WashU weekly Neuroscience publications

GATA2 Regulates Constitutive PD-L1 and PD-L2 Expression in Brain Tumors
(2020) Scientific Reports, 10 (1), art. no. 9027, .

Fu, Y.^a b , Liu, C.J.^a b , Kobayashi, D.K.^a b , Johanns, T.M.^b c , Bowman-Kirigin, J.A.^a , Schaettler, M.O.^a , Mao, D.D.^a , Bender, D.^b , Kelley, D.G.^d , Uppaluri, R.^e , Bi, W.L.^f , Dunn, I.F.^g , Tao, Y.^h i , Luo, J.^h i , Kim, A.H.^a , Dunn, G.P.^a b

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^d Division of Pulmonary and Critical Care Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^e Dana-Farber Cancer Insititute, Boston, MA, United States
^f Center for Skull Base and Pituitary Surgery, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^g Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
^h Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Biostatistics Shared Resource, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Encouraging clinical results using immune checkpoint therapies to target the PD-1 axis in a variety of cancer types have paved the way for new immune therapy trials in brain tumor patients. However, the molecular mechanisms that regulate expression of the PD-1 pathway ligands, PD-L1 and PD-L2, remain poorly understood. To address this, we explored the cell-intrinsic mechanisms of constitutive PD-L1 and PD-L2 expression in brain tumors. PD-L1 and PD-L2 expression was assessed by flow cytometry and qRT-PCR in brain tumor cell lines and patient tumor-derived brain tumor-initiating cells (BTICs). Immunologic effects of PD-L2 overexpression were evaluated by IFN-γ ELISPOT. CD274 and PDCD1LG2 cis-regulatory regions were cloned from genomic DNA and assessed in full or by mutating and/or deleting regulatory elements by luciferase assays. Correlations between clinical responses and PD-L1 and PD-L2 expression status were evaluated in TCGA datasets in LGG and GBM patients. We found that a subset of brain tumor cell lines and BTICs expressed high constitutive levels of PD-L1 and PD-L2 and that PD-L2 overexpression inhibited neoantigen specific T cell IFN-γ production. Characterization of novel cis-regulatory regions in CD274 and PDCD1LG2 lead us to identify that GATA2 is sufficient to drive PD-L1 and PD-L2 expression and is necessary for PD-L2 expression. Importantly, in TCGA datasets, PD-L2 correlated with worse clinical outcomes in glioma patients. By perturbing GATA2 biology, targeted therapies may be useful to decrease inhibitory effects of PD-L2 in the microenvironment. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Effects of early life exposure to traffic-related air pollution on brain development in juvenile Sprague-Dawley rats
(2020) Translational Psychiatry, 10 (1), art. no. 166, .

Patten, K.T.^a , González, E.A.^a , Valenzuela, A.^a , Berg, E.^b , Wallis, C.^c , Garbow, J.R.^d , Silverman, J.L.^b e , Bein, K.J.^c f , Wexler, A.S.^c g , Lein, P.J.^a e

^a Molecular Biosciences, UC Davis School of Veterinary Medicine, Davis, CA, United States
^b Psychiatry, UC Davis School of Medicine, Sacramento, CA, United States
^c Air Quality Research Center, UC Davis, Davis, CA, United States
^d Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^e The MIND Institute, UC Davis School of Medicine, Sacramento, CA, United States
^f Center for Health and the Environment, UC Davis, Davis, CA, United States
^g Mechanical and Aerospace Engineering, Civil and Environmental Engineering, and Land, Air and Water Resources, UC Davis, Davis, CA, United States

Abstract
Epidemiological studies link traffic-related air pollution (TRAP) to increased risk for various neurodevelopmental disorders (NDDs); however, there are limited preclinical data demonstrating a causal relationship between TRAP and adverse neurodevelopmental outcomes. Moreover, much of the preclinical literature reports effects of concentrated ambient particles or diesel exhaust that do not recapitulate the complexity of real-world TRAP exposures. To assess the developmental neurotoxicity of more realistic TRAP exposures, we exposed male and female rats during gestation and early postnatal development to TRAP drawn directly from a traffic tunnel in Northern California and delivered to animals in real-time. We compared NDD-relevant neuropathological outcomes at postnatal days 51–55 in TRAP-exposed animals versus control subjects exposed to filtered air. As indicated by immunohistochemical analyses, TRAP significantly increased microglial infiltration in the CA1 hippocampus, but decreased astrogliosis in the dentate gyrus. TRAP exposure had no persistent effect on pro-inflammatory cytokine levels in the male or female brain, but did significantly elevate the anti-inflammatory cytokine IL-10 in females. In male rats, TRAP significantly increased hippocampal neurogenesis, while in females, TRAP increased granule cell layer width. TRAP had no effect on apoptosis in either sex. Magnetic resonance imaging revealed that TRAP-exposed females, but not males, also exhibited decreased lateral ventricular volume, which was correlated with increased granule cell layer width in the hippocampus in females. Collectively, these data indicate that exposure to real-world levels of TRAP during gestation and early postnatal development modulate neurodevelopment, corroborating epidemiological evidence of an association between TRAP exposure and increased risk of NDDs. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

The validity and reliability of the Farsi version of the Body, Eating, and Exercise Comparison Orientation Measure (F-BEECOM) among Iranian male and female students
(2020) Body Image, 34, pp. 72-84.

Sahlan, R.N.^a , Saunders, J.F.^b , Fitzsimmons-Craft, E.E.^c , Taravatrooy, F.^d

^a Department of Clinical Psychology, Iran University of Medical Sciences, Tehran, Iran
^b Werklund School of Education, University of Calgary, Canada
^c Department of Psychiatry, Washington University in St. Louis, United States
^d Department of Psychology, Shiraz Branch, Islamic Azad University, Shiraz, Iran

Abstract
Body-, eating-, and exercise-related social comparison tendencies are implicated in body dissatisfaction and disordered eating among Western women. To date, no published study examines eating- and exercise-related comparisons in a male or non-Western sample. The current series of studies fills these gaps in the literature by translating and validating the existing measure of these comparisons (the 18-item Body, Eating, and Exercise Comparison Orientation Measure [BEECOM]) in samples of Iranian men and women. In Studies 1 and 2, female (n = 284) and male (n = 302) participants completed the translated Farsi BEECOM. Scores were analyzed by exploratory factor analyses (EFA) revealing two different three factor, 15-item scale structures for men and women. In Studies 3 and 4, participants (female n = 384; male n = 253) completed measures of social comparison and psychological functioning in one session. These data were analyzed using confirmatory factor analyses (CFA) and Pearson correlations. Each CFA yielded adequately fitting models. Results support the use of two different 15-item Farsi BEECOM measures with women and men and highlight unique gender differences in social comparison tendencies. The resulting F-BEECOM demonstrates strong psychometric properties and will be a useful research tool in Iranian women and men. © 2020 Elsevier Ltd

Author Keywords
Iran;  Psychometrics;  Scale translation;  Social comparison

Document Type: Article
Publication Stage: Final
Source: Scopus

The effect of exposure to long working hours on stroke: A systematic review and meta-analysis from the WHO/ILO Joint Estimates of the Work-related Burden of Disease and Injury
(2020) Environment International, 142, art. no. 105746, .

Descatha, A.^a b c d , Sembajwe, G.^e , Pega, F.^f , Ujita, Y.^g , Baer, M.^h , Boccuni, F.ⁱ , Di Tecco, C.ⁱ , Duret, C.^b , Evanoff, B.A.^j , Gagliardi, D.ⁱ , Godderis, L.^k l , Kang, S.-K.^m , Kim, B.J.ⁿ , Li, J.^o , Magnusson Hanson, L.L.^p , Marinaccio, A.ⁱ , Ozguler, A.^h q , Pachito, D.^r , Pell, J.^s , Pico, F.^t , Ronchetti, M.ⁱ , Roquelaure, Y.^a , Rugulies, R.^u v w , Schouteden, M.^l , Siegrist, J.^x , Tsutsumi, A.^y , Iavicoli, S.ⁱ

^a UNIV Angers, CHU Angers, Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) – UMR_S 1085, Angers, F-49000, France
^b AP-HP (Paris Hospital), Occupational Health Unit, Poincaré University Hospital, Garches, France
^c Versailles St-Quentin Univ–Paris Saclay Univ (UVSQ), UMS 011, UMR-S 1168, France
^d Inserm, U1168 UMS 011, Villejuif, France
^e Department of Occupational Medicine Epidemiology and Prevention, Zucker School of Medicine at Hofstra University, Feinstein Institutes for Medical Research, Northwell HealthNY, United States
^f Environment, Climate Change and Health Department, World Health Organization, 20 Avenue Appia, Geneva 27, 1211, Switzerland
^g Labour Administration, Labour Inspection and Occupational Safety and Health Branch, International Labour Organization, Route des Morillons 4, Geneva, 1211, Switzerland
^h AP-HP (Paris Hospital), SAMU92, Poincaré University Hospital, Garches, France
ⁱ Inail, Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Via Fontana Candida 1, Monte Porzio Catone (Rome), 00078, Italy
^j Division of General Medical Sciences, Washington University School of Medicine, Campus Box 8005, 660 South Euclid Ave, St. Louis, MO 63110, United States
^k Environment and Health, Kapucijnenvoer 35 blok d – box 7001, Leuven, 3000, Belgium
^l IDEWE, External Service for Prevention and Protection at Work, Interleuvenlaan 58, Leuven, 3001, Belgium
^m Department of Occupational and Environmental Medicine, Gachon University Gil Medical Center, Incheon, South Korea
ⁿ Seoul National University Bundang Hospital, Bundang-gu, South Korea
^o Department of Environmental Health Sciences, Fielding School of Public Health, School of Nursing, University of California, Los Angeles, United States
^p Stress Research Institute, Stockholm University, Stockholm, Sweden
^q Inserm UMS 011, Villejuif, France
^r Núcleo de Avaliação de Tecnologias em Saúde, Hospital Sírio-Libanês, 142 Barata Ribeiro, Sao Paulo, Brazil
^s Hunter College Libraries, Social Work and Public Health Library, 2180 3rd Avenue, 110D, New York, NY 10035, United States
^t Neurology and Stroke Unit, Versailles Hospital, Le Chesnay, France
^u National Research Centre for the Working Environment, Lersø Parkallé 105, Copenhagen, DK-2100, Denmark
^v Department of Public Health, University of Copenhagen, Øster Farimagsgade 5, Copenhagen, DK-1014, Denmark
^w Department of Psychology, University of Copenhagen, Øster Farimagsgade 2A, Copenhagen, DK-1353, Denmark
^x Life Science Centre, University of Düsseldorf, Merowingerplatz 1a, Düsseldorf, 40225, Germany
^y Kitasato University School of Medicine, 1-15-1 Kitasato, Minami, Sagamihara 252-0374, Japan

