenter. PATIENT/STUDY POPULATION: Subjects meeting inclusion criteria: (1) history of optic neuritis; (2) seropositivity (MOG-IgG binding index > 2.5); 87 MOG-IgG-seropositive patients with optic neuritis were included (Mayo Clinic, 76; other medical centers, 11). MOG-IgG was detected using full-length MOG-transfected live HEK293 cells in a clinically validated flow cytometry assay. MAIN OUTCOME MEASURES: Clinical and radiologic characteristics and visual outcomes. Results: Fifty-seven percent were female and median age at onset was 31 (range 2–79) years. Median number of optic neuritis attacks was 3 (range 1–8), median follow-up 2.9 years (range 0.5–24 years), and annualized relapse rate 0.8. Average visual acuity (VA) at nadir of worst attack was count fingers. Average final VA was 20/30; for 5 patients (6%) it was ≤20/200 in either eye. Optic disc edema and pain each occurred in 86% of patients. Magnetic resonance imaging showed perineural enhancement in 50% and longitudinally extensive involvement in 80%. Twenty-six patients (30%) had recurrent optic neuritis without other neurologic symptoms, 10 (12%) had single optic neuritis, 14 (16%) had chronic relapsing inflammatory optic neuropathy, and 36 (41%) had optic neuritis with other neurologic symptoms (most neuromyelitis optica spectrum disorder–like phenotype or acute disseminated encephalomyelitis). Only 1 patient was diagnosed with MS (MOG-IgG-binding index 2.8; normal range ≤ 2.5). Persistent MOG-IgG seropositivity occurred in 61 of 62 (98%). A total of 61% received long-term immunosuppressant therapy. Conclusions: Manifestations of MOG-IgG-positive optic neuritis are diverse. Despite recurrent attacks with severe vision loss, the majority of patients have significant recovery and retain functional vision long-term. © 2018 Elsevier Inc.

Document Type: Article
Source: Scopus

The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex
(2018) Epilepsia, 59 (9), pp. 1796-1806.

Zhang, B., Zou, J., Han, L., Beeler, B., Friedman, J.L., Griffin, E., Piao, Y.-S., Rensing, N.R., Wong, M. 

Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Microglial abnormalities have been reported in pathologic specimens from patients with tuberous sclerosis complex (TSC), a genetic disorder characterized by epilepsy, intellectual disability, and autism. However, the pathogenic role of microglia in epilepsy in TSC is poorly understood, particularly whether microglia defects may be a primary contributor to epileptogenesis or are secondary to seizures or simply epiphenomena. In this study, we tested the hypothesis that Tsc1 gene inactivation in microglia is sufficient to cause epilepsy in mouse models of TSC. Methods: Using a chemokine receptor, Cx3cr1, to target microglia, conventional Tsc1Cx3cr1-CreCKO (conditional knockout) mice and postnatal-inducible Tsc1Cx3cr1-Cre ERCKO mice were generated and assessed for molecular and histopathologic evidence of microglial abnormalities, mechanistic target of rapamycin 1 (mTORC1) pathway activation, and epilepsy. Results: Tsc1Cx3cr1-CreCKO mice exhibited a high efficiency of microglia Tsc1 inactivation, mTORC1 activation, increased microglial size and number, and robust epilepsy, which were rapamycin-dependent. However, Cre reporter studies demonstrated that constitutive Cx3cr1 expression affected not only microglia, but also a large percentage of cortical neurons, confounding the role of microglia in epileptogenesis in Tsc1 Cx3cr1-CreCKO mice. In contrast, postnatal inactivation of Tsc1 utilizing a tamoxifen-inducible Cx3cr1-CreER resulted in a more-selective microglia Tsc1 inactivation with high efficiency, mTORC1 activation, and increased microglial size and number, but no documented epilepsy. Significance: Microglia abnormalities may contribute to epileptogenesis in the context of neuronal involvement in TSC mouse models, but selective Tsc1 gene inactivation in microglia alone may not be sufficient to cause epilepsy, suggesting that microglia have more supportive roles in the pathogenesis of seizures in TSC. Wiley Periodicals, Inc. © 2018 International League Against Epilepsy

Author Keywords
epilepsy;  microglia;  seizure;  tuberous sclerosis, rapamycin

Document Type: Article
Source: Scopus

In Reply I—Root Causes of the Opioid Crisis
(2018) Mayo Clinic Proceedings, 93 (9), pp. 1329-1330. 

Srivastava, A.B., Gold, M.S.

Washington University in St Louis School of Medicine, St Louis, MO, United States

Document Type: Letter
Source: Scopus

Application of machine learning to automated analysis of cerebral edema in large cohorts of ischemic stroke patients
(2018) Frontiers in Neurology, 9 (AUG), art. no. 687, . 

Dhar, R.^a , Chen, Y.^b , An, H.^c , Lee, J.-M.^b

^a Division of Neurocritical Care, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Division of Cerebrovascular Diseases, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Cerebral edema contributes to neurological deterioration and death after hemispheric stroke but there remains no effective means of preventing or accurately predicting its occurrence. Big data approaches may provide insights into the biologic variability and genetic contributions to severity and time course of cerebral edema. These methods require quantitative analyses of edema severity across large cohorts of stroke patients. We have proposed that changes in cerebrospinal fluid (CSF) volume over time may represent a sensitive and dynamic marker of edema progression that can be measured from routinely available CT scans. To facilitate and scale up such approaches we have created a machine learning algorithm capable of segmenting and measuring CSF volume from serial CT scans of stroke patients. We now present results of our preliminary processing pipeline that was able to efficiently extract CSF volumetrics from an initial cohort of 155 subjects enrolled in a prospective longitudinal stroke study. We demonstrate a high degree of reproducibility in total cranial volume registration between scans (R = 0.982) as well as a strong correlation of baseline CSF volume and patient age (as a surrogate of brain atrophy, R = 0.725). Reduction in CSF volume from baseline to final CT was correlated with infarct volume (R = 0.715) and degree of midline shift (quadratic model, p &lt; 2.2 × 10-16). We utilized generalized estimating equations (GEE) to model CSF volumes over time (using linear and quadratic terms), adjusting for age. This model demonstrated that CSF volume decreases over time (p &lt; 2.2 × 10-13) and is lower in those with cerebral edema (p = 0.0004). We are now fully automating this pipeline to allow rapid analysis of even larger cohorts of stroke patients from multiple sites using an XNAT (eXtensible Neuroimaging Archive Toolkit) platform. Data on kinetics of edema across thousands of patients will facilitate precision approaches to prediction of malignant edema as well as modeling of variability and further understanding of genetic variants that influence edema severity. © 2018 Dhar, Chen, An and Lee.

Author Keywords
Cerebral edema;  CSF volume;  CT scan;  GEE;  Image analysis and processing;  Ischemic stroke;  Machine learning

Document Type: Article
Source: Scopus
Access Type: Open Access

Brain nutrition: A life span approach
(2018) Annual Review of Nutrition, 38, pp. 381-399. 

Goyal, M.S.^a , Iannotti, L.L.^b , Raichle, M.E.^a

^a Mallinckrodt Institute of Radiology and Department of Neurology, Washington University School of Medicine, Washington University, St. Louis, MO 63130, United States
^b Brown School, Institute for Public Health, Washington University, St. Louis, MO 63130, United States

Abstract
Appraising success in meeting the world’s nutritional needs has largely focused on infant mortality and anthropometric measurements with an emphasis on the first 1,000 days (conception to approximately age 2 years). This ignores the unique nutritional needs of the human brain. Although the intrauterine environment and the early postnatal years are important, equally critical periods follow during which the brain’s intricate wiring is established for a lifetime of experience-driven remodeling. At the peak of this process during childhood, the human brain may account for 50% of the body’s basal nutritional requirement. Thus, the consequences of proper nutritional management of the brain play out over a lifetime. Our motivation in preparing this review was to move the human brain into a more central position in the planning of nutritional programs. Here we review the macro- and micronutrient requirements of the human brain and how they are delivered, from conception to adulthood. Copyright © 2018 by Annual Reviews. All rights reserved.