Abstract
Background: The World Health Organization (WHO) and the International Labour Organization (ILO) are developing joint estimates of the work-related burden of disease and injury (WHO/ILO Joint Estimates), with contributions from a large network of individual experts. Evidence from mechanistic data and prior studies suggests that exposure to long working hours may cause stroke. In this paper, we present a systematic review and meta-analysis of parameters for estimating the number of deaths and disability-adjusted life years from stroke that are attributable to exposure to long working hours, for the development of the WHO/ILO Joint Estimates. Objectives: We aimed to systematically review and meta-analyse estimates of the effect of exposure to long working hours (three categories: 41–48, 49–54 and ≥55 h/week), compared with exposure to standard working hours (35–40 h/week), on stroke (three outcomes: prevalence, incidence, and mortality). Data sources: A protocol was developed and published, applying the Navigation Guide to systematic reviews as an organizing framework where feasible. We searched electronic databases for potentially relevant records from published and unpublished studies, including Ovid MEDLINE, PubMed, EMBASE, Scopus, Web of Science, CISDOC, PsycINFO, and WHO ICTRP. We also searched grey literature databases, Internet search engines, and organizational websites; hand-searched reference lists of previous systematic reviews; and consulted additional experts. Study eligibility and criteria: We included working-age (≥15 years) individuals in the formal and informal economy in any WHO and/or ILO Member State but excluded children (aged < 15 years) and unpaid domestic workers. We included randomized controlled trials, cohort studies, case-control studies and other non-randomized intervention studies with an estimate of the effect of exposure to long working hours (41–48, 49–54 and ≥55 h/week), compared with exposure to standard working hours (35–40 h/week), on stroke (prevalence, incidence or mortality). Study appraisal and synthesis methods: At least two review authors independently screened titles and abstracts against the eligibility criteria at a first review stage and full texts of potentially eligible records at a second stage, followed by extraction of data from qualifying studies. Missing data were requested from principal study authors. We combined relative risks using random-effects meta-analysis. Two or more review authors assessed the risk of bias, quality of evidence and strength of evidence, using the Navigation Guide and GRADE tools and approaches adapted to this project. Results: Twenty-two studies (20 cohort studies, 2 case-control studies) met the inclusion criteria, comprising a total of 839,680 participants (364,616 females) in eight countries from three WHO regions (Americas, Europe, and Western Pacific). The exposure was measured using self-reports in all studies, and the outcome was assessed with administrative health records (13 studies), self-reported physician diagnosis (7 studies), direct diagnosis by a physician (1 study) or during a medical interview (1 study). The outcome was defined as an incident non-fatal stroke event in nine studies (7 cohort studies, 2 case-control studies), incident fatal stroke event in one cohort study and incident non-fatal or fatal (“mixed”) event in 12 studies (all cohort studies). Cohort studies were judged to have a relatively low risk of bias; therefore, we prioritized evidence from these studies, but synthesised evidence from case-control studies as supporting evidence. For the bodies of evidence for both outcomes with any eligible studies (i.e. stroke incidence and mortality), we did not have serious concerns for risk of bias (at least for the cohort studies). Eligible studies were found on the effects of long working hours on stroke incidence and mortality, but not prevalence. Compared with working 35–40 h/week, we were uncertain about the effect on incidence of stroke due to working 41–48 h/week (relative risk (RR) 1.04, 95% confidence interval (CI) 0.94–1.14, 18 studies, 277,202 participants, I2 0%, low quality of evidence). There may have been an increased risk for acquiring stroke when working 49–54 h/week compared with 35–40 h/week (RR 1.13, 95% CI 1.00–1.28, 17 studies, 275,181participants, I2 0%, p 0.04, moderate quality of evidence). Compared with working 35–40 h/week, working ≥55 h/week may have led to a moderate, clinically meaningful increase in the risk of acquiring stroke, when followed up between one year and 20 years (RR 1.35, 95% CI 1.13 to 1.61, 7 studies, 162,644 participants, I2 3%, moderate quality of evidence). Compared with working 35–40 h/week, we were very uncertain about the effect on dying (mortality) of stroke due to working 41–48 h/week (RR 1.01, 95% CI 0.91–1.12, 12 studies, 265,937 participants, I2 0%, low quality of evidence), 49–54 h/week (RR 1.13, 95% CI 0.99–1.29, 11 studies, 256,129 participants, I2 0%, low quality of evidence) and 55 h/week (RR 1.08, 95% CI 0.89–1.31, 10 studies, 664,647 participants, I2 20%, low quality of evidence). Subgroup analyses found no evidence for differences by WHO region, age, sex, socioeconomic status and type of stroke. Sensitivity analyses found no differences by outcome definition (exclusively non-fatal or fatal versus “mixed”) except for the comparison working ≥55 h/week versus 35–40 h/week for stroke incidence (p for subgroup differences: 0.05), risk of bias (“high”/“probably high” ratings in any domain versus “low”/“probably low” in all domains), effect estimate measures (risk versus hazard versus odds ratios) and comparator (exact versus approximate definition). Conclusions: We judged the existing bodies of evidence for human evidence as “inadequate evidence for harmfulness” for all exposure categories for stroke prevalence and mortality and for exposure to 41–48 h/week for stroke incidence. Evidence on exposure to 48–54 h/week and ≥55 h/week was judged as “limited evidence for harmfulness” and “sufficient evidence for harmfulness” for stroke incidence, respectively. Producing estimates for the burden of stroke attributable to exposures to working 48–54 and ≥55 h/week appears evidence-based, and the pooled effect estimates presented in this systematic review could be used as input data for the WHO/ILO Joint Estimates. Protocol identifier: https://doi.org/10.1016/j.envint.2018.06.016. PROSPERO registration number: CRD42017060124. © 2020, World Health Organization and International Labour Organization

Author Keywords
Global Burden of Disease;  Long working hours;  Meta-analysis;  Occupational;  Stroke;  Systematic review

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Cadmium activates AMPA and NMDA receptors with M3 helix cysteine substitutions
(2020) Journal of General Physiology, 152 (7), art. no. e201912537, .

Wilding, T.J., Huettner, J.E.

Department of Cell Biology and Physiology, Washington University Medical School, St. Louis, MO, United States

Abstract
AMPA and NMDA receptors are ligand-gated ion channels that depolarize postsynaptic neurons when activated by the neurotransmitter L-glutamate. Changes in the distribution and activity of these receptors underlie learning and memory, but excessive change is associated with an array of neurological disorders, including cognitive impairment, developmental delay, and epilepsy. All of the ionotropic glutamate receptors (iGluRs) exhibit similar tetrameric architecture, transmembrane topology, and basic framework for activation; conformational changes induced by extracellular agonist binding deform and splay open the inner helix bundle crossing that occludes ion flux through the channel. NMDA receptors require agonist binding to all four subunits, whereas AMPA and closely related kainate receptors can open with less than complete occupancy. In addition to conventional activation by agonist binding, we recently identified two locations along the inner helix of the GluK2 kainate receptor subunit where cysteine (Cys) substitution yields channels that are opened by exposure to cadmium ions, independent of agonist site occupancy. Here, we generate AMPA and NMDA receptor subunits with homologous Cys substitutions and demonstrate similar activation of the mutant receptors by Cd. Coexpression of the auxiliary subunit stargazin enhanced Cd potency for activation of Cys-substituted GluA1 and altered occlusion upon treatment with sulfhydryl-reactive MTS reagents. Mutant NMDA receptors displayed voltage-dependent Mg block of currents activated by agonist and/or Cd as well as asymmetry between Cd effects on Cys-substituted GluN1 versus GluN2 subunits. In addition, Cd activation of each Cys-substituted iGluR was inhibited by protons. These results, together with our earlier work on GluK2, reveal a novel mechanism shared among the three different iGluR subtypes for prying open the gate that controls ion entry into the pore. © 2020 Wilding and Huettner. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Oliceridine and its potential to revolutionize GI endoscopy sedation
(2020) Saudi Journal of Anaesthesia, 14 (3), pp. 349-354.

Goudra, B.^a , Singh, P.^b

^a Anesthesiology and Critical Care Medicine, Perelman School of Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, United States
^b Department of Anesthesiology, Washington University in Saint Louis, 660 South Euclid Avenue, St Louis, MO, United States

Abstract
Providing sedation to patients undergoing gastrointestinal (GI) endoscopy is a controversial and emotive issue. The mainstay of sedation is propofol, whose administration is within the sole jurisdiction of anesthesia providers, at least in the USA. Attempts have been made to seize the authority by the GI community. One of the first attempts was the use of the prodrug of propofol -fospropofol. However, as the drug has a similar adverse effect profile as propofol in terms of respiratory depression, the FDA did not approve its use by providers other than those trained in airway management. Sedasys® was the next attempt, which was a computer-assisted personalized sedation system. As a result of insufficient sedation that could be provided with the device, although very successful in research settings, it was not a commercial success. It seems that remimazolam is the next effort in this direction. It is likely to fail in this regard unless its respiratory depressant properties and failure rates could be addressed. G protein-biased µ-receptor agonists are a new class of opioids exhibiting analgesic properties similar to morphine without equivalent respiratory depressant properties. Oliceridine is the prototype. As a result, the drug can be additive to midazolam or remimazolam and allow screening colonoscopy to be comfortably completed without the need for propofol. For an anesthesia provider, the administration of oliceridine can eliminate the need for drugs such as fentanyl that add to the respiratory depressant properties of propofol. As a result, oliceridine has the potential to render the sedation for GI endoscopy procedures both safe and cost-effective. © 2020 Wolters Kluwer Medknow Publications. All rights reserved.

Author Keywords
Endoscopy;  oliceridine;  propofol;  remimazolam;  sedation

Document Type: Review
Publication Stage: Final
Source: Scopus

Tempo and Pattern of Avian Brain Size Evolution
(2020) Current Biology, 30 (11), pp. 2026-2036.e3.