Author Keywords
brain metabolism;  evolution;  life span;  neurodevelopment;  nutrients;  plasticity

Document Type: Review
Source: Scopus

The acyl-CoA synthetase, pudgy, promotes sleep and is required for the homeostatic response to sleep deprivation
(2018) Frontiers in Endocrinology, 9 (AUG), art. no. 464, . 

Thimgan, M.S.^a , Kress, N.^b , Lisse, J.^a , Fiebelman, C.^a , Hilderbrand, T.^a

^a Department of Biological Sciences, Missouri University of Science and Technology, Rolla, MO, United States
^b Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
The regulation of sleep and the response to sleep deprivation rely on multiple biochemical pathways. A critical connection is the link between sleep and metabolism. Metabolic changes can disrupt sleep, and conversely decreased sleep can alter the metabolic environment. There is building evidence that lipid metabolism, in particular, is a critical part of mounting the homeostatic response to sleep deprivation. We have evaluated an acyl-CoA synthetase, pudgy (pdgy), for its role in sleep and response to sleep deprivation. When pdgy transcript levels are decreased through transposable element disruption of the gene, mutant flies showed lower total sleep times and increased sleep fragmentation at night compared to genetic controls. Consistent with disrupted sleep, mutant flies had a decreased lifespan compared to controls. pdgy disrupted fatty acid handling as pdgy mutants showed increased sensitivity to starvation and exhibited lower fat stores. Moreover, the response to sleep deprivation is reduced when compared to a control flies. When we decreased the transcript levels for pdgy using RNAi, the response to sleep deprivation was decreased compared to background controls. In addition, when the pdgy transcription is rescued throughout the fly, the response to sleep deprivation is restored. These data demonstrate that the regulation and function of acyl-CoA synthetase plays a critical role in regulating sleep and the response to sleep deprivation. Endocrine and metabolic signals that alter transcript levels of pdgy impact sleep regulation or interfere with the homeostatic response to sleep deprivation. © 2018 Thimgan, Kress, Lisse, Fiebelman and Hilderbrand.

Author Keywords
Acyl-CoA synthetase;  Drosophila;  Lifespan;  Lipid metabolism;  Sleep deprivation;  Sleep fragmentation;  Sleep regulation

Document Type: Article
Source: Scopus
Access Type: Open Access

Erratum: Psychometric function estimation by probabilistic classification (Journal of the Acoustical Society of America (2017) 141:4 (2513-2525) DOI: 10.1121/1.4979594)
(2018) Journal of the Acoustical Society of America, 144 (2), p. 841. 

Barbour, D.L.

Laboratory of Sensory Neuroscience and Neuroengineering, Department of Biomedical Engineering, Washington University in St. Louis, Campus Box 1097, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
In the original version of this manuscript the authors neglected to mention a conflict of interest. D.L.B. has a patent pending on technology described in the manuscript. © 2018 Acoustical Society of America..

Document Type: Erratum
Source: Scopus

Life stress as a risk factor for sustained anxiety and cortisol dysregulation during the first year of survivorship in ovarian cancer
(2018) Cancer, 124 (16), pp. 3401-3408. 

Armer, J.S.^a , Clevenger, L.^b , Davis, L.Z.^c , Cuneo, M.^a , Thaker, P.H.^d , Goodheart, M.J.^{e f} , Bender, D.P.^e , Dahmoush, L.^g , Sood, A.K.^h , Cole, S.W.ⁱ , Slavich, G.M.^j , Lutgendorf, S.K.^{a e f k}

^a Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, United States
^b Department of Psychiatry, University of Iowa, Iowa City, IA, United States
^c Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI, United States
^d Gynecologic Oncology, Obstetrics and Gynecology, Washington University School of Medicine, St Louis, MO, United States
^e Gynecologic Oncology, Obstetrics and Gynecology, University of Iowa, Iowa City, IA, United States
^f Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States
^g Department of Pathology, University of Iowa, Iowa City, IA, United States
^h Gyneclogic Oncology, Cancer Biology, and Center for RNA Interference and Noncoding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
ⁱ Hematology/Oncology, David Geffen School of Medicine, and the Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, CA, United States
^j Cousins Center for Psychoneuroimmunology and Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, United States
^k Department of Urology, University of Iowa, Iowa City, IA, United States

Abstract
BACKGROUND: Patients with ovarian cancer often report elevated anxiety at diagnosis that decreases posttreatment. However, a minority of patients experience sustained anxiety. Few studies have examined risk factors for persistent anxiety or its physiologic sequelae in ovarian cancer. Therefore, the authors investigated associations between prior life events, anxiety, inflammation (plasma levels of interleukin-6), and diurnal cortisol profiles in patients with ovarian cancer during the first year postdiagnosis. METHODS: Participants (n = 337) completed surveys and had blood and salivary sampling prediagnosis, postchemotherapy (6 months), and 12 months after diagnosis. The Life Events and Difficulties Schedule was administered to a patient subset (n = 127) within 1 month of diagnosis. Linear mixed-effects models were used to analyze relations between anxiety and biologic variables over time. Linear regression models assessed whether anxiety trajectories mediated associations between prior stress exposure and biologic variables. Age, chemotherapy at 1 year, and cancer stage were covariates. RESULTS: Decreased anxiety was associated with a more normalized cortisol slope over time (β = 0.092; P =.047). Early life adversity was related to flatter cortisol slopes over time (β = −0.763; P =.002); this relation was partially mediated by anxiety trajectory (P =.046). More danger-related events prediagnosis were associated with sustained anxiety (β = 0.537; P =.019) and flatter cortisol slopes over time (β = −0.243; P =.047); anxiety partially mediated the relation between danger and cortisol slope (P =.037). Neither anxiety nor prior stress exposure was related to levels of interleukin-6. CONCLUSIONS: Because dysregulated cortisol has been related to fatigue, poorer quality of life, and shorter survival in patients with ovarian cancer, those who have prior life events and chronic anxiety during the first year postdiagnosis may be at risk for more negative outcomes. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society

Author Keywords
anxiety;  cortisol;  early life stress;  interleukin-6;  ovarian cancer

Document Type: Article
Source: Scopus

Statistical learning and spelling
(2018) Language, Speech, and Hearing Services in Schools, 49 (3S), pp. 644-652. Cited 4 times.

Treiman, R.

Department of Psychological & Brain Sciences, Washington University in St. Louis, United States

Abstract
Purpose: The purpose of this article is to provide a tutorial on statistical learning and its role in learning to spell and to discuss the implications of the research for educators. Method: The tutorial begins with a discussion of statistical learning and its characteristics. It then discusses research on how statistical learning plays out in learning to spell, how spelling should be taught, and similarities and differences among learners. The focus is on the learning of English, although studies of other alphabetic writing systems are also considered. Research shows that, from an early age, children use their statistical learning skills to learn about the visual characteristics of written words. Children also use their statistical learning skills to help learn about the relations between visual units and units of language, supplementing what they are explicitly taught in school. Conclusion: Statistical learning plays an important role in learning to spell, and this can help to explain why some aspects of spelling are more difficult to learn than others. If children are to learn to spell effectively and efficiently, structured instruction is also important. © 2018 American Speech-Language-Hearing Association.

Document Type: Article
Source: Scopus

Stronger prediction of motor recovery and outcome post-stroke by cortico-spinal tract integrity than functional connectivity
(2018) PLoS ONE, 13 (8), art. no. e0202504, . 

Lin, L.Y.^a , Ramsey, L.^b , Metcalf, N.V.^c , Rengachary, J.^c , Shulman, G.L.^c , Shimony, J.S.^d , Corbetta, M.^{c d e f}

^a Department of Radiology, University of Kentucky, Lexington, KY, United States
^b Physical Therapy Department, Carroll University, Waukesha, WI, United States
^c Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^d Mallinckrodt Inst. of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
^e Department of Bioengineering, Washington University School of Medicine, Saint Louis, MO, United States
^f Department of Neurology, University of Padua, Padua, Italy

Abstract
Objectives To examine longitudinal changes in structural and functional connectivity post-stroke in patients with motor impairment, and define their importance for recovery and outcome at 12 months. Methods First-time stroke patients (N = 31) were studied at 1–2 weeks, 3 months, and 12 months post-injury with a validated motor battery and resting-state fMRI to measure inter-hemispheric functional connectivity (FC). Fractional anisotropy (FA) of the cortico-spinal tract (CST) was derived from diffusion tensor imaging as a measure of white matter organization. ANOVAs were used to test for changes in FC, FA, and motor performance scores over time, and regression analysis related motor outcome to clinical and neuroimaging variables. Results FA of the ipsilesional CST improved significantly from 3 to 12 months and was strongly correlated with motor performance. FA improved even in the absence of direct damage to the CST. Inter-hemispheric FC also improved over time, but did not correlate with motor performance at 12 months. Clinical variables (early motor score, education level, and age) predicted 80.4% of the variation of motor outcome, and FA increased the predictability to 84.6%. FC did not contribute to the prediction of motor outcome. Conclusions Stroke causes changes to the CST microstructure that can account for behavioral variability even in the absence of demonstrable lesion. Ipsilesional CST undergoes remodeling post-stroke, even past the three-month window when most of the motor recovery happens. FA of the CST, but not inter-hemispheric FC, can improve to the prediction of motor outcome based on early motor scores. © 2018 Lin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus
Access Type: Open Access

Unexpected similarities between C9ORF72 and sporadic forms of ALS/FTD suggest a common disease mechanism
(2018) eLife, 7, art. no. e37754, . 

Conlon, E.G.^a , Fagegaltier, D.^b , Agius, P.^c , Davis-Porada, J.^a , Gregory, J.^b , Hubbard, I.^b , Kang, K.^b , Kim, D.^b , Phatnani, H.^b , Shneider, N.A.^d , Manley, J.L.^a , Kwan, J.^e , Sareen, D.^{f g} , Broach, J.R.^h , Simmons, Z.ⁱ , Arcila-Londono, X.^j , Lee, E.B.^k , Van Deerlin, V.M.^k , Fraenkel, E.^l , Ostrow, L.W.^m , Baas, F.ⁿ , Zaitlen, N.^o , Berry, J.D.^{p q} , Malaspina, A.^{r s} , Fratta, P.^t , Cox, G.A.^u , Thompson, L.M.^{v w} , Finkbeiner, S.^x , Dardiotis, E.^y , Miller, T.M.^z , Chandran, S.^aa , Pal, S.^aa , Hornstein, E.^ab , Macgowan, D.J.^ac , Heiman-Patterson, T.^ad , Hammell, M.G.^ae , Patsopoulos, N.A.^{af ag ah} , Dubnau, J.^ai , Nath, A.^aj , The New York Genome Center ALS Consortium^ak

^a Department of Biological Sciences, Columbia University, New York, NY 10027, United States
^b Center for Genomics of Neurodegenerative Disease, New York Genome Center, New York, NY 10013, United States
^c New York Genome Center, New York, NY 10013, United States
^d Department of Neurology, Columbia University Medical Center, New York, United States
^e Department of Neurology, University of Maryland School of Medicine, University of Maryland ALS Clinic, Baltimore, United States
^f Cedars-Sinai Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, United States
^g Department of Medicine, University of California, Los Angeles, United States
^h Department of Biochemistry and Molecular Biology, Penn State Institute for Personalized Medicine, The Pennsylvania State University, Hershey, United States
ⁱ Department of Neurology, The Pennsylvania State University, Hershey, United States
^j Department of Neurology, Henry Ford Health System, Detroit, United States
^k Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^l Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United States
^m Department of Neurology, Johns Hopkins School of Medicine, Baltimore, United States
ⁿ Department of Neurogenetics, Academic Medical Centre, Amsterdam and Leiden University Medical Center, Leiden, Netherlands
^o Department of Medicine, Lung Biology Center, University of California, San Francisco, United States
^p ALS Multidisciplinary Clinic, Neuromuscular Division, Department of Neurology, Harvard Medical School, Boston, United States
^q Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, United States
^r Centre for Neuroscience and Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry Queen Mary University of London, London, United Kingdom
^s Department of Neurology, Basildon University Hospital, Basildon, United Kingdom
^t Institute of Neurology, National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom
^u The Jackson Laboratory, Bar Harbor, United States
^v Department of Psychiatry and Human Behavior and Department of Biological Chemistry, School of Medicine, University of California Irvine, Irvine, United States
^w Department of Neurobiology and Behavior, School of Biological Sciences, University of California Irvine, Irvine, United States
^x Taube/Koret Center for Neurodegenerative Disease Research, Roddenberry Center for Stem Cell Biology and Medicine, Gladstone Institute, San Francisco, United States
^y Department of Neurology and Sensory Organs, University of Thessaly, Thessaly, Greece
^z Department of Neurology, Washington University in St. Louis, St. Louis, United States
^aa Centre for Clinical Brain Sciences, Anne Rowling Regenerative Neurology Clinic, Euan MacDonald Centre for Motor Neurone Disease Research University of Edinburgh, Edinburgh, United Kingdom
^ab Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
^ac Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, United States
^ad Center for Neurodegenerative Disorders, Department of Neurology, the Lewis Katz School of Medicine, Temple University, Philadelphia, United States
^ae Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
^af Ann Romney Center for Neurological Diseases Department of Neurology Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
^ag Division of Genetics in Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States
^ah Broad Institute, Cambridge, United States
^ai Department of Anesthesiology, Stony Brook University, Stony Brook, United States
^aj Section of Infections of the Nervous System, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, United States

Abstract
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of a disease spectrum with shared clinical, genetic and pathological features. These include near ubiquitous pathological inclusions of the RNA-binding protein (RBP) TDP-43, and often the presence of a GGGGCC expansion in the C9ORF72 (C9) gene. Previously, we reported that the sequestration of hnRNP H altered the splicing of target transcripts in C9ALS patients (Conlon et al., 2016). Here, we show that this signature also occurs in half of 50 postmortem sporadic, non-C9 ALS/FTD brains. Furthermore, and equally surprisingly, these ‘like-C9’ brains also contained correspondingly high amounts of insoluble TDP-43, as well as several other disease-related RBPs, and this correlates with widespread global splicing defects. Finally, we show that the like-C9 sporadic patients, like actual C9ALS patients, were much more likely to have developed FTD. We propose that these unexpected links between C9 and sporadic ALS/FTD define a common mechanism in this disease spectrum. © 2018, eLife Sciences Publications Ltd. All rights reserved.

Document Type: Article
Source: Scopus
Access Type: Open Access

BK channel inhibition by strong extracellular acidification
(2018) eLife, 7, art. no. e38060, . 

Zhou, Y., Xia, X.-M., Lingle, C.J.

Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States

Abstract
Mammalian BK-type voltage- and Ca2+-dependent K+ channels are found in a wide range of cells and intracellular organelles. Among different loci, the composition of the extracellular microenvironment, including pH, may differ substantially. For example, it has been reported that BK channels are expressed in lysosomes with their extracellular side facing the strongly acidified lysosomal lumen (pH ~4.5). Here we show that BK activation is strongly and reversibly inhibited by extracellular H+, with its conductance-voltage relationship shifted by more than +100 mV at pHO 4. Our results reveal that this inhibition is mainly caused by H+ inhibition of BK voltage-sensor (VSD) activation through three acidic residues on the extracellular side of BK VSD. Given that these key residues (D133, D147, D153) are highly conserved among members in the voltage-dependent cation channel superfamily, the mechanism underlying BK inhibition by extracellular acidification might also be applicable to other members in the family. © Zhou et al.

Document Type: Article
Source: Scopus
Access Type: Open Access

Stem nourished by branches: Glioblastomas co-opt classic neurotrophic factor signaling to maintain stem-like cell pool
(2018) Stem Cell Investigation, 5 (July), art. no. 22, . 