Ksepka, D.T.^a b c d , Balanoff, A.M.^e f , Smith, N.A.^c g , Bever, G.S.^f h , Bhullar, B.-A.S.ⁱ , Bourdon, E.^j , Braun, E.L.^k , Burleigh, J.G.^k , Clarke, J.A.^l , Colbert, M.W.^l , Corfield, J.R.^m , Degrange, F.J.ⁿ , De Pietri, V.L.^o , Early, C.M.^p q , Field, D.J.^r , Gignac, P.M.^s , Gold, M.E.L.^f t , Kimball, R.T.^u , Kawabe, S.^v , Lefebvre, L.^w , Marugán-Lobón, J.^x y , Mongle, C.S.^z , Morhardt, A.^aa , Norell, M.A.^f , Ridgely, R.C.^ab , Rothman, R.S.^ac , Scofield, R.P.^o , Tambussi, C.P.ⁿ , Torres, C.R.^ad , van Tuinen, M.^ae , Walsh, S.A.^af , Watanabe, A.^f ag ah , Witmer, L.M.^ab , Wright, A.K.^ai , Zanno, L.E.^aj ak , Jarvis, E.D.^al am , Smaers, J.B.^z an

^a Bruce Museum, GreenwichCT 06830, United States
^b Department of Ornithology, American Museum of Natural History, New York, NY 10024, United States
^c Division of Science and Education, Field Museum of Natural History, Chicago, IL 60605, United States
^d Department of Paleobiology, Smithsonian Institution, Washington, DC 20013, United States
^e Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218, United States
^f Division of Paleontology, American Museum of Natural History, New York, NY 10024, United States
^g Campbell Geology Museum, Clemson University, Clemson, SC 29634, United States
^h Center for Functional Anatomy and Evolution, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
ⁱ Department of Geology & Geophysics and Peabody Museum of Natural History, Yale University, New Haven, CT 06511, United States
^j UMR 7205 Laboratoire Informatique et Systématique, Muséum National d’Histoire Naturelle, Paris, 75005, France
^k Department of Biology, University of Florida, Gainesville, FL 32611, United States
^l The Jackson School of Geosciences, The University of Texas at Austin, Austin, TX 78712, United States
^m Salisbury University, Salisbury, MD 28101, United States
ⁿ Centro de Investigaciones en Ciencias de la Tierra, UNC, CONICET, Córdoba, X5016GCA, Argentina
^o Canterbury Museum, Christchurch, 8013, New Zealand
^p Department of Biological Sciences, Ohio University, OH, Athens 45701, United States
^q Florida Museum of Natural History, University of Florida, Gainesville, FL 32611, United States
^r Department of Earth Sciences, University of Cambridge, Cambridge, CB2 3EQ, United Kingdom
^s Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, United States
^t Biology Department, Suffolk University, Boston, MA 02108, United States
^u Department of Anatomical Sciences, Stony Brook University, Stony Brook, NY 11794, United States
^v Fukui Prefectural Dinosaur Museum, 51-11 Terao, Muroko, Katsuyama, Fukui, 911-8601, Japan
^w Department of Biology, McGill University, Montréal, QC H3A 0G4, Canada
^x Departamento de Biología, Universidad Autónoma de Madrid, Madrid, 28049, Spain
^y Dinosaur Institute, Natural History Museum of Los Angeles, Los Angeles, CA 90007, United States
^z Division of Anthropology, American Museum of Natural History, New York, NY 10024, United States
^aa Washington University School of Medicine in St. Louis, St. Louis, MO 06130, United States
^ab Department of Biomedical Sciences, Ohio University Heritage College of Osteopathic Medicine, Ohio Center for Ecology and Evolutionary Studies, Athens, OH, 45701, United States
^ac Interdepartmental Doctoral Program in Anthropological Sciences, Stony Brook University, Stony Brook, NY 11794, United States
^ad Department of Integrative Biology, University of Texas at Austin, Austin, TX 78712, United States
^ae Department of Otorhinolaryngology, University Medical Center, Groningen, 9713, Netherlands
^af National Museum of Scotland, Edinburgh, EH1 1JF, United Kingdom
^ag Department of Anatomy, New York Institute of Technology, College of Osteopathic Medicine, Old Westbury, NY 11568, United States
^ah Life Sciences Department, Vertebrates Division, Natural History Museum, London, SW7 5BD, United Kingdom
^ai Sea Mammal Research Unit, University of St Andrews, St Andrews, KY16 9XL, United Kingdom
^aj Paleontology, North Carolina Museum of Natural Sciences, Raleigh, NC 27601, United States
^ak Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695, United States
^al The Rockefeller University, New York, NY 10065, United States
^am The Howard Hughes Medical Institute, Chevy Chase, MD 20815, United States
^an Department of Anthropology, Stony Brook University, Stony Brook, NY 11794, United States

Abstract
Relative brain sizes in birds can rival those of primates, but large-scale patterns and drivers of avian brain evolution remain elusive. Here, we explore the evolution of the fundamental brain-body scaling relationship across the origin and evolution of birds. Using a comprehensive dataset sampling> 2,000 modern birds, fossil birds, and theropod dinosaurs, we infer patterns of brain-body co-variation in deep time. Our study confirms that no significant increase in relative brain size accompanied the trend toward miniaturization or evolution of flight during the theropod-bird transition. Critically, however, theropods and basal birds show weaker integration between brain size and body size, allowing for rapid changes in the brain-body relationship that set the stage for dramatic shifts in early crown birds. We infer that major shifts occurred rapidly in the aftermath of the Cretaceous-Paleogene mass extinction within Neoaves, in which multiple clades achieved higher relative brain sizes because of a reduction in body size. Parrots and corvids achieved the largest brains observed in birds via markedly different patterns. Parrots primarily reduced their body size, whereas corvids increased body and brain size simultaneously (with rates of brain size evolution outpacing rates of body size evolution). Collectively, these patterns suggest that an early adaptive radiation in brain size laid the foundation for subsequent selection and stabilization. © 2020 Elsevier Inc.

Ksepka et al. reconstruct brain-body scaling in a study of >2,000 birds and non-avian dinosaurs. Their results show that avian brain size evolution was profoundly impacted by the K-Pg mass extinction, in the aftermath of which many clades achieved larger relative brain sizes via body size reduction. © 2020 Elsevier Inc.

Author Keywords
allometry;  aves;  co-variation;  encephalization;  endocast;  neurobiology;  paleontology

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Functions of Gtf2i and Gtf2ird1 in the developing brain: transcription, DNA binding and long-term behavioral consequences
(2020) Human Molecular Genetics, 29 (9), pp. 1498-1519.

Kopp, N.D.^a b , Nygaard, K.R.^a b , Liu, Y.^a b , McCullough, K.B.^a b , Maloney, S.E.^b c , Gabel, H.W.^d , Dougherty, J.D.^a b c

^a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
^c Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63110, USA
^d Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110, USA

Abstract
Gtf2ird1 and Gtf2i are two transcription factors (TFs) among the 28 genes deleted in Williams syndrome, and prior mouse models of each TF show behavioral phenotypes. Here we identify their genomic binding sites in the developing brain and test for additive effects of their mutation on transcription and behavior. GTF2IRD1 binding targets were enriched for transcriptional and chromatin regulators and mediators of ubiquitination. GTF2I targets were enriched for signal transduction proteins, including regulators of phosphorylation and WNT. Both TFs are highly enriched at promoters, strongly overlap CTCF binding and topological associating domain boundaries and moderately overlap each other, suggesting epistatic effects. Shared TF targets are enriched for reactive oxygen species-responsive genes, synaptic proteins and transcription regulators such as chromatin modifiers, including a significant number of highly constrained genes and known ASD genes. We next used single and double mutants to test whether mutating both TFs will modify transcriptional and behavioral phenotypes of single Gtf2ird1 mutants, though with the caveat that our Gtf2ird1 mutants, like others previously reported, do produce low levels of a truncated protein product. Despite little difference in DNA binding and transcriptome-wide expression, homozygous Gtf2ird1 mutation caused balance, marble burying and conditioned fear phenotypes. However, mutating Gtf2i in addition to Gtf2ird1 did not further modify transcriptomic or most behavioral phenotypes, suggesting Gtf2ird1 mutation alone was sufficient for the observed phenotypes. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Document Type: Article
Publication Stage: Final
Source: Scopus

Transcriptional profiling of multiple system atrophy cerebellar tissue highlights differences between the parkinsonian and cerebellar sub-types of the disease
(2020) Acta Neuropathologica Communications, 8 (1), p. 76.

Piras, I.S.^a , Bleul, C.^a , Schrauwen, I.^a b , Talboom, J.^a , Llaci, L.^a c , De Both, M.D.^a , Naymik, M.A.^a , Halliday, G.^d , Bettencourt, C.^e , Holton, J.L.^e , Serrano, G.E.^f , Sue, L.I.^f , Beach, T.G.^f , Stefanova, N.^g , Huentelman, M.J.^a

^a Neurogenomics Division, Translational Genomics Research Institute, AZ, Phoenix, United States
^b Present Address: Department of Neurology, Center for Statistical Genetics, Gertrude H. Sergievsky Center, Columbia University Medical Center, 630 W 168th St, NY, NY 10032, United States
^c Present address: Division of Biology and Biomedical Sciences, Molecular Genetics and Genomics Program, Washington University in St. Louis, St. Louis, MO, 63110, USA
^d University of Sydney Brain and Mind Centre and Faculty of Medicine and Health, School of Medical Science, Neuroscience Research Australia, Sydney, Australia
^e Queen Square Brain Bank for Neurological Disorders and Department of Clinical and Movement Neurosciences ,UCL Queen Square Institute of Neurology, London, United Kingdom
^f Civin Laboratory of Neuropathology at Banner Sun Health Research Institute, AZ, Sun City, 85351, United States
^g Department of Neurology, Division of Neurobiology, Medical University of Innsbruck, Innsbruck, Austria

Abstract
Multiple system atrophy (MSA) is a rare adult-onset neurodegenerative disease of unknown cause, with no effective therapeutic options, and no cure. Limited work to date has attempted to characterize the transcriptional changes associated with the disease, which presents as either predominating parkinsonian (MSA-P) or cerebellar (MSC-C) symptoms. We report here the results of RNA expression profiling of cerebellar white matter (CWM) tissue from two independent cohorts of MSA patients (n = 66) and healthy controls (HC; n = 66). RNA samples from bulk brain tissue and from oligodendrocytes obtained by laser capture microdissection (LCM) were sequenced. Differentially expressed genes (DEGs) were obtained and were examined before and after stratifying by MSA clinical sub-type.We detected the highest number of DEGs in the MSA-C group (n = 747) while only one gene was noted in MSA-P, highlighting the larger dysregulation of the transcriptome in the MSA-C CWM. Results from both bulk tissue and LCM analysis showed a downregulation of oligodendrocyte genes and an enrichment for myelination processes with a key role noted for the QKI gene. Additionally, we observed a significant upregulation of neuron-specific gene expression in MSA-C and enrichment for synaptic processes. A third cluster of genes was associated with the upregulation of astrocyte and endothelial genes, two cell types with a key role in inflammation processes. Finally, network analysis in MSA-C showed enrichment for β-amyloid related functional classes, including the known Alzheimer’s disease (AD) genes, APP and PSEN1.This is the largest RNA profiling study ever conducted on post-mortem brain tissue from MSA patients. We were able to define specific gene expression signatures for MSA-C highlighting the different stages of the complex neurodegenerative cascade of the disease that included alterations in several cell-specific transcriptional programs. Finally, several results suggest a common transcriptional dysregulation between MSA and AD-related genes despite the clinical and neuropathological distinctions between the two diseases.