Taiwo, R.^a , Mahlokozera, T.^a , Kim, A.H.^{a b c d e}

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Developmental Biology, Washington University School of Medicine, 660 S Euclid Ave., Campus Box 8057, St. Louis, MO 63110, United States

Document Type: Review
Source: Scopus

Examining the reversibility of long-term behavioral disruptions in progeny of maternal ssri exposure
(2018) eNeuro, 5 (4), art. no. e0120-18.2018, . 

Maloney, S.E.^{a b} , Akula, S.^{a b} , Rieger, M.A.^{a b} , McCullough, K.B.^{a b} , Chandler, K.^{a b} , Corbett, A.M.^c , McGowin, A.E.^d , Dougherty, J.D.^{a b}

^a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neuroscience, Cell Biology and Physiology, Wright State University, Dayton, OH 45435, United States
^d Department of Chemistry, Wright State University, Dayton, OH 45435, United States

Abstract
Serotonergic dysregulation is implicated in numerous psychiatric disorders. Serotonin plays widespread trophic roles during neurodevelopment; thus perturbations to this system during development may increase risk for neurodevelopmental disorders. Epidemiological studies have examined association between selective serotonin reuptake inhibitor (SSRI) treatment during pregnancy and increased autism spectrum disorder (ASD) risk in offspring. It is unclear from these studies whether ASD susceptibility is purely related to maternal psychiatric diagnosis, or if treatment poses additional risk. We sought to determine whether maternal SSRI treatment alone or in combination with genetically vulnerable background was sufficient to induce offspring behavior disruptions relevant to ASD. We exposed C57BL/6J or Celf6+/- mouse dams to fluoxetine (FLX) during different periods of gestation and lactation and characterized offspring on tasks assessing social communicative interaction and repetitive behavior patterns including sensory sensitivities. We demonstrate robust reductions in pup ultrasonic vocalizations (USVs) and alterations in social hierarchy behaviors, as well as perseverative behaviors and tactile hypersensitivity. Celf6 mutant mice demonstrate social communicative deficits and perseverative behaviors, without further interaction with FLX. FLX re-exposure in adulthood ameliorates the tactile hypersensitivity yet exacerbates the dominance phenotype. This suggests acute deficiencies in serotonin levels likely underlie the abnormal responses to sensory stimuli, while the social alterations are instead due to altered development of social circuits. These findings indicate maternal FLX treatment, independent of maternal stress, can induce behavioral disruptions in mammalian offspring, thus contributing to our understanding of the developmental role of the serotonin system and the possible risks to offspring of SSRI treatment during pregnancy. © 2018 Maloney et al.

Author Keywords
Autism;  Fluoxetine;  Sensory sensitivity;  Serotonin;  Social behavior;  SSRI

Document Type: Article
Source: Scopus

Understanding Emotion in Adolescents: A Review of Emotional Frequency, Intensity, Instability, and Clarity
(2018) Emotion Review, . Article in Press. 

Bailen, N.H., Green, L.M., Thompson, R.J.

Department of Psychological and Brain Sciences, Washington University in St. Louis, United States

Abstract
Adolescence is a time of transition from childhood to adulthood during which significant changes occur across multiple domains, including emotional experience. This article reviews the relevant literature on adolescents’ experience of four specific dimensions of emotion: emotional frequency, intensity, instability, and clarity. In an effort to examine how emotional experiences change as individuals approach adulthood, we examine these dimensions across ages 10 to 19, and review how the emotional functioning of adolescents compares to that of adults. In addition, we explore whether and how gender and puberty explain age differences in emotional experience. Finally, we discuss how these findings could inform future research on both the typical trajectory of emotional experience and the development of psychopathology in adolescence. © The Author(s) 2018.

Author Keywords
adolescence;  development;  emotion;  gender;  puberty

Document Type: Article in Press
Source: Scopus

Disrupted cholesterol metabolism promotes age-related photoreceptor neurodegeneration
(2018) Journal of Lipid Research, 59 (8), pp. 1414-1423. 

Ban, N.^a , Lee, T.J.^a , Sene, A.^a , Dong, Z.^a , Santeford, A.^a , Lin, J.B.^{a c} , Ory, D.S.^d , Apte, R.S.^{a b c}

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^b Department of Medicine and Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^c Department of Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^d Department of Diabetic Cardiovascular Disease Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Photoreceptors have high intrinsic metabolic demand and are exquisitely sensitive to metabolic perturbation. In addition, they shed a large portion of their outer segment lipid membranes in a circadian manner, increasing the metabolic burden on the outer retina associated with the resynthesis of cell membranes and disposal of the cellular cargo. Here, we demonstrate that deletion of both ABCA1 and ABCG1 in rod photoreceptors leads to age-related accumulation of cholesterol metabolites in the outer retina, photoreceptor dysfunction, degeneration of rod outer segments, and ultimately blindness. A high-fat diet significantly accelerates rod neurodegeneration and vision loss, further highlighting the role of lipid homeostasis in regulating photoreceptor neurodegeneration and vision.—Ban, N., T. J. Lee, A. Sene, Z. Dong, A. Santeford, J. B. Lin, D. S. Ory, and R. S. Apte. Disrupted cholesterol metabolism promotes age-related photoreceptor neurodegeneration. Copyright © 2018 Ban et al.

Author Keywords
Aging;  ATP binding cassette transporter G1;  Cholesterol/dietary;  Cholesterol/efflux;  Eye/retina;  Neurons

Document Type: Article
Source: Scopus

Human non-REM sleep and the mean global BOLD signal
(2018) Journal of Cerebral Blood Flow and Metabolism, . Article in Press. 

McAvoy, M.P.^a , Tagliazucchi, E.^b , Laufs, H.^{c d} , Raichle, M.E.^{a e}

^a Department of Radiology, Washington University, Saint Louis, MO, United States
^b PICNIC Lab, Institut du Cerveau et de la Moelle épinière, Paris, France
^c Department of Neurology, Brain Imaging Center, Goethe-Universität Frankfurt am Main, Frankfurt, Germany
^d Department of Neurology, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
^e Alan and Edith L. Wolff Distinguished Professor of Medicine, Washington University, Saint Louis, MO, United States

Abstract
A hallmark of non-rapid eye movement (REM) sleep is the decreased brain activity as measured by global reductions in cerebral blood flow, oxygen metabolism, and glucose metabolism. It is unknown whether the blood oxygen level dependent (BOLD) signal undergoes similar changes. Here we show that, in contrast to the decreases in blood flow and metabolism, the mean global BOLD signal increases with sleep depth in a regionally non-uniform manner throughout gray matter. We relate our findings to the circulatory and metabolic processes influencing the BOLD signal and conclude that because oxygen consumption decreases proportionately more than blood flow in sleep, the resulting decrease in paramagnetic deoxyhemoglobin accounts for the increase in mean global BOLD signal. © The Author(s) 2018.

Author Keywords
Bohr effect;  fMRI BOLD;  Global signal;  oxyhemoglobin dissociation curve;  sleep

Document Type: Article in Press
Source: Scopus

Genome-wide association meta-analysis of age at first cannabis use
(2018) Addiction, . Article in Press. 

Minică, C.C.^a , Verweij, K.J.H.^{a b az} , van der Most, P.J.^c , Mbarek, H.^a , Bernard, M.^d , van Eijk, K.R.^e , Lind, P.A.^f , Liu, M.Z.^g , Maciejewski, D.F.^{h i} , Palviainen, T.^j , Sánchez-Mora, C.^{k l m} , Sherva, R.ⁿ , Taylor, M.^{o p} , Walters, R.K.^{q r s} , Abdellaoui, A.^{a az} , Bigdeli, T.B.^t , Branje, S.J.T.^u , Brown, S.A.^v , Casas, M.^{k l m w} , Corley, R.P.^g , Davey-Smith, G.^{o p} , Davies, G.E.^x , Ehli, E.A.^x , Farrer, L.^y , Fedko, I.O.^a , Garcia-Martínez, I.^{k l} , Gordon, S.D.^z , Hartman, C.A.^aa , Heath, A.C.^ab , Hickie, I.B.^ac , Hickman, M.^p , Hopfer, C.J.^ad , Hottenga, J.J.^a , Kahn, R.S.^ae , Kaprio, J.^{j af} , Korhonen, T.^{j ag} , Kranzler, H.R.^ah , Krauter, K.^ai , van Lier, P.A.C.^{h aj} , Madden, P.A.F.^ab , Medland, S.E.^f , Neale, M.C.^ak , Meeus, W.H.J.^{u al} , Montgomery, G.W.^am , Nolte, I.M.^c , Oldehinkel, A.J.^aa , Pausova, Z.^{d an} , Ramos-Quiroga, J.A.^{k l m w} , Richarte, V.^{k l m} , Rose, R.J.^ao , Shin, J.^d , Stallings, M.C.^g , Wall, T.L.^ap , Ware, J.J.^{o p} , Wright, M.J.^aq , Zhao, H.^ar , Koot, H.M.^h , Paus, T.^{as at au} , Hewitt, J.K.^g , Ribasés, M.^{k l m} , Loukola, A.^j , Boks, M.P.^ae , Snieder, H.^c , Munafò, M.R.^{o av} , Gelernter, J.^aw , Boomsma, D.I.^a , Martin, N.G.^z , Gillespie, N.A.^{t z} , Vink, J.M.^b , Derks, E.M.^{ax ay}

^a Department of Biological Psychology/Netherlands Twin Register, VU University, Amsterdam, Netherlands
^b Behavioral Science Institute, Radboud University, Nijmegen, Netherlands
^c Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
^d Hospital for Sick Children Research Institute, Toronto, Canada
^e Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
^f Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^g Institute for Behavioral Genetics, Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, United States
^h Department of Clinical Developmental Psychology, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
ⁱ GGZ inGeest and Department of Psychiatry, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, Netherlands
^j Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
^k Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
^l Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain
^m Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
ⁿ Biomedical Genetics Department, Boston University School of Medicine, Boston, MA, United States
^o MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, United Kingdom
^p School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom
^q Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
^r Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^s Department of Medicine, Harvard Medical School, Boston, MA, United States
^t Department of Psychiatry, Virginia Institute for Psychiatric and Behavior Genetics, Virginia Commonwealth University, Richmond, VA, United States
^u Research Centre Adolescent Development, Utrecht University, Utrecht, Netherlands
^v Department of Psychology and Psychiatry, University of California San Diego, La Jolla, CA, United States
^w Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
^x Avera Institute for Human Genetics, Sioux Falls, SD, United States
^y Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States
^z Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^aa Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
^ab Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^ac Brain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia
^ad Department of Psychiatry, University of Colorado Denver, Aurora, CO, United States
^ae Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
^af Department of Public Health, University of Helsinki, Helsinki, Finland
^ag University of Eastern Finland, Institute of Public Health and Clinical Nutrition, Kuopio, Finland
^ah Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^ai Department of Molecular, Cellular and Developmental Biology, University of Colorado Boulder, Boulder, CO, United States
^aj Department of Psychology, Education and Child Studies, Erasmus University Rotterdam, Rotterdam, Netherlands
^ak Department of Psychiatry and School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
^al Developmental Psychology, Tilburg University, Tilburg, Netherlands
^am Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
^an Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada
^ao Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
^ap Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
^aq Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
^ar Department of Biostatistics, Yale School of Public Health and VA CT, New Haven, CT, United States
^as Rotman Research Institute, Baycrest, Toronto, Canada
^at Psychology and Psychiatry, University of Toronto, Toronto, Canada
^au Center for the Developing Brain, Child Mind Institute, New York, NY, United States
^av UK Centre for Tobacco and Alcohol Studies, School of Experimental Psychology, University of Bristol, Bristol, United Kingdom
^aw Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine and VA CT, West Haven, CT, United States
^ax Department of Psychiatry, Academic Medical Centre, Amsterdam, Netherlands
^ay Translational Neurogenomics group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^az Amsterdam UMC, University of Amsterdam, Department of Psychiatry, Amsterdam, Netherlands

Abstract
Background and aims: Cannabis is one of the most commonly used substances among adolescents and young adults. Earlier age at cannabis initiation is linked to adverse life outcomes, including multi-substance use and dependence. This study estimated the heritability of age at first cannabis use and identified associations with genetic variants. Methods: A twin-based heritability analysis using 8055 twins from three cohorts was performed. We then carried out a genome-wide association meta-analysis of age at first cannabis use in a discovery sample of 24 953 individuals from nine European, North American and Australian cohorts, and a replication sample of 3735 individuals. Results: The twin-based heritability for age at first cannabis use was 38% [95% confidence interval (CI) = 19–60%]. Shared and unique environmental factors explained 39% (95% CI = 20–56%) and 22% (95% CI = 16–29%). The genome-wide association meta-analysis identified five single nucleotide polymorphisms (SNPs) on chromosome 16 within the calcium-transporting ATPase gene (ATP2C2) at P &lt; 5E-08. All five SNPs are in high linkage disequilibrium (LD) (r2 &gt; 0.8), with the strongest association at the intronic variant rs1574587 (P = 4.09E-09). Gene-based tests of association identified the ATP2C2 gene on 16q24.1 (P = 1.33e-06). Although the five SNPs and ATP2C2 did not replicate, ATP2C2 has been associated with cocaine dependence in a previous study. ATP2B2, which is a member of the same calcium signalling pathway, has been associated previously with opioid dependence. SNP-based heritability for age at first cannabis use was non-significant. Conclusion: Age at cannabis initiation appears to be moderately heritable in western countries, and individual differences in onset can be explained by separate but correlated genetic liabilities. The significant association between age of initiation and ATP2C2 is consistent with the role of calcium signalling mechanisms in substance use disorders. © 2018 Society for the Study of Addiction

Author Keywords
Age at first use;  ATP2C2;  cannabis initiation;  genome-wide association;  heritability;  substance use

Document Type: Article in Press
Source: Scopus

Analysis of High Molecular Weight Isoforms of Nesprin-1 and Nesprin-2 with Vertical Agarose Gel Electrophoresis
(2018) Methods in Molecular Biology, 1840, pp. 25-33. 

Potter, C., Hodzic, D.

Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The biochemical characterization of proteins most often require their identification by immunoblotting. Whereas SDS-PAGE provides satisfactory results for most proteins, the identification of larger proteins requires alternative methods to ensure their separation and complete transfer onto nitrocellulose membranes. Here, we describe the application of vertical agarose gel electrophoresis to identify large isoforms of nesprin-1 and nesprin-2. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
LINC complexes;  Nesprin-1 giant;  Nesprin-2 giant;  Nesprins;  SUN proteins;  VAGE;  Vertical agarose gel electrophoresis

Document Type: Book Chapter
Source: Scopus

Super-resolution Imaging of Amyloid Structures over Extended Times by Using Transient Binding of Single Thioflavin T Molecules
(2018) ChemBioChem, . Article in Press. 

Spehar, K.^a , Ding, T.^b , Sun, Y.^{a c} , Kedia, N.^a , Lu, J.^b , Nahass, G.R.^a , Lew, M.D.^b , Bieschke, J.^{a d}

^a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^c Department of Energy, Environmental, and Chemical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^d MRC Prion Unit, UCL Institute of Prion Diseases, Gower Street, London, WC1E 6BT, United Kingdom

Abstract
Oligomeric amyloid structures are crucial therapeutic targets in Alzheimer’s and other amyloid diseases. However, these oligomers are too small to be resolved by standard light microscopy. We have developed a simple and versatile tool to image amyloid structures by using thioflavin T without the need for covalent labeling or immunostaining. The dynamic binding of single dye molecules generates photon bursts that are used for fluorophore localization on a nanometer scale. Thus, photobleaching cannot degrade image quality, allowing for extended observation times. Super-resolution transient amyloid binding microscopy promises to directly image native amyloid by using standard probes and record amyloid dynamics over minutes to days. We imaged amyloid fibrils from multiple polypeptides, oligomeric, and fibrillar structures formed during different stages of amyloid-β aggregation, as well as the structural remodeling of amyloid-β fibrils by the compound epi-gallocatechin gallate. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Author Keywords
amyloid beta-peptides;  long-term imaging;  single-molecule localization microscopy;  single-molecule studies

Document Type: Article in Press
Source: Scopus

Exploration of Sulfur-Containing Analogues for Imaging Vesicular Acetylcholine Transporter in the Brain
(2018) ChemMedChem, . Article in Press. 