Author Keywords
Multiple system atrophy;  Neurodegeneration;  Oligodendrocytes;  RNA sequencing

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Top Ten Tips Palliative Care Clinicians Should Know About Amyotrophic Lateral Sclerosis
(2020) Journal of Palliative Medicine, 23 (6), pp. 842-847.

^a John T. Milliken Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Icahn School of Medicine at Mount SinaiNY, United States
^c Department of Neurology, Hennepin Healthcare, Minneapolis, MN, United States
^d Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^e Department of Supportive Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^f Department of Medicine, University of California, Los Angeles, CA, United States
^g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States

Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder with enormous palliative care (PC) needs that begin at the time of diagnosis. Although it is an uncommon disease, clinicians who work in PC or hospice are likely to encounter ALS somewhat frequently given the needs of patients with ALS with regard to psychosocial support, symptom management, advance care planning (ACP), caregiver support, and end-of-life care. As such, PC clinicians should be familiar with the basic principles of ALS symptoms, treatments, disease course, and issues around ACP. This article, written by a team of neurologists and PC physicians, seeks to provide PC clinicians with tips to improve their comfort and skills caring for patients with ALS and their families.

Author Keywords
ALS;  amyotrophic lateral sclerosis;  hospice;  palliative care;  symptom control

Document Type: Article
Publication Stage: Final
Source: Scopus

Accuracy of Dopamine Transporter Imaging with 123I-Ioflupane in Hispanic and Non-Hispanic Patients
(2020) Journal of Nuclear Medicine Technology, 48 (2), pp. 154-157.

Lundeen, T.F.^a , Covington, M.^b , Krupinski, E.A.^c , Avery, R.^d , Lei, H.^e , Sherman, S.J.^e , Kuo, P.H.^f g

^a Department of Medical Imaging, University of Arizona/Banner University Medical Center, Tucson, AZ, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia
^d Northwestern University, Chicago, IL, Mexico
^e Department of Neurology, University of Arizona/Banner University Medical Center, Tucson, Arizona; and
^f Department of Medical Imaging, University of Arizona/Banner University Medical Center, Tucson, AZ, United States
^g Departments of Medicine and Biomedical Engineering, University of Arizona, Tucson, AZ, United States

Abstract
Racial and ethnic disparities in the prevalence of neurodegenerative diseases exist. This study examined the agreement between gold standard diagnosis and visual assessment of dopamine transporter (DaT) imaging in Hispanic and non-Hispanic patients being evaluated for Parkinsonian syndromes (PS). Methods: A retrospective review of DaT imaging and demographic data was performed with institutional review board approval. Documented interpretation by visual assessment was used to classify scans as normal or abnormal. The gold standard for the final diagnosis of PS was determined by a neurologist after 2 or more years of clinical follow-up. Data were analyzed with a z-test for uncorrelated samples. Results: In 30 Hispanic patients, DaT imaging was abnormal in 17, normal in 12, and nondiagnostic in 1. Of those with abnormal imaging, PS was confirmed in 16 of 17. Of those with normal imaging, no PS was confirmed in any patient. Sensitivity was 100%, and specificity was 92%. The single patient with nondiagnostic imaging was excluded. Of 77 non-Hispanic patients, visual assessment of DaT imaging was abnormal in 51. Of those with abnormal imaging, PS was confirmed in 48 of 51. Of those with normal imaging, no PS was confirmed in 22 of 26. Sensitivity was 92%, and specificity was 88%. There was no statistically significant difference (z = 0.34) in the rates of agreement between the gold standard and DaT imaging in Hispanic versus non-Hispanic patients. The study sample size afforded a power of 0.60. Conclusion: No significant difference was found in the accuracy of DaT imaging between Hispanic and non-Hispanic patients. Accuracy was high for both groups. © 2020 by the Society of Nuclear Medicine and Molecular Imaging.

Author Keywords
123I-ioflupane;  dopamine transporter imaging;  ethnic disparity;  Hispanic;  Parkinsonian syndrome

Document Type: Article
Publication Stage: Final
Source: Scopus

Burden of cerebral hypoperfusion in patients with delayed cerebral ischemia after subarachnoid hemorrhage
(2020) Journal of Neurosurgery, 132 (6), pp. 1872-1879.

Jafri, H.^b , Diringer, M.N.^a , Allen, M.^a , Zazulia, A.R.^a b , Zipfel, G.J.^c , Dhar, R.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) may result in focal neurological deficits and cerebral infarction, believed to result from critical regional rather than global impairments in cerebral blood flow (CBF). However, the burden of such regional hypoperfusion has not been evaluated by gold-standard voxel-by-voxel CBF measurements. Specifically, the authors sought to determine whether the proportion of brain affected by hypoperfusion was greater in patients with DCI than in SAH controls without DCI and whether the symptomatic hemisphere (in those with lateralizing deficits) exhibited a greater cerebral hypoperfusion burden. Methods: Sixty-one patients with aneurysmal SAH underwent 15O PET to measure regional CBF during the period of risk for DCI (median 8 days after SAH, IQR 7-10 days). Regions of visibly abnormal brain on head CT studies, including areas of hemorrhage and infarction, were excluded. Burden of hypoperfusion was defined as the proportion of PET voxels in normal-appearing brain with CBF < 25 ml/100 g/min. Global CBF and hypoperfusion burden were compared between patients with and those without DCI at the time of PET. For patients with focal impairments from DCI, the authors also compared average CBF and hypoperfusion burden in symptomatic versus asymptomatic hemispheres. Results: Twenty-three patients (38%) had clinical DCI at the time of PET. Those with DCI had higher mean arterial pressure (MAP; 126 ± 14 vs 106 ± 12 mm Hg, p < 0.001) and 18 (78%) were on vasopressor therapy at the time of PET study. While global CBF was not significantly lower in patients with DCI (mean 39.4 ± 11.2 vs 43.0 ± 8.3 ml/100 g/min, p = 0.16), the burden of hypoperfusion was greater (20%, IQR 12%-23%, vs 12%, 9%-16%, p = 0.006). Burden of hypoperfusion performed better than global CBF as a predictor of DCI (area under the curve 0.71 vs 0.65, p = 0.044). Neither global CBF nor hypoperfusion burden differed in patients who responded to therapy compared to those who had not improved by the time of PET. Although hemispheric CBF was not lower in the symptomatic versus contralateral hemisphere in the 13 patients with focal deficits, there was a trend toward greater burden of hypoperfusion in the symptomatic hemisphere (21% vs 18%, p = 0.049). Conclusions: The burden of hypoperfusion was greater in patients with DCI, despite hemodynamic therapies, higher MAP, and equivalent global CBF. Similarly, hypoperfusion burden was greater in the symptomatic hemisphere of DCI patients with focal deficits even though the average CBF was similar to that in the contralateral hemisphere. Evaluating the proportion of the brain with critical hypoperfusion after SAH may better capture the extent of DCI than averaging CBF across heterogenous brain regions. © AANS 2020, except where prohibited by US copyright law.

Author Keywords
Cerebral blood flow;  Delayed cerebral ischemia;  Subarachnoid hemorrhage;  Vascular disorders

Document Type: Article
Publication Stage: Final
Source: Scopus

Circulating Insulin-Like Growth Factor-1 Is Positively Associated with Growth and Cognition in 6- to 9-Year-Old Schoolchildren from Ghana
(2020) The Journal of Nutrition, 150 (6), pp. 1405-1412.

Grenov, B.^a , Larnkjær, A.^a , Lee, R.^b , Serena, A.^c , Mølgaard, C.^a , Michaelsen, K.F.^a , Manary, M.J.^b d e

^a Department of Nutrition, Exercise, Sports, University of Copenhagen, Frederiksberg C, Denmark
^b Department of Pediatrics, Washington University, St Louis, MO, USA
^c Global Nutrition, Arla Foods amba, Skejby, Denmark
^d School of Public Health and Family Medicine, College of Medicine, University of Malawi, Blantyre, Malawi
^e Children’s Nutrition Research Center, Baylor College of Medicine, TX, Houston, United States

Abstract
BACKGROUND: Milk intake stimulates linear growth and improves cognition in children from low-income countries. These effects may be mediated through insulin-like growth factor-1 (IGF-1). OBJECTIVE: The objective was to assess the effect of milk supplement on circulating IGF-1 and to assess IGF-1 as a correlate of growth and cognition in children. METHODS: Secondary data on blood spot IGF-1 from a randomized, double-blind, controlled trial in 6-9-y-old children from rural Ghana were analyzed. Intervention groups received porridge with non-energy-balanced supplements: 8.8 g milk protein/d, 100 kcal/d (Milk8); 4.4 g milk and 4.4 g rice protein/d, 100 kcal/d (Milk/rice); 4.4 g milk protein/d, 48 kcal/d (Milk4); or a control (no protein, 10 kcal/d). IGF-1, length, body composition, and Cambridge Neuropsychological Test Automated Battery (CANTAB) were measured at 3.5 or 8.5 mo. Linear regressions were used to assess the effect of milk interventions on IGF-1 and IGF-1 as a correlate of growth and cognition. RESULTS: The increase in IGF-1 was 15.3 (95% CI: 3.3, 27.3) ng/mL higher in children receiving Milk8 compared with the control. The IGF-1 increases in the isonitrogenous, isoenergetic Milk/rice or the Milk4 groups were not different from the control (P ≥ 0.49). The increase in IGF-1 was associated with improvements in 4 out of 5 CANTAB domains. The strongest associations included reductions in “mean correct latency” from Pattern Recognition Memory and “pre-extradimensional (pre-ED) shift errors” from Intra/Extradimensional Set Shift (P ≤ 0.005). In addition, change in IGF-1 was positively associated with changes in height, weight, and fat-free mass (P ≤ 0.001). CONCLUSIONS: Intake of skimmed milk powder corresponding to one, but not half a glass of milk on school days stimulates IGF-1 in 6-9-y-old Ghanian children. IGF-1 seems to mediate the effect of milk intake on growth and cognition. The association between IGF-1 and cognition in relation to milk intake is novel and opens possibilities for dietary interventions to improve cognition. Copyright © The Author(s) 2020.