Luo, Z.^a , Liu, H.^a , Jin, H.^a , Gu, J.^a , Yu, Y.^a , Kaneshige, K.^c , Perlmutter, J.S.^{a b} , Parsons, S.M.^c , Tu, Z.^a

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Neurology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA 93106, United States

Abstract
Sixteen new sulfur-containing compounds targeting the vesicular acetylcholine transporter (VAChT) were synthesized and assessed for in vitro binding affinities. Enantiomers (−)-(1-(3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)piperidin-4-yl)(4-(methylthio)phenyl)methanone [(−)-8] and (−)-(4-((2-fluoroethyl)thio)phenyl)(1-(3-hydroxy-1,2,3,4-tetrahydronaph-thalen-2-yl)piperidin-4-yl)methanone [(−)-14 a] displayed high binding affinities, with respective Ki values of 1.4 and 2.2 nm for human VAChT, moderate and high selectivity for human VAChT over σ1 (≈13-fold) and σ2 receptors (&gt;420-fold). Radiosyntheses of (−)-[11C]8 and (−)-[18F]14 a were achieved using conventional methods. Ex vivo autoradiography and biodistribution studies in Sprague–Dawley rats indicated that both radiotracers have the capacity to penetrate the blood–brain barrier, with high initial brain uptake at 5 min and rapid washout. The striatal region had the highest accumulation for both radiotracers. Pretreating the rats with the VAChT ligand (−)-vesamicol decreased brain uptake for both radiotracers. Pretreating the rats with the σ1 ligand YUN-122 (N-(4-benzylcyclohexyl)-2-(2-fluorophenyl)acetamide) also decreased brain uptake, suggesting these two radiotracers also bind to the σ1 receptor in vivo. The microPET study of (−)-[11C]8 in the brain of a non-human primate showed high striatal accumulation that peaked quickly and washed out rapidly. Although preliminary results indicated these two sulfur-containing radiotracers have high binding affinities for VAChT with rapid washout kinetics from the striatum, their σ1 receptor binding properties limit their potential as radiotracers for quantifying VAChT in vivo. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Author Keywords
biodistribution;  neurodegenerative diseases;  positron emission tomography;  radiotracers;  vesicular acetylcholine transporter

Document Type: Article in Press
Source: Scopus

HCN channels in the hippocampus regulate active coping behavior
(2018) Journal of Neurochemistry, . Article in Press. 

Fisher, D.W.^a , Han, Y.^a , Lyman, K.A.^a , Heuermann, R.J.^{a b} , Bean, L.A.^c , Ybarra, N.^c , Foote, K.M.^a , Dong, H.^d , Nicholson, D.A.^c , Chetkovich, D.M.^{a e}

^a Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
^d Department of Psychiatry & Behavioral Sciences, Northwestern University, Feinberg School of medicine, Chicago, IL, United States
^e Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States

Abstract
Abstract: Active coping is an adaptive stress response that improves outcomes in medical and neuropsychiatric diseases. To date, most research into coping style has focused on neurotransmitter activity and little is known about the intrinsic excitability of neurons in the associated brain regions that facilitate coping. Previous studies have shown that HCN channels regulate neuronal excitability in pyramidal cells and that HCN channel current (Ih) in the CA1 area increases with chronic mild stress. Reduction of Ih in the CA1 area leads to antidepressant-like behavior, and this region has been implicated in the regulation of coping style. We hypothesized that the antidepressant-like behavior achieved with CA1 knockdown of Ih is accompanied by increases in active coping. In this report, we found that global loss of TRIP8b, a necessary subunit for proper HCN channel localization in pyramidal cells, led to active coping behavior in numerous assays specific to coping style. We next employed a viral strategy using a dominant negative TRIP8b isoform to alter coping behavior by reducing HCN channel expression. This approach led to a robust reduction in Ih in CA1 pyramidal neurons and an increase in active coping. Together, these results establish that changes in HCN channel function in CA1 influences coping style. (Figure presented.). © 2018 International Society for Neurochemistry

Author Keywords
coping;  HCN Channel;  hippocampus;  mice;  TRIP8b

Document Type: Article in Press
Source: Scopus

Social anxiety and eating disorder comorbidity and underlying vulnerabilities: Using network analysis to conceptualize comorbidity
(2018) International Journal of Eating Disorders, . Article in Press. 

Levinson, C.A.^a , Brosof, L.C.^a , Vanzhula, I.^a , Christian, C.^a , Jones, P.^b , Rodebaugh, T.L.^c , Langer, J.K.^c , White, E.K.^d , Warren, C.^e , Weeks, J.W.^f , Menatti, A.^f , Lim, M.H.^c , Fernandez, K.C.^c

^a Department of Psychological and Brain Sciences, University of Louisville, Louisville, KY 40292, United States
^b Department of Psychology, Harvard University, Cambridge, MA, United States
^c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^d Neurological Institute Cleveland Clinic, Cleveland, OH, United States
^e Department of Psychology, University of Nevada, Reno, NV, United States
^f Department of Psychology, Ohio University, Columbus, OH, United States

Abstract
Objective: Eating disorders (EDs) and social anxiety disorder (SAD) are highly co-occurring. This comorbidity is extremely relevant, given that individuals with comorbid ED-SAD are less likely to seek and/or benefit from ED treatment. Method: We used network analysis to conceptualize ED-SAD comorbidity in a sample of 2,215 participants with a primary diagnosis of ED, SAD, or no known diagnosis. We used novel network analyses methods to select symptoms for our models, identify potential illness pathways (i.e., bridge symptoms) between disorders and underlying vulnerabilities (e.g., perfectionism, social appearance anxiety), and to compare across sample types (e.g., clinical vs. nonclinical). We also tested several novel network analyses methods aimed at the following methodological concerns: (a) topological concerns (i.e., which items should be included in NA models), (b) how to use empirical indices to quantify bridge symptoms and (c) what differences in networks across samples mean. Results: We found that difficulty with drinking beverages and eating in public were bridge symptoms between ED and SAD. We also found that feeling nervous about one’s appearance was a bridge symptom. Conclusions: We identified public eating and drinking as bridge symptoms between EDs and SAD. Future research is needed to test if interventions focused on public eating and drinking might decrease symptoms of both EDs and SAD. Researchers can use this study (code provided) as an exemplar for how to use network analysis, as well as to use network analysis to conceptualize ED comorbidity and compare network structure and density across samples. © 2018 Wiley Periodicals, Inc.

Author Keywords
comorbidity;  eating disorders;  network analysis;  social anxiety disorder

Document Type: Article in Press
Source: Scopus

Effect of BDNFVal66Met on disease markers in dominantly inherited Alzheimer’s disease
(2018) Annals of Neurology, . Article in Press. 

Lim, Y.Y.^a , Hassenstab, J.^b , Goate, A.^c , Fagan, A.M.^b , Benzinger, T.L.S.^d , Cruchaga, C.^e , McDade, E.^b , Chhatwal, J.^{f g} , Levin, J.^h , Farlow, M.R.ⁱ , Graff-Radford, N.R.^j , Laske, C.^{k l} , Masters, C.L.^a , Salloway, S.^m , Schofield, P.^{n o} , Morris, J.C.^b , Maruff, P.^{a p} , Bateman, R.J.^b , on behalf of the Dominantly Inherited Alzheimer Network^q

^a The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
^b Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^c Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Department of Radiology, Washington University in St Louis, St Louis, MO, United States
^e Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^f Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^g Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^h Department of Neurology, University of Munich, Munich, Germany
ⁱ Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
^j Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^k German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^l Section for Dementia Research, Department of Cellular Neurology, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
^m Department of Neurology, Warren Alpert Medical School of Brown University, Providence, RI, United States
ⁿ Neuroscience Research Australia, Sydney, NSW, Australia
^o School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
^p Cogstate Ltd, Melbourne, VIC, Australia

Abstract
Objective: Previous studies suggest that the brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may influence symptom onset in Alzheimer’s disease (AD). Our recent cross-sectional findings suggest that Met66 may influence clinical expression in dominantly inherited AD (DIAD) through its effects on tau. However, it remains unclear whether carriage of Met66 in DIAD results in faster increases in cerebrospinal fluid (CSF) tau and ptau181, and whether these increases are associated with accelerated brain volume loss and memory decline. Methods: A total of 211 subjects (101 mutation noncarriers, 110 mutation carriers), who were cognitively normal, as defined by a Clinical Dementia Rating global score of 0, completed assessments of cognitive function, neuroimaging, and CSF sampling over 3.5 years as part of the Dominantly Inherited Alzheimer’s Network. Results: In mutation carriers, Met66 carriers showed faster memory decline (4×), hippocampal volume loss (16×), and CSF tau and ptau181 increases (6×) than Val66 homozygotes. BDNF did not influence rates of cortical β-amyloid accumulation or change in CSF Aβ42 levels in mutation carriers. In mutation noncarriers, BDNF genotype had no effect on change in cognition, brain volume, cortical β-amyloid accumulation, or change in any CSF measures of tau, ptau181, and CSF Aβ42. Interpretation: As in sporadic AD, the deleterious effects of β-amyloid on cognitive function, brain volume loss, and CSF tau in DIAD mutation carriers are less in Val66 homozygotes. The BDNF Val66Met polymorphism should be considered as a potential moderator of clinical trial outcomes in current treatment and prevention trials in DIAD and sporadic AD. Ann Neurol 2018. © 2018 American Neurological Association

Document Type: Article in Press
Source: Scopus

Response to: ‘Dementia and advance directives: Some empirical and normative concerns’ by Jongsma et al
(2018) Journal of Medical Ethics, . Article in Press. 

Kim, S.Y.H.^a , Miller, D.G.^a , Dresser, R.^b

^a Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States
^b Washington University, School of Law, St. Louis, MO, United States

Author Keywords
dementia;  Euthanasia;  living wills/advance directives

Document Type: Article in Press
Source: Scopus

Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation
(2018) Molecular Psychiatry, . Article in Press. 

Bis, J.C.^a , Jian, X.^b , Kunkle, B.W.^c , Chen, Y.^d , Hamilton-Nelson, K.L.^c , Bush, W.S.^e , Salerno, W.J.^f , Lancour, D.^g , Ma, Y.^g , Renton, A.E.^h , Marcora, E.^{h i} , Farrell, J.J.^g , Zhao, Y.^j , Qu, L.^j , Ahmad, S.^k , Amin, N.^l , Amouyel, P.^{l m n} , Beecham, G.W.^c , Below, J.E.^o , Campion, D.^{p q} , Charbonnier, C.^p , Chung, J.^g , Crane, P.K.^a , Cruchaga, C.^r , Cupples, L.A.^{d s} , Dartigues, J.-F.^t , Debette, S.^{t u} , Deleuze, J.-F.^v , Fulton, L.^w , Gabriel, S.B.^x , Genin, E.^y , Gibbs, R.A.^f , Goate, A.^{h i} , Grenier-Boley, B.^l , Gupta, N.^x , Haines, J.L.^e , Havulinna, A.S.^{z aa} , Helisalmi, S.^ab , Hiltunen, M.^ac , Howrigan, D.P.^{ad ae} , Ikram, M.A.^k , Kaprio, J.^z , Konrad, J.^r , Kuzma, A.^j , Lander, E.S.^x , Lathrop, M.^af , Lehtimäki, T.^ag , Lin, H.^ah , Mattila, K.^ag , Mayeux, R.^ai , Muzny, D.M.^f , Nasser, W.^f , Neale, B.^{ad ae} , Nho, K.^aj , Nicolas, G.^p , Patel, D.^g , Pericak-Vance, M.A.^c , Perola, M.^{z aa ak} , Psaty, B.M.^{a al am an} , Quenez, O.^p , Rajabli, F.^c , Redon, R.^ao , Reitz, C.^ai , Remes, A.M.^{ab ap} , Salomaa, V.^aa , Sarnowski, C.^d , Schmidt, H.^aq , Schmidt, M.^c , Schmidt, R.^aq , Soininen, H.^{ab ar} , Thornton, T.A.^as , Tosto, G.^ai , Tzourio, C.^t , van der Lee, S.J.^k , van Duijn, C.M.^k , Vardarajan, B.^ai , Wang, W.^j , Wijsman, E.^{at au} , Wilson, R.K.^w , Witten, D.^{as au} , Worley, K.C.^f , Zhang, X.^{d g} , Bellenguez, C.^l , Lambert, J.-C.^l , Kurki, M.I.^{z ad ae} , Palotie, A.^{z ad ae} , Daly, M.^{x z ae} , Boerwinkle, E.^{f av} , Lunetta, K.L.^d , Destefano, A.L.^{d aw} , Dupuis, J.^d , Martin, E.R.^c , Schellenberg, G.D.^j , Seshadri, S.^{s aw ax} , Naj, A.C.^j , Fornage, M.^{b av} , Farrer, L.A.^{d g aw ay az} , Alzheimer’s Disease Sequencing Project^ba

^a Department of Medicine (General Internal Medicine), University of Washington, Seattle, WA, United States
^b Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
^c John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, FL, United States
^d Departments of Biostatistics, Boston University School of Public Health, Boston, MA, United States
^e Case Western Reserve University, Cleveland Heights, OH, United States
^f Human Genome Sequencing Center and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
^g Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States
^h Department of Neuroscience and Ronald M Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ⁱ Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^j University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^k Erasmus University Medical Center, Rotterdam, Netherlands
^l Inserm, U1167, RID-AGE-Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France
^m Institut Pasteur de Lille, Lille, France
ⁿ University Lille, U1167-Excellence Laboratory LabEx DISTALZ, Lille, France
^o Department of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, United States
^p Department of Genetics and CNR-MAJ, Normandie Université, UNIROUEN, Inserm U1245 and Rouen University Hospital, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France
^q Department of Research, Centre Hospitalier du Rouvray, Sotteville-lès-, Rouen, France
^r Department of Psychiatry, Washington University, St. Louis, MO, United States
^s National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA, United States
^t University of Bordeaux, Inserm, Bordeaux Population Health Research Center, team VINTAGE, UMR 1219, Bordeaux, F-33000, France
^u Department of Neurology and Institute for Neurodegenerative Diseases, Bordeaux University Hospital, Memory Clinic, Bordeaux, F-33000, France
^v Centre National de Recherche en Génomique Humaine, Institut François Jacob, Direction de le Recherche Fondamentale, CEA, Evry, France
^w McDonnell Genome Institute, Washington University, St. Louis, MO, United States
^x Broad Institute of MIT and Harvard, Cambridge, MA, United States
^y Inserm UMR-1078, CHRU Brest, Université Brest, Brest, France
^z Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
^aa National Institute for Health and Welfare, Helsinki, Finland
^ab Institute of Clinical Medicine – Neurology and Department of Neurology, University of Eastern Finland, Kuopio, Finland
^ac Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
^ad Program in Medical and Population Genetics and Genetic Analysis Platform, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^ae Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
^af McGill University and Génome Québec Innovation Centre, Montréal, Canada
^ag Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
^ah Department of Medicine (Computational Biomedicine), Boston University School of Medicine, Boston, MA, United States
^ai Columbia University, New York, NY, United States
^aj Indiana University School of Medicine, Indianapolis, IN, United States
^ak University of Tartu, Estonian Genome Center, Tartu, Estonia
^al Department of Epidemiology, University of Washington, Seattle, WA, United States
^am Department of Health Services, University of Washington, Seattle, WA, United States
^an Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States
^ao Inserm, CNRS, Univ. Nantes, CHU Nantes, l’institut du thorax, Nantes, France
^ap Unit of Clinical Neuroscience, Neurology, University of Oulu and Medical Research Center, Oulu University Hospital, Oulu, Finland
^aq Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Graz, Austria
^ar Department of Neurology, Kuopio University Hospital, Kuopio, Finland
^as Department of Statistics, University of Washington, Seattle, WA, United States
^at Department of Medicine (Medical Genetics), University of Washington, Seattle, WA, United States
^au Department of Biostatistics, University of Washington, Seattle, WA, United States
^av School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, United States
^aw Departments of Neurology, Boston University School of Medicine, Boston, MA, United States
^ax Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, United States
^ay Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
^az Department of Ophthalmology, Boston University School of Medicine, Boston, MA, United States

Abstract
The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis. © 2018, Macmillan Publishers Limited, part of Springer Nature.