Author Keywords
Africa;  children;  cognition;  growth;  insulin-like growth factor-1 (IGF-1);  low-income country;  milk

Document Type: Article
Publication Stage: Final
Source: Scopus

Temporal Patterns of Emergence and Spatial Distribution of Sulcal Pits During Fetal Life
(2020) Cerebral Cortex (New York, N.Y. : 1991), 30 (7), pp. 4257-4268.

Yun, H.J.^a b , Vasung, L.^a b , Tarui, T.^c d , Rollins, C.K.^e , Ortinau, C.M.^f , Grant, P.E.^a b , Im, K.^a b

^a Fetal Neonatal Neuroimaging and Developmental Science Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^b Division of Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^c Mother Infant Research Institute, Tufts University School of Medicine, Tufts Medical Center, Boston, United States
^d Department of Pediatrics, Tufts University School of Medicine, Tufts Medical Center, Boston, United States
^e Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^f Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, USA

Abstract
Sulcal pits are thought to represent the first cortical folds of primary sulci during neurodevelopment. The uniform spatial distribution of sulcal pits across individuals is hypothesized to be predetermined by a human-specific protomap which is related to functional localization under genetic controls in early fetal life. Thus, it is important to characterize temporal and spatial patterns of sulcal pits in the fetal brain that would provide additional information of functional development of the human brain and crucial insights into abnormal cortical maturation. In this paper, we investigated temporal patterns of emergence and spatial distribution of sulcal pits using 48 typically developing fetal brains in the second half of gestation. We found that the position and spatial variance of sulcal pits in the fetal brain are similar to those in the adult brain, and they are also temporally uniform against dynamic brain growth during fetal life. Furthermore, timing of pit emergence shows a regionally diverse pattern that may be associated with the subdivisions of the protomap. Our findings suggest that sulcal pits in the fetal brain are useful anatomical landmarks containing detailed information of functional localization in early cortical development and maintaining their spatial distribution throughout the human lifetime. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

Author Keywords
brain development;  cortical sulci;  fetal brain;  first folds;  sulcal pattern

Document Type: Article
Publication Stage: Final
Source: Scopus

Antidepressants, Pregnancy, and Autism: Setting the Record(s) Straight
(2020) The American Journal of Psychiatry, 177 (6), pp. 479-481.

Maloney, S.E., Rogers, C.E., Constantino, J.N.

Department of Psychiatry, Intellectual and Developmental Disabilities Research Center (Maloney, Department of Pediatrics (Rogers, Washington University School of Medicine, Rogers, Saint Louis, Seychelles

Author Keywords
Antidepressants;  Autism;  Prenatal Anxiety;  Prenatal Depression

Document Type: Editorial
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Sleep Onset Problems and Subcortical Development in Infants Later Diagnosed With Autism Spectrum Disorder
(2020) The American Journal of Psychiatry, 177 (6), pp. 518-525.

MacDuffie, K.E., Shen, M.D., Dager, S.R., Styner, M.A., Kim, S.H., Paterson, S., Pandey, J., St John, T., Elison, J.T., Wolff, J.J., Swanson, M.R., Botteron, K.N., Zwaigenbaum, L., Piven, J., Estes, A.M.

Department of Speech and Hearing Sciences (MacDuffie, St. John, Estes), and Department of Radiology (Dager), University of Washington, Seattle; Department of Psychiatry (Shen, Styner, Kim), Biomedical Research Imaging Center (Styner), and Neurodevelopmental Research Center (Piven), University of North Carolina Chapel Hill; Department of Psychology, Temple University, Philadelphia (Paterson); Department of Child Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia (Pandey); Institute of Child Development (Elison), Department of Educational Psychology (Wolff), University of Minnesota, Minneapolis; Department of Behavioral and Brain Sciences, University of Texas at Dallas (Swanson); Department of Child Psychiatry, Washington University School of Medicine in St. Louis (Botteron); and Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada (Zwaigenbaum)

Abstract
OBJECTIVE: Sleep patterns in children with autism spectrum disorder (ASD) appear to diverge from typical development in the second or third year of life. Little is known, however, about the occurrence of sleep problems in infants who later develop ASD and possible effects on early brain development. In a longitudinal neuroimaging study of infants at familial high or low risk for ASD, parent-reported sleep onset problems were examined in relation to subcortical brain volumes in the first 2 years of life. METHODS: A total of 432 infants were included across three study groups: infants at high risk who developed ASD (N=71), infants at high risk who did not develop ASD (N=234), and infants at low risk (N=127). Sleep onset problem scores (derived from an infant temperament measure) were evaluated in relation to longitudinal high-resolution T1 and T2 structural imaging data acquired at 6, 12, and 24 months of age. RESULTS: Sleep onset problems were more common at 6-12 months among infants who later developed ASD. Infant sleep onset problems were related to hippocampal volume trajectories from 6 to 24 months only for infants at high risk who developed ASD. Brain-sleep relationships were specific to the hippocampus; no significant relationships were found with volume trajectories of other subcortical structures examined (the amygdala, caudate, globus pallidus, putamen, and thalamus). CONCLUSIONS: These findings provide initial evidence that sleep onset problems in the first year of life precede ASD diagnosis and are associated with altered neurodevelopmental trajectories in infants at high familial risk who go on to develop ASD. If replicated, these findings could provide new insights into a potential role of sleep difficulties in the development of ASD.

Author Keywords
Autism Spectrum Disorder;  Infants;  Sleep Problems. Development

Document Type: Article
Publication Stage: Final
Source: Scopus

Augmenting Computerized Cognitive Training With Vortioxetine for Age-Related Cognitive Decline: A Randomized Controlled Trial
(2020) The American Journal of Psychiatry, 177 (6), pp. 548-555.

Lenze, E.J., Stevens, A., Waring, J.D., Pham, V.T., Haddad, R., Shimony, J., Miller, J.P., Bowie, C.R.

Healthy Mind Lab, Department of Psychiatry (Lenze, Stevens, Pham, Haddad), Department of Radiology (Shimony), and Division of Biostatistics (Miller), Washington University School of Medicine, St. Louis; Department of Psychology, St. Louis University, St. Louis (Waring); and Department of Psychology, Queen’s University, Kingston, Ontario (Bowie)

Abstract
OBJECTIVE: Age-related cognitive decline, the deterioration in functions such as memory and executive function, is faced by most older adults and affects function and quality of life. No approved treatments exist for age-related cognitive decline. Computerized cognitive training has been shown to provide consistent albeit modest improvements in cognitive function as measured by neuropsychological testing. Vortioxetine, an antidepressant medication, has putative procognitive and proneuroplastic properties and therefore may be able to augment cognitive training. In this placebo-controlled study, the authors tested the cognitive benefits of vortioxetine added to cognitive training for adults age 65 or older with age-related cognitive decline. METHODS: After a 2-week lead-in period of cognitive training, 100 participants were randomly assigned to receive either vortioxetine or placebo in addition to cognitive training for 26 weeks. The primary outcome measure was global cognitive performance, assessed by the NIH Toolbox Cognition Battery Fluid Cognition Composite. The secondary outcome measure was functional cognition, assessed by the UCSD Performance-Based Skills Assessment. All participants received motivational messaging and support from study staff to maximize adherence to the training. RESULTS: Participants who received vortioxetine with cognitive training showed a greater increase in global cognitive performance compared with those who received placebo with cognitive training. This separation was significant at week 12 but not at other assessment time points. Both groups showed improvement in the secondary outcome measure of functional cognition, with no significant difference between groups. CONCLUSIONS: Vortioxetine may be beneficial for age-related cognitive decline when combined with cognitive training. These findings provide new treatment directions for combating cognitive decline in older adults.

Author Keywords
Antidepressant;  Cognitive Decline;  Cognitive Interventions;  Cognitive Training;  Combination Strategies;  Neuroplasticity

Document Type: Article
Publication Stage: Final
Source: Scopus

Towards an Individual Differences Perspective in Mindfulness Training Research: Theoretical and Empirical Considerations
(2020) Frontiers in Psychology, 11, art. no. 818, .

Tang, R., Braver, T.S.

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

Abstract
A growing body of research indicates that mindfulness training can have beneficial effects on critical aspects of psychological well-being, cognitive function, and brain health. Although these benefits have been generalized to the population level, individual variability in observed effects of mindfulness training has not been systematically investigated. Research on other similar forms of psychological intervention demonstrates that individual differences are prominent in terms of intervention responsiveness and outcomes. Furthermore, individual characteristics such as personality traits have been shown to play a crucial role in influencing the effects of intervention. In light of these lines of evidence, we review representative work on individual differences in mindfulness training and advocate for an individual difference perspective in mindfulness training research. We discuss relevant empirical evidence of individual differences potentially influencing behavioral outcomes of mindfulness training, focusing on both cognitive function and psychological well-being. Finally, theoretical considerations and potentially fruitful research strategies and directions for studying individual differences in mindfulness training are discussed, including those involving cognitive neuroscience methods. © Copyright © 2020 Tang and Braver.