Document Type: Article in Press
Source: Scopus
Access Type: Open Access

Trends in Adult Alcohol Use and Binge Drinking in the Early 21st-Century United States: A Meta-Analysis of 6 National Survey Series
(2018) Alcoholism: Clinical and Experimental Research, . Article in Press. 

Grucza, R.A.^a , Sher, K.J.^b , Kerr, W.C.^c , Krauss, M.J.^a , Lui, C.K.^c , McDowell, Y.E.^b , Hartz, S.^a , Virdi, G.^a , Bierut, L.J.^a

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
^c Alcohol Research Group, Public Health Institute, Emeryville, CA, United States

Abstract
Background: Recent trends in alcoholic liver disease, alcohol-related emergency room admissions, and alcohol use disorder prevalence as measured by general-population surveys have raised concerns about rising alcohol-related morbidity and mortality in the United States. In contrast, upward trends in per capita alcohol consumption have been comparatively modest. Methods: To resolve these discordant observations, we sought to examine trends in the prevalence of alcohol use and binge drinking from 6 regularly or periodically administered national surveys using a meta-analytic approach. Annual or periodic prevalence estimates for past-12-month or past-30-day alcohol use and binge drinking were estimated for available time points between the years 2000 and 2016. Estimates were combined in a random-effects regression model in which prevalence was modeled as a log-linear function of time to obtain meta-analytic trend estimates for the full population and by sex, race, age, and educational attainment. Results: Meta-analysis–derived estimates of average annual percentage increase in the prevalence of alcohol use and binge drinking were 0.30% per year (95% CI: 0.22%, 0.38%) and 0.72% per year (95% CI: 0.46%, 0.98%), respectively. There was substantial between-survey heterogeneity among trend estimates, although there was notable consistency in the degree to which trends have impacted various demographic groups. For example, most surveys found that the changes in prevalence for alcohol use and binge drinking were large and positive for ages 50 to 64 and 65 and up, and smaller, negative, or nonsignificant for ages 18 to 29. Conclusions: Significant increases in the prevalence of alcohol use and of binge drinking over the past 10 to 15 years were observed, but not for all demographic groups. However, the increase in binge drinking among middle-aged and older adults is substantial and may be driving increasing rates of alcohol-related morbidity and mortality. © 2018 by the Research Society on Alcoholism

Author Keywords
Adults;  Binge Drinking;  Epidemiology;  Morbidity;  Trends

Document Type: Article in Press
Source: Scopus

Treatment of pediatric intracranial aneurysms: Case series and meta-analysis
(2018) Journal of NeuroInterventional Surgery, . Article in Press. 

Yasin, J.T.^{a b} , Wallace, A.N.^a , Madaelil, T.P.^a , Osbun, J.W.^{a c d} , Moran, C.J.^{a c} , Cross, D.T.^{a c} , Limbrick, D.D.^c , Zipfel, G.J.^{c d} , Dacey, R.G.^c , Kansagra, A.P.^{a c d}

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
^b School of Medicine, University of Missouri-Columbia, Columbia, MO, United States
^c Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: There are limited outcome data to guide the choice of treatment in pediatric patients with cerebral aneurysms. Objective: To describe our institutional experience treating pediatric patients with cerebral aneurysms and to conduct a meta-analysis of available studies to provide the best current evidence on treatment related outcomes. Methods: We identified pediatric patients with cerebral aneurysms evaluated or treated at our institution using a comprehensive case log. We also identified studies to include in a meta-analysis through a systematic search of Pubmed, SCOPUS, EMBASE, and the Cochrane Database of Systematic Reviews. As part of both the local analysis and meta-analysis, we recorded patient characteristics, aneurysm characteristics, management, and outcomes. Statistical analysis was performed using Fisher’s exact test and the two tailed Student’s t test, as appropriate. Results: 42 pediatric patients with 57 aneurysms were evaluated at our institution, and treatment specific outcome data were available in 560 patients as part of our meta-analysis. Endovascular and surgical treatments yielded comparable rates of favorable outcome in all children (88.3% vs 82.7%, respectively, P=0.097), in children with ruptured aneurysms (75% vs 83%, respectively, P=0.357), and in children with unruptured aneurysms (96% vs 97%, respectively, P=1.000). Conclusion: Endovascular and surgical treatment yield comparable long term clinical outcomes in pediatric patients with cerebral aneurysms. © 2018 Author(s) (or their employer(s)). Published by BMJ.

Author Keywords
aneurysm;  hemorrhage;  pediatrics;  subarachnoid

Document Type: Article in Press
Source: Scopus

Clinical/Scientific Notes: The Alzheimer’s disease sequencing project: Study design and sample selection
(2017) Neurology: Genetics, 3 (5), art. no. e194, . Cited 4 times.

Beecham, G.W.^{a b} , Bis, J.C.^c , Martin, E.R.^{a b} , Choi, S.-H.^g , DeStefano, A.L.^{g h i} , Van Duijn, C.M.^j , Fornage, M.^{k l} , Gabriel, S.B.^{m n} , Koboldt, D.C.^o , Larson, D.E.^{o p} , Naj, A.C.^q , Psaty, B.M.^{d s} , Salerno, W.^t , Bush, W.S.^u , Foroud, T.M.^v , Wijsman, E.^{e f} , Farrer, L.A.^{g i w x y} , Goate, A.^z , Haines, J.L.^u , Pericak-Vance, M.A.^{a b} , Boerwinkle, E.^{t aa} , Mayeux, R.^{ab ac ad ae} , Seshadri, S.^{h i} , Schellenberg, G.^r

^a John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of MiamiFL, United States
^b Dr. John T. MacDonald Foundation, Department of Human Genetics, Miller School of Medicine, University of MiamiFL, United States
^c Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, United States
^d Department of Medicine, Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, Health Services, Department of Medicine, University of Washington, Seattle, United States
^e Department of Biostatistics, Department of Medicine, University of Washington, Seattle, United States
^f Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, United States
^g Department of Biostatistics, Boston University School of Public HealthMA, United States
^h Framingham Heart StudyMA, United States
ⁱ Department of Neurology, Boston University School of MedicineMA, United States
^j Department of Epidemiology, Erasmus MC, Rotterdam, Netherlands
^k Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, United States
^l Human Genetics Center, University of Texas Health Science Center, Houston, United States
^m Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology, Cambridge, United States
ⁿ Harvard University, Cambridge, MA, United States
^o McDonnell Genome Institute, Washington University, St. Louis, MO, United States
^p Department of Genetics, Washington University, St. Louis, MO, United States
^q Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, United States
^r Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^s Group Health Research Institute, Group Health Cooperative, Seattle, WA, United States
^t Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
^u Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, United States
^v Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, United States
^w Department of Medicine (Biomedical Genetics), Boston University School of Medicine and Public HealthMA, United States
^x Department of Ophthalmology, Boston University School of Medicine and Public HealthMA, United States
^y Department of Epidemiology, Boston University School of Medicine and Public HealthMA, United States
^z Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^aa Human Genetics Center, UT Health School of Public Health, Houston, TX, United States
^ab Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, United States
^ac Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, United States
^ad Department of Neurology, Columbia University Medical Center, New York Presbyterian HospitalNY, United States
^ae Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States

Document Type: Article
Source: Scopus