Author Keywords
disposition;  individual differences;  meditation;  mindfulness training;  personality traits;  personalized medicine;  precision medicine

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Clinical predictors of 3- and 6-month outcome for mild traumatic brain injury patients with a negative head CT scan in the emergency department: A TRACK-TBI pilot study
(2020) Brain Sciences, 10 (5), art. no. 269, .

Madhok, D.Y.^a , Yue, J.K.^b c , Sun, X.^d , Suen, C.G.^c e , Coss, N.A.^b c , Jain, S.^d , Manley, G.T.^b c , Cooper, S.R.^f , Dams-O’connor, K.^g , Gordon, W.A.^g , Hricik, A.J.^h , Lingsma, H.F.ⁱ , Maas, A.I.R.^j , Menon, D.K.^k , Okonkwo, D.O.^h , Mukherjee, P.^m , Morabito, D.J.^l , Puccio, A.M.^h , Schnyer, D.M.ⁿ , Taylor, S.R.^l , Valadka, A.B.^o , Vassar, M.J.^l , Yuh, E.L.^m , The TRACK-TBI Investigators^p

^a Department of Emergency Medicine and Neurology, University of California San Francisco, Suite 6A, 1001 Potrero Ave, Building 5, Suite 6A, San Francisco, CA 94110, United States
^b Department of Neurological Surgery, University of California San Francisco, 505 Parnassus Ave, Rm M779, San Francisco, CA 94143, United States
^c Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, 1001 Potrero Ave, Bldg. 1, Rm 101, San Francisco, CA 94110, United States
^d Department of Family Medicine and Public Health, University of California San Diego, 9500 Gilman Drive, San Diego, CA 92093, United States
^e Department of Neurology, University of Utah School of Medicine, 175 North Medical Drive East, Salt Lake City, UT 84132, United States
^f Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^h Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
ⁱ Department of Public Health, Erasmus Medical Center, Rotterdam, Netherlands
^j Department of Neurosurgery, University Hospital Antwerp, Edegem, Belgium
^k Division of Anaesthesia, University of Cambridge, Cambridge, United Kingdom
^l Department of Neurosurgery, University of California San Francisco, San Francisco, CA, United States
^m Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
ⁿ Department of Psychology, University of Texas, Austin, TX, United States
^o Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, United States

Abstract
Aconsiderable subset of mild traumatic brain injury (mTBI) patients fail to return to baseline functional status at or beyond 3 months postinjury. Identifying at-risk patients for poor outcome in the emergency department (ED) may improve surveillance strategies and referral to care. Subjects with mTBI (Glasgow Coma Scale 13–15) and negative ED initial head CT < 24 h of injury, completing 3- or 6-month functional outcome (Glasgow Outcome Scale-Extended; GOSE), were extracted from the prospective, multicenter Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot study. Outcomes were dichotomized to full recovery (GOSE = 8) vs functional deficits (GOSE < 8). Univariate predictors with p < 0.10 were considered for multivariable regression. Adjusted odds ratios (AOR) were reported for outcome predictors. Significance was assessed at p < 0.05. Subjects who completed GOSE at 3- and 6-month were 211 (GOSE < 8: 60%) and 185 (GOSE < 8: 65%). Risk factors for 6-month GOSE < 8 included less education (AOR = 0.85 per-year increase, 95% CI: (0.74–0.98)), prior psychiatric history (AOR = 3.75 (1.73–8.12)), Asian/minority race (American Indian/Alaskan/Hawaiian/Pacific Islander) (AOR = 23.99 (2.93–196.84)), and Hispanic ethnicity (AOR = 3.48 (1.29–9.37)). Risk factors for 3-month GOSE < 8 were similar with the addition of injury by assault predicting poorer outcome (AOR = 3.53 (1.17–10.63)). In mTBI patients seen in urban trauma center EDs with negative CT, education, injury by assault, Asian/minority race, and prior psychiatric history emerged as risk factors for prolonged disability. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Clinical predictors;  Emergency department;  Mild traumatic brain injury;  Outcome

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

What Does It Mean to Be Transdiagnostic and How Would We Know?
(2020) American Journal of Psychiatry, 177 (5), pp. 370-372. Cited 1 time.

Barch, D.M.

Departments of Psychological and Brain Sciences, Psychiatry, and Radiology, Washington University, St. Louis, United States

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Shedding light on thyroid hormone disorders and Parkinson disease pathology: mechanisms and risk factors
(2020) Journal of Endocrinological Investigation, .

Mohammadi, S.^a b , Dolatshahi, M.^a b , Rahmani, F.^c

^a Student’s Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran
^b NeuroImaging Network (NIN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
^c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Dopaminergic system is interconnected with the hypothalamic–pituitary–thyroid axis. Dopamine (DA) upregulates thyrotropin releasing hormone (TRH) while downregulating thyroid stimulating hormone (TSH) and thyroid hormones. Moreover, TRH stimulates DA release. PD is associated with impaired regulation of TSH and thyroid hormones (TH) levels, which in turn associate with severity and different subtypes of PD, while levodopa and bromocriptine treatment can interfere with hypothalamic–pituitary–thyroid axis. Thyroid disturbances, including hypothyroidism, Hashimoto’s thyroiditis (HT), hyperthyroidism and Graves’ disease (GD) not only increase the risk of PD but also share some clinical signs with PD. Also, several genes including RASD2, WSB1, MAPT, GIRK2, LRRK2 and gene products like neurotensin and NOX/DUOX affect the risk for both PD and thyroid disease. Hypothyroidism is associated with obesity, hypercholesterolemia, anemia and altered cerebral blood flow which are associated with PD pathology. Herein we provide a comprehensive view on the association between PD and thyroid hormones regulation and dysregulations, hoping to provide new avenues towards targeted treatment of PD. We performed a comprehensive search in literature using Pubmed and Scopus, yielding to a total number of 36 original articles that had addressed the association between thyroid hormone disorders and PD. © 2020, Italian Society of Endocrinology (SIE).

Author Keywords
Dopamine;  Parkinson’s disease;  Prolactin;  Thyroid

Document Type: Review
Publication Stage: Article in Press
Source: Scopus

Randomized Clinical Trial of First-Line Genome Sequencing in Pediatric White Matter Disorders
(2020) Annals of Neurology, .

Vanderver, A.^a b , Bernard, G.^c d e , Helman, G.^f g , Sherbini, O.^a , Boeck, R.^h i , Cohn, J.^j , Collins, A.^k , Demarest, S.^k , Dobbins, K.^l , Emrick, L.^m , Fraser, J.^n o , Masser-Frye, D.^p , Hayward, J.^q , Karmarkar, S.^r s , Keller, S.^t , Mirrop, S.^u v , Mitchell, W.^w , Pathak, S.^x y , Sherr, E.^z , van Haren, K.^aa , Waters, E.^ab , Wilson, J.L.^ac , Zhorne, L.^ad , Schiffmann, R.^ae , van der Knaap, M.S.^af ag , Pizzino, A.^a , Dubbs, H.^a , Shults, J.^ah , Simons, C.^f g , Taft, R.J.^ai , LeukoSEQ Workgroup^aj

^a Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^b Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^c Departments of Neurology and Neurosurgery, Pediatrics, and Human Genetics, McGill University, Montreal, QC, Canada
^d Department of Medical Genetics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC, Canada
^e Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
^f Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
^g Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, VIC, Australia
^h Child Neurology Consultants of Austin, Austin, TX, United States
ⁱ University of Texas at Austin Dell Medical School, Austin, TX, United States
^j Family Medicine, Broadlands Family Practice at Ashburn, Ashburn, VA, United States
^k Department of Neurology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO, United States
^l Walter Reed National Military Medical Center, Bethesda, MD, United States
^m Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
ⁿ Division of Genetics and Metabolism, Rare Disease Institute, Children’s National Health System, Washington, DC, United States
^o George Washington University, Washington, DC, United States
^p Rady Children’s Hospital, San Diego, CA, United States
^q Department of Pediatrics, Kaiser Oakland, Oakland, CA, United States
^r Department of Neurology, Le Bonheur Children’s Hospital, Memphis, TN, United States
^s Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, United States
^t Division of Neurology, Department of Pediatrics, Emory University, Atlanta, GA, United States
^u Division of Neurology, Children’s Hospital of Los Angeles, Los Angeles, CA, United States
^v Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^w Pediatric Associates of Austin, Austin, TX, United States
^x Clinical Neurology, Washington University Clinical Associates, St Louis, MO, United States
^y Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^z Department of Neurology, University of California, San Francisco School of Medicine, San Francisco, CA, United States
^aa Department of Neurology, Stanford University Medical Center, Stanford, CA, United States
^ab Pediatric Associates of Stockton, Stockton, CA, United States
^ac Division of Pediatric Neurology, Oregon Health & Science University School of Medicine, Portland, OR, United States
^ad Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa Health Care, Iowa City, IA, United States
^ae Institute of Metabolic Disease, Baylor Scott & White Research Institute, Dallas, TX, United States
^af Department of Child Neurology, VU University Medical Center, Amsterdam, Netherlands
^ag Department of Functional Genomics, Amsterdam Neuroscience, VU University, Amsterdam, Netherlands
^ah Department of Biostatistics, University of Pennsylvania, Philadelphia, PA, United States
^ai Illumina, San Diego, CA, United States

Abstract
Objective: Genome sequencing (GS) is promising for unsolved leukodystrophies, but its efficacy has not been prospectively studied. Methods: A prospective time-delayed crossover design trial of GS to assess the efficacy of GS as a first-line diagnostic tool for genetic white matter disorders took place between December 1, 2015 and September 27, 2017. Patients were randomized to receive GS immediately with concurrent standard of care (SoC) testing, or to receive SoC testing for 4 months followed by GS. Results: Thirty-four individuals were assessed at interim review. The genetic origin of 2 patient’s leukoencephalopathy was resolved before randomization. Nine patients were stratified to the immediate intervention group and 23 patients to the delayed-GS arm. The efficacy of GS was significant relative to SoC in the immediate (5/9 [56%] vs 0/9 [0%]; Wild–Seber, p < 0.005) and delayed (control) arms (14/23 [61%] vs 5/23 [22%]; Wild–Seber, p < 0.005). The time to diagnosis was significantly shorter in the immediate-GS group (log-rank test, p = 0.04). The overall diagnostic efficacy of combined GS and SoC approaches was 26 of 34 (76.5%, 95% confidence interval = 58.8–89.3%) in <4 months, greater than historical norms of <50% over 5 years. Owing to loss of clinical equipoise, the trial design was altered to a single-arm observational study. Interpretation: In this study, first-line GS provided earlier and greater diagnostic efficacy in white matter disorders. We provide an evidence-based diagnostic testing algorithm to enable appropriate clinical GS utilization in this population. ANN NEUROL 2020. © 2020 American Neurological Association

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Combinatorial PharmacogenomicTesting Improves Outcomes for Older Adults With Depression
(2020) American Journal of Geriatric Psychiatry, .

Forester, B.P.^a , Parikh, S.V.^b , Weisenbach, S.^c , Ajilore, O.^d , Vahia, I.^a , Rothschild, A.J.^e , Thase, M.E.^f , Dunlop, B.W.^g , DeBattista, C.^h , Conway, C.R.ⁱ , Shelton, R.C.^j , Macaluso, M.^k , Li, J.^l , Traxler, P.^l , Logan, J.^m , Brown, L.^l , Dechairo, B.^m , Greden, J.F.^b

^a Division of Geriatric Psychiatry (BPF, IV), McLean Hospital, Harvard Medical School, Belmont, MA, United States
^b University of Michigan Comprehensive Depression Center and Department of Psychiatry (SVP, JFG), National Network of Depression Centers, Ann Arbor, MI, United States
^c Stony Brook University, Department of Psychiatry & Behavioral Health (SW), Stony Brook, NY, United States
^d University of Illinois at Chicago, School of Public Health/Psychiatric Institute (OJ), Chicago, IL, United States
^e University of Massachusetts Medical School and UMass Memorial Healthcare (AJR), Worcester, MA, United States
^f Perelman School of Medicine of the University of Pennsylvania, the Corporal Michael Crescenz VAMC (MET), Philadelphia, PA, United States
^g Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences (BWD), Atlanta, GA, United States
^h Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences (CDB), Stanford, CA, United States
ⁱ Washington University School of Medicine, Department of Psychiatry, and the John Cochran Veteran’s Administration Hospital (CRC), St. Louis, MO, United States
^j The University of Alabama at Birmingham, Department of Psychiatry and School of Medicine (RCS), Birmingham, AL, United States
^k University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences (MM), Wichita, KS, United States
^l Assurex Health, Inc./Myriad Neuroscience (PT, LB), Mason, OH, United States
^m Myriad Genetics, Inc. (JL, BD), Salt Lake City, UT, United States

Abstract
Objective: Evaluate the clinical utility of combinatorial pharmacogenomic testing for informing medication selection among older adults who have experienced antidepressant medication failure for major depressive disorder (MDD). Design: Post hoc analysis of data from a blinded, randomized controlled trial comparing two active treatment arms. Setting: Psychiatry specialty and primary care clinics across 60 U.S. community and academic sites. Participants: Adults age 65 years or older at baseline (n = 206), diagnosed with MDD and inadequate response to at least one medication on the combinatorial pharmacogenomic test report during the current depressive episode. Intervention: Combinatorial pharmacogenomic testing to inform medication selection (guided-care), compared with treatment as usual (TAU). Outcomes: Mean percent symptom improvement, response rate, and remission rateat week 8, measured using the 17-item Hamilton Depression Rating Scale; medication switching; and comorbidity moderator analysis. Results: At week 8, symptom improvement was not significantly different for guided-care than for TAU (∆ = 8.1%, t = 1.64, df = 187; p = 0.102); however, guided-care showed significantly improved response (∆ = 13.6%, t = 2.16, df = 187; p = 0.032) and remission (∆ = 12.7%, t = 2.49, df = 189; p = 0.014) relative to TAU. By week 8, more than twice as many patients in guided-care than in TAU were on medications predicted to have no gene-drug interactions (χ2 = 19.3, df = 2; p &lt;0.001). Outcomes in the guided-care arm showed consistent improvement through the end of the open-design 24-week trial, indicating durability of the effect. Differences in outcomes between arms were not significantly impacted by comorbidities. Conclusions: Combinatorial pharmacogenomic test-informed medication selection improved outcomes over TAU among older adults with depression. © 2020 The Authors

Author Keywords
antidepressant;  clinical trial;  geriatric depression;  Late-life depression;  major depressive disorder;  medication selection;  pharmacogenomics

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

Focused ultrasound for safe and effective release of brain tumor biomarkers into the peripheral circulation
(2020) PloS One, 15 (6), p. e0234182.

Zhu, L.^a , Nazeri, A.^b , Pacia, C.P.^a , Yue, Y.^a , Chen, H.^a c

^a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The development of noninvasive approaches for brain tumor diagnosis and monitoring continues to be a major medical challenge. Although blood-based liquid biopsy has received considerable attention in various cancers, limited progress has been made for brain tumors, at least partly due to the hindrance of tumor biomarker release into the peripheral circulation by the blood-brain barrier. Focused ultrasound (FUS) combined with microbubbles induced BBB disruption has been established as a promising technique for noninvasive and localized brain drug delivery. Building on this established technique, we propose to develop FUS-enabled liquid biopsy technique (FUS-LBx) to enhance the release of brain tumor biomarkers (e.g., DNA, RNA, and proteins) into the circulation. The objective of this study was to demonstrate that FUS-LBx could sufficiently increase plasma levels of brain tumor biomarkers without causing hemorrhage in the brain. Mice with orthotopic implantation of enhanced green fluorescent protein (eGFP)-transfected murine glioma cells were treated using magnetic resonance (MR)-guided FUS system in the presence of systemically injected microbubbles at three peak negative pressure levels (0.59, 1.29, and 1.58 MPa). Plasma eGFP mRNA levels were quantified with the quantitative polymerase chain reaction (qPCR). Contrast-enhanced MR images were acquired before and after the FUS sonication. FUS at 0.59 MPa resulted in an increased plasma eGFP mRNA level, comparable to those at higher acoustic pressures (1.29 MPa and 1.58 MPa). Microhemorrhage density associated with FUS at 0.59 MPa was significantly lower than that at higher acoustic pressures and not significantly different from the control group. MRI analysis revealed that post-sonication intratumoral and peritumoral hyperenhancement had strong correlations with the level of FUS-induced biomarker release and the extent of hemorrhage. This study suggests that FUS-LBx could be a safe and effective brain-tumor biomarker release technique, and MRI could be used to develop image-guided FUS-LBx.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Client processing is altered by novel myopathy-causing mutations in the HSP40 J domain
(2020) PloS One, 15 (6), p. e0234207.

Pullen, M.Y.^a , Weihl, C.C.^b , True, H.L.^a

^a Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
The misfolding and aggregation of proteins is often implicated in the development and progression of degenerative diseases. Heat shock proteins (HSPs), such as the ubiquitously expressed Type II Hsp40 molecular chaperone, DNAJB6, assist in protein folding and disaggregation. Historically, mutations within the DNAJB6 G/F domain have been associated with Limb-Girdle Muscular Dystrophy type 1D, now referred to as LGMDD1, a dominantly inherited degenerative disease. Recently, novel mutations within the J domain of DNAJB6 have been reported in patients with LGMDD1. Since novel myopathy-causing mutations in the Hsp40 J domain have yet to be characterized and both the function of DNAJB6 in skeletal muscle and the clients of this chaperone are unknown, we set out to assess the effect of these mutations on chaperone function using the genetically tractable yeast system. The essential yeast Type II Hsp40, Sis1, is homologous to DNAJB6 and is involved in the propagation of yeast prions. Using phenotypic, biochemical, and functional assays we found that homologous mutations in the Sis1 J domain differentially alter the processing of specific yeast prion strains, as well as a non-prion substrate. These data suggest that the newly-identified mutations in the J domain of DNAJB6 cause aberrant chaperone function that leads to the pathogenesis in LGMDD1.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Adverse childhood experiences and psychotic-like experiences are associated above and beyond shared correlates: Findings from the adolescent brain cognitive development study
(2020) Schizophrenia Research, .

Karcher, N.R.^a , Niendam, T.A.^b , Barch, D.M.^a c

^a Washington University School of Medicine, Department of Psychiatry, United States
^b Department of Psychiatry and Behavioral Sciences, Imaging Research Center, United States
^c Washington University in St. Louis, Dept. of Psychological and Brain Sciences, United States

Abstract
Adverse childhood experiences (ACEs) are associated with increased risk for psychotic-like experiences (PLEs). However, ACEs and PLEs are also both associated with several shared factors (e.g., internalizing symptoms, suicidality). Few studies have explicitly examined whether the association between ACEs and PLEs remains over and above shared correlates. To address this question, using 10,800 9–11-year-olds, we examined whether ACEs and school-aged PLEs were associated when accounting for shared correlates, and whether there was evidence of mediation in associations between PLEs, ACEs, and these shared factors. Greater number of ACEs were associated with greater PLEs, including several specific ACEs (e.g., bullying). Importantly, ACEs and PLEs were related even when accounting for shared correlates. Further, PLEs partially mediated the relationships between ACEs and both internalizing symptoms and suicidality, including suicidal behavior. The current study helps clarify the nature of the associations between PLEs and ACE and has important clinical implications for addressing PLEs. © 2020 Elsevier B.V.

Author Keywords
Adverse childhood experiences;  Internalizing symptoms;  Psychotic-like experiences;  Suicidality;  Trauma

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Amyotrophic lateral sclerosis care and research in the United States during the COVID-19 pandemic: Challenges and opportunities
(2020) Muscle and Nerve, .

Andrews, J.A.^a , Berry, J.D.^b , Baloh, R.H.^c , Carberry, N.^a , Cudkowicz, M.E.^b , Dedi, B.^a , Glass, J.^d , Maragakis, N.J.^e , Miller, T.M.^f , Paganoni, S.^b , Rothstein, J.D.^e , Shefner, J.M.^g , Simmons, Z.^h , Weiss, M.D.ⁱ , Bedlack, R.S.^j

^a The Neurological Institute, Columbia University, New York, NY, United States
^b Healey Center for ALS, Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^c Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^d Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^e Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States
^f Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^g Barrow Neurological Institute, Phoenix, AZ, United States
^h Neurology, Penn State Health Milton S Hershey Medical Center, Hershey, PA, United States
ⁱ Department of Neurology, University of Washington, Seattle, WA, United States
^j Department of Neurology, Duke University, Durham, NC, United States

Abstract
Coronavirus disease 2019 has created unprecedented challenges for amyotrophic lateral sclerosis (ALS) clinical care and research in the United States. Traditional evaluations for making an ALS diagnosis, measuring progression, and planning interventions rely on in-person visits that may now be unsafe or impossible. Evidence- and experience-based treatment options, such as multidisciplinary team care, feeding tubes, wheelchairs, home health, and hospice, have become more difficult to obtain and in some places are unavailable. In addition, the pandemic has impacted ALS clinical trials by impairing the ability to obtain measurements for trial eligibility, to monitor safety and efficacy outcomes, and to dispense study drug, as these also often rely on in-person visits. We review opportunities for overcoming some of these challenges through telemedicine and novel measurements. These can reoptimize ALS care and research in the current setting and during future events that may limit travel and face-to-face interactions. © 2020 Wiley Periodicals, Inc.

Author Keywords
amyotrophic lateral sclerosis;  clinical care;  clinical trials;  COVID-19;  pandemic

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

Cisplatin-associated neuropathy characteristics compared with those associated with other neurotoxic chemotherapy agents (Alliance A151724)
(2020) Supportive Care in Cancer, .

Albany, C.^a , Dockter, T.^b , Wolfe, E.^b , Le-Rademacher, J.^b , Wagner-Johnston, N.^c , Einhorn, L.^a , Lafky, J.M.^b , Smith, E.^d , Pachman, D.^e , Staff, N.^e , Ma, C.^f , Loprinzi, C.L.^e , Costello, B.A.^e

^a Indiana University Simon Cancer Center, Indianapolis, IN, United States
^b Alliance Statistics and Data Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, United States
^c Johns Hopkins, Baltimore, MD, United States
^d University of Michigan, Ann Arbor, MI, United States
^e Mayo Clinic, Rochester, MN, United States
^f Washington University, St Louis, MO, United States

Abstract
Purpose: The current project was developed to obtain natural history information regarding cisplatin-induced peripheral neuropathy in males with testicular/germ cell cancers and to compare such neuropathy data with similarly obtained data in patients receiving other chemotherapy drugs in similarly conducted clinical trials. Methods: Patients without baseline neuropathy symptoms, who were initiating cisplatin-based chemotherapy, completed the EORTC CIPN 20 patient-reported instrument to evaluate chemotherapy-induced peripheral neuropathy (CIPN). Results were compared with EORTC CIPN 20 data obtained from independent study sets regarding patients receiving (1) paclitaxel, (2) combined paclitaxel and carboplatin, (3) oxaliplatin, or (4) a combination of doxorubicin and cyclophosphamide (AC). The last study set of patients on AC was selected to evaluate the use of EORTC CIPN 20 data in patients receiving chemotherapy not known to cause CIPN. Results: Cisplatin-induced neuropathy was more similar to neuropathy in patients receiving oxaliplatin than in those receiving paclitaxel. The cisplatin and oxaliplatin groups exhibited the coasting phenomenon and more prominent upper extremity symptoms than lower extremity symptoms during chemotherapy administration weeks. In contrast, paclitaxel-treated patients did not, on average, exhibit the coasting phenomenon; additionally, lower extremity symptoms were more prominent during the weeks when paclitaxel was administered. Cisplatin-induced neuropathy was less severe than was seen in patients in the other two groups, potentially because the cisplatin-receiving patients were younger. Patients receiving AC did not report substantial EORTC CIPN 20 changes. Conclusion: Understanding neuropathy similarities and differences with various chemotherapy agents may help elucidate CIPN processes and facilitate means to prevent and/or treat established CIPN. Trial registration: NCT02677727. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Chemotherapy-induced peripheral neuropathy;  CIPN;  Cisplatin;  Neuropathy

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Outdoor light at night and postmenopausal breast cancer risk in the NIH-AARP diet and health study
(2020) International Journal of Cancer, .

Xiao, Q.^a , James, P.^b , Breheny, P.^c , Jia, P.^d e , Park, Y.^f , Zhang, D.^g , Fisher, J.A.^h , Ward, M.H.^h , Jones, R.R.^h

^a Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston, Houston, TX, United States
^b Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, United States
^c Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, United States
^d Department of Land Surveying and Geo-Informatics, The Hong Kong Polytechnic University, Hong Kong
^e International Initiative on Spatial Lifecourse Epidemiology, Hong Kong
^f Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St Louis, St. Louis, MO, United States
^g Department of Health and Human physiology, College of Liberal Arts and Sciences, University of Iowa, Iowa City, IA, United States
^h Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD, United States

Abstract
Circadian disruption may play a role in breast carcinogenesis. Previous studies reported relationships between outdoor light at night (LAN) and the breast cancer risk, but their findings are mixed. There is also a need to examine LAN and breast cancer incidence according to different individual and environmental characteristics to identify subpopulations at greater risk associated with LAN exposure. We studied residential outdoor LAN estimated from satellite imagery at baseline (1996) in relation to postmenopausal breast cancer incidence over ~16 years of follow-up in 186 981 postmenopausal women including 12 318 incident postmenopausal breast cancer cases in the NIH-AARP Diet and Health Study. We used Cox proportional hazards models to estimate hazard ratios (HR) and two-sided 95% confidence intervals (CI) of the relationship between quintiles of LAN and postmenopausal breast cancer risk, overall and by hormone receptor status and cancer stage. We found that when compared to women in the lowest quintile of baseline LAN, those in the highest quintile had a 10% increase in postmenopausal breast cancer risk (HR (95% CI), 1.10 (1.02, 1.18), P-trend,.002). The association appeared to be stronger for estrogen receptor (ER) positive breast cancer (1.12 [1.02, 1.24],.007) than for ER-negative cancer (1.07 [0.85, 1.34],.66). Our findings also suggested that the relationship between LAN and breast cancer risk may differ by individual characteristics, such as smoking, alcohol drinking, sleep duration and BMI, and neighborhood environment. In conclusion, our study suggests that higher outdoor LAN exposure may be a risk factor for postmenopausal breast cancer. © 2020 UICC

Author Keywords
circadian disruption;  outdoor light at night;  postmenopausal breast cancer;  prospective cohort

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Detecting inflammatory responses in live animal models with near-infrared ROS probes
(2019) Optical Molecular Probes, Imaging and Drug Delivery – Proceedings Biophotonics Congress: Optics in the Life Sciences Congress 2019 (BODA, BRAIN, NTM, OMA, OMP), .

Zhou, H.^a , Akers, W.^b , Brody, S.^a , Wood, M.^a , Berezin, M.Y.^a

^a Washington University in St. Louis School of Medicine, 4115 McKinley Ave, St. Louis, MO 63110, United States
^b St. Jude Children’s Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105, United States

Abstract
Near-infrared contrast agents and optical methods are useful in detection of reactive oxygen species in vivo in the small animal models of acute lung injury, angiogenesis and peripheral neuropathies. © 2019 The Author(s).

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Long-term super-resolution imaging of amyloid structures using transient binding of thioflavin T
(2019) Optical Molecular Probes, Imaging and Drug Delivery – Proceedings Biophotonics Congress: Optics in the Life Sciences Congress 2019 (BODA, BRAIN, NTM, OMA, OMP), .

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

^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 MRC Prion Unit, UCL Institute of Prion Diseases, Gower Street, London, WC1E 6BT, United Kingdom

Abstract
Amyloids are implicated in Alzheimer’s disease but cannot be well resolved by standard light microscopy. We developed a tool to directly image native amyloid structures and dynamics at nanometer resolution over minutes to days. © 2019 The Author(s).

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Patterns of intrinsic neural and hemodynamic activity recover uniquely following stroke
(2019) Optics and the Brain – Proceedings Biophotonics Congress: Optics in the Life Sciences Congress 2019 (BODA, BRAIN, NTM, OMA, OMP), .

Kim, B.^a , Rosenthal, Z.^b , Culver, J.P.^a c d , Lee, J.-M.^a d e , Bauer, A.Q.^a d

^a Departments of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
^b Departments of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United States
^c Departments of Physics, Washington University School of Medicine, Saint Louis, MO 63110, United States
^d Departments of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO 63110, United States
^e Departments of Neurology Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Longitudinal functional imaging of intrinsic and stimulus-evoked neural and hemodynamic activity was performed in mice pre- A nd post-stroke. Hemodynamic connectivity is restored by 8 weeks while neural activity patterns are permanently affected. © 2019 The Authors.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Excitatory and inhibitory circuits differentially regulate local and distant cerebral hemodynamics
(2019) Optics and the Brain – Proceedings Biophotonics Congress: Optics in the Life Sciences Congress 2019 (BODA, BRAIN, NTM, OMA, OMP), .

Lee, J.^a , Bice, A.R.^a , Rosenthal, Z.P.^a b c , Lee, J.-M.^a b c , Bauer, A.Q.^a

^a Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
^b Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110, United States
^c Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
Optogenetic photostimulation of excitatory or inhibitory circuits differentially regulated local cerebral blood volume and flow in awake, transgenic mice. Each neural subclass also uniquely influenced distant cortical hemodynamic activity. © 2019 The Authors.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Anesthesia affects forepaw motor output and movement complexity during light-based motor mapping
(2019) Optics and the Brain – Proceedings Biophotonics Congress: Optics in the Life Sciences Congress 2019 (BODA, BRAIN, NTM, OMA, OMP), .

Voss, T.R.C.^a , Bice, A.R.^a , Lee, J.-M.^a b c , Bauer, A.Q.^a b

^a Department of Radiology, Washington University School of Medicine, Saint Louis, MO 63110, United States
^b Department of Biomedical Engineering, Washington University School of Medicine, Saint Louis, MO 63110, United States
^c Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
We used automated, light-based optogenetic mapping in Thy1-ChR2 mice to map forepaw motor movements under titrated levels of ketamine anesthesia. Anesthesia dose affected the amplitude, direction, and complexity of photostimulus-evoked movement types. © 2019 The Authors.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Long-term super-resolution imaging of amyloid structures using transient binding of Thioflavin T
(2019) Optics InfoBase Conference Papers, Part F163-OMP 2019, .

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

^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 MRC Prion Unit, UCL Institute of Prion Diseases, Gower Street, London, WC1E 6BT, United Kingdom

Abstract
Amyloids are implicated in Alzheimer’s disease but cannot be well resolved by standard light microscopy. We developed a tool to directly image native amyloid structures and dynamics at nanometer resolution over minutes to days. © 2019 The Author(s).

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